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Wawro, Marta Ewelina, Katarzyna Sobierajska, Wojciech Michał Ciszewski, and Jolanta Niewiarowska. "Nonsteroidal Anti-Inflammatory Drugs Prevent Vincristine-Dependent Cancer-Associated Fibroblasts Formation." International Journal of Molecular Sciences 20, no. 8 (April 20, 2019): 1941. http://dx.doi.org/10.3390/ijms20081941.
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Vincristine is used in the clinical treatment of colon cancer, especially in patients diagnosed in the advanced phase of cancer development. Unfortunately, similar to other agents used during antitumor therapy, vincristine might induce chemoresistance. Studies of this process focus mainly on the analysis of the molecular mechanisms within cancer, usually ignoring the role of stromal cells. Our present findings confirm that vincristine stimulates the secretion of tumor growth factors class beta and interleukin-6 from cancer-associated fibroblasts as a result of paracrine stimulation by cancer cells. Based on alterations in morphology, modulation of capillary formation, and changes in endothelial and mesenchymal marker profile, our findings demonstrate that higher levels of tumor growth factor-βs and interleukin-6 enhance cancer-associated fibroblast-like cell formation through endothelial–mesenchymal transition and that nonsteroidal anti-inflammatory drug treatment (aspirin and ibuprofen) is able to inhibit this phenomenon. The process appears to be regulated by the rate of microtubule polymerization, depending on β-tubulin composition. While higher levels of tubulin-β2 and tubulin-β4 caused slowed polymerization and reduced the level of factors secreted to the extracellular matrix, tubulin-β3 induced the opposite effect. We conclude that nonsteroidal anti-inflammatory drugs should be considered for use during vincristine monotherapy in the treatment of patients diagnosed with colorectal cancer.
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Moha, Rico. "Chemotherapy medication of Vincristine and Vinblastine." Cancer Research and Cellular Therapeutics 1, no. 1 (December 8, 2017): 01–02. http://dx.doi.org/10.31579/2640-1053/007.
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Cancers treated with Vincristine and vinblastine include: acute leukemia, Hodgkin's and non- Hodgkin's lymphoma, neuroblastoma, rhabdomyosarcoma, Ewing's sarcoma, Wilms' tumor, multiple myeloma, chronic leukemias, thyroid cancer, brain tumors, non-small cell lung cancer, bladder cancer, melanoma, and testicular cancer andIt is also used to treat some blood disorders. It is given by injection into a vein. Vincristine and vinblastine exhibit differential activity against tumors and normal tissues. In this work, a number of cultured cell lines were assayed for their sensitivity to the antiproliferative and cytotoxic effects of the two drugs following short-term (4 hr) or during continuous exposures. Differential activity was not seen when cells were subjected to continuous exposures. The concentrations of Vincristine and vinblastine, respectively, that inhibited growth rates by 50% were: mouse leukemia L1210 cells, 4.4 and 4.0 nw; mouse lymphoma S49 cells, 5 and 3.5 nM; mouse neuroblastoma cells, 33 and 15 nw; HeLa cells, 1.4 and 2.6 nw; and human leukemia HL-60 cells, 4.1 and 5.3 nM. In contrast, differential toxicity was seen when cells were subjected to 4-hr exposures and transferred to drug-free medium: the 50% growth-inhibitory concentrations for Vincristine and vinblastine, respectively, for inhibition (a) of proliferation of L1210 cells were 100 and 380 nM and of HL-60 cells were 23 and 900 nM and (b) of colony formation of L1210 cells were 6 and >600 nM and of HeLa cells were 33 and 62 nM. Uptake and release of [3H]- vincristine and [3H]vinblastine were examined in L1210 cells under the conditions of growth experiments. Uptake of both drugs was dependent on the pH of culture media, and signifi cantly greater amounts of [3H]vinblastine than of [3H]vincristine were associated with cells after 4-hr exposures to equal concen trations of either drug. When cells were transferred to drug-free medium after 4-hr exposures, vinblastine was released much more rapidly from cells than was Vincristine, and by 0.5 hr after resuspension of cells, the amount of Vincristine associated with the cells was greater than the amount of vinblastine and remained so for up to at least 6 hr.
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Bowman, Laura C., Janet A. Houghton, and Peter J. Houghton. "Formation and stability of vincristine-tubulin complex in kidney cytosols." Biochemical Pharmacology 37, no. 7 (April 1988): 1251–57. http://dx.doi.org/10.1016/0006-2952(88)90778-2.
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Takahashi, Tsutomu, Yoshio Honma, Koshi Kawakami, and Junji Suzumiya. "Cotylenin Α, a Fusicoccane Diterpene Glycoside with a Complex Sugar Moiety, and Vincristine Synergistically Inhibit the Growth of Myeloma Cell in Vitro and in Vivo." Blood 124, no. 21 (December 6, 2014): 5721. http://dx.doi.org/10.1182/blood.v124.21.5721.5721.
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Abstract Introduction: Multiple myeloma is still incurable and optimize existing chemotherapeutic strategies and development of novel agents are necessary to improve the outcome of patients. Cotylenin A, a fusicoccane diterpene glycoside with a complex sugar moiety, was isolated as a plant-growth regulator. Cotylenin A modulates the 14-3-3 intracellular signaling pathway and has been shown to inhibit the growth of several cancer cells. Herein, we examined the antitumor effects of cotylenin A to develop a novel treatment against myeloma. Methods: Five human myeloma cell lines, RPMI8226, KMS-11, KMS-26, KMS-12 PE and KMS-12 BM were cultured with cotylenin A alone or in combination with several anticancer drugs. To measure the effects of various drugs on the growth of myeloma cells, the number of viable cells was determined by the MTT assay after 6 days of exposure to various concentrations of drugs with or without 2 μg/ml cotylenin A. The growth-inhibiting effects of the drugs were examined by determining the concentrations of drugs required to reduce the cell number to one-half of that in untreated cells (IC50). Xenografts in six-week-old female (Fox Chase SCID C.B-17/Icr-scid Jcl) mice were used to determine the in vivoefficacy of cotylenin A. Results: Cotylenin A alone inhibited the growth of myeloma cells in dose dependent manner, but the effect of growth inhibition was relatively weak. Cotylenin A and vincristine synergistically inhibited the growth and induced apoptosis in myeloma cells. While other microtubule-disturbing agents also showed co-operative effects with cotylenin A, other anticancer agents, such as doxorubicin, cisplatin, camptothecin, methotrexate, gemcitabine and 5-fluorouracil, did not show such co-operation with cotylenin A (Table 1). Cotylenin A had synergistic effects with vincristine and the results were confirmed by an isobologram analysis. These differences might be attributed to the effects on autophagic responses. Combined treatment with cotylenin A and vincristine induced autophagy (formation of LC3-II and degradation of p62 protein). However, doxorubicin did not enhance the autophagy induced by cotylenin A. The induction of apoptosis was confirmed by an analysis of the DNA histogram and the expression of annexin V. The expression of cleaved caspase-3 was increased in treatment with 2 ng/ml vincristine and enhanced by 2 μg/ml cotylenin A by western blot analysis. An invasion assay using transwell chamber revealed that low concentration cotylenin A (0.6 μg/ml) effectively inhibited the invasive activity of RPMI 8226 myeloma cells without inhibiting growth. A colony-forming assay indicated that 2 μg/ml cotylenin A preferentially inhibited the formation of large colonies, which have high self-renewal activity. The combined treatment with 3 μg/ml cotylenin A and 3 ng/ml vincristine more effectively suppressed the formation of large colonies than vincristine alone. Expression of pluripotency-associated transcription factor Sox2 mRNA in RPMI 8226 myeloma cells was significantly suppressed by treatment with 4 μg/ml cotylenin A. Combined treatment with 5 mg/kg cotylenin A and 0.5 mg/kg vincristine significantly inhibited the growth of KMS-26 myeloma cells as xenografts. In addition, mice with cotylenin A and vincristine showed the reduction of body weight loss comparing with those of mice by vincristine alone. This result supported that the combination of cotylenin A and vincristine might be safe. Conclusions: Cotylenin A and vincristine synergistically inhibited the growth of myeloma cells in vitro and in vivo, and the invasion of myeloma cells. Our results suggest that the combination of cotylenin A and vincristine may have therapeutic value for myeloma. Table 1. Potentiation of the growth-inhibitory activities of various anticancer agents in RPMI8226 myeloma cells by cotylenin A. Growth inhibition (IC50) Anticancer agent (ng/ml) - Cotylenin A + Cotylenin A Ratio(-/+) Doxorubicin 5.5 ± 0.6 5.3 ± 0.5 1.03 Cisplatin 246 ± 30.2 237 ± 28.4 1.03 Camptotecin 1.42 ± 0.16 1.38 ± 0.14 1.03 Methotrexate 2.76 ± 0.3 1.81 ± 0.2 1.52 Gemcitabine 4.3 ± 0.4 3.1 ± 0.3 1.39 5-Fluorouracil 56.5 ± 5.1 57.8 ± 6.3 0.98 Vincristine 6.3 ± 0.6 1.6 ± 0.1 3.94 Vinblastine 0.91 ± 0.11 0.42 ± 0.05 2.17 Paclitaxel 16.4 ± 1.9 7.7 ± 0.9 2.13 Ratio (-/+), IC50 without cotylenin A: IC50 with cotylenin A. The values are the mean ± SD of four determinations. Disclosures No relevant conflicts of interest to declare.
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Singh, Akannsha, Mariana Zapata, Yong Sung Choi, and Sun-Ok Yoon. "GSI promotes vincristine-induced apoptosis by enhancing multi-polar spindle formation." Cell Cycle 13, no. 1 (October 29, 2013): 157–66. http://dx.doi.org/10.4161/cc.26951.
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Diouf, Barthelemy, Kristine Crews, Glen Lew, Deqing Pei, Cheng Cheng, Ju Bao, Jie Zheng, et al. "Genome-Wide Association Analyses Identify Susceptibility Loci For Vincristine-Induced Peripheral Neuropathy In Children With Acute Lymphoblastic Leukemia." Blood 122, no. 21 (November 15, 2013): 618. http://dx.doi.org/10.1182/blood.v122.21.618.618.
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Abstract Introduction Vincristine, a vinca alkaloid, is one of the most widely used and effective medications for acute lymphoblastic leukemia (ALL). Vincristine exerts its cytotoxic effects by interfering with microtubule formation and mitotic spindle dynamics, leading to mitotic arrest and cell death. However its use often causes neuropathy characterized by abdominal pain, sensory and motor dysfunctions. To date, various candidate gene studies have failed to identify consistent genetic variants associated with an increased risk of vincristine-induced neuropathy. Methods Vincristine-induced neuropathy was assessed in children enrolled on SJCRH protocol study XIIIB for the treatment of newly diagnosed ALL and a subset of children with relapsed ALL enrolled on a Children’s Oncology Group protocol (COG AALL0433). Neuropathy was graded using CTCAE v1.0 (XIIIB) or a modified (“Balis”) pediatric scale (AALL0433). We performed a genome wide analysis of germline SNPs using the Affymetrix 500K or 6.0 array and imputed SNPs. Weighted logistic regression was used to test the association between genotypes and vincristine neuropathy in patients experiencing multiple episodes of grade 2-4 vincristine-induced neuropathy during their treatment. We also performed a meta-analysis that estimated p values across the two cohorts using Fisher’s method. Results Genome -wide SNP analysis and vincristine-induced neuropathy were assessed in 321 patients (222 on SJCRH protocol and 99 on COG protocol). The meta-analysis identified several loci that were significant in both patient cohorts in the same direction related to the risk of multiple episodes of neuropathy, with Rs924607 reaching genome-wide significance (p<10-8). After adjusting for genetically defined race and for vincristine dose, Rs924607 (localized in chromosome 5, near the CEP72 gene) remained significant (p = 4.68 x10-8). The cumulative incidence of developing multiple episodes of Vincristine-induced neuropathy differed among the three genotypes (p<0.0001) for this SNP, and this SNP was also associated with low expression of the CEP72 mRNA in the HapMap cells (CEU); the rs924607 risk allele (T) was associated with lower expression of CEP72 compared to the C allele. CEP72 regulates the localization of key centrosomal proteins and proper bipolar spindle formation, making it plausible that this SNP alters the pharmacologic effects of vincristine. We subsequently confirmed that this SNP was associated with lower expression of CEP72 in a luciferase reporter construct containing 2612 bp of the CEP72 promoter region, including the Rs924607 SNP (comparing constructs containing either the C allele or the T allele of Rs924607). The T allele of this SNP creates a DNA binding sequence for the NKX family of transcription repressors. Molecular dynamics and binding free energy calculations indicated that NKX-6.3 bound with a higher affinity (the binding free energy of NKX-6.3 bound to T allele is 7.67 kcal/mol lower than bound to C allele, which is equivalent to approximately 400000 fold decrease of kd) to the T allele than the C allele, consistent with our finding of lower expression of CEP72 in the presence of the T allele. When expressed in SHSY5Y or NALM6 cells, the construct containing the T allele had significantly lower expression than the construct containing the C allele, and knockdown of NKX-6.3 rescued the low expression of the construct with the T allele. When CEP72 was knocked down in human ALL cells, there was increased accumulation of the cells at G2M after vincristine treatment, consistent with augmented vincristine effects. Thus, these findings have revealed a new and plausible inherited SNP in the CEP72 promoter region that is linked to the risk of vincristine-induced neuropathy in children with ALL. Conclusions Our genome-wide analysis has revealed a novel genomic region that is associated with increased risk of vincristine-induced neuropathy, providing new insights into this treatment complication and a means to identify patients at highest risk. Disclosures: No relevant conflicts of interest to declare.
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Zhang, Jiandi, Mary C. Reedy, Yusuf A. Hannun, and Lina M. Obeid. "Inhibition of Caspases Inhibits the Release of Apoptotic Bodies: Bcl-2 Inhibits the Initiation of Formation of Apoptotic Bodies in Chemotherapeutic Agent-induced Apoptosis." Journal of Cell Biology 145, no. 1 (April 5, 1999): 99–108. http://dx.doi.org/10.1083/jcb.145.1.99.
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During apoptosis, the cell actively dismantles itself and reduces cell size by the formation and pinching off of portions of cytoplasm and nucleus as “apoptotic bodies.” We have combined our previously established quantitative assay relating the amount of release of [3H]-membrane lipid to the degree of apoptosis with electron microscopy (EM) at a series of timepoints to study apoptosis of lymphoid cells exposed to vincristine or etoposide. We find that the [3H]-membrane lipid release assay correlates well with EM studies showing the formation and release of apoptotic bodies and cell death, and both processes are regulated in parallel by inducers or inhibitors of apoptosis. Overexpression of Bcl-2 or inhibition of caspases by DEVD inhibited equally well the activation of caspases as indicated by PARP cleavage. They also inhibited [3H]-membrane lipid release and release of apoptotic bodies. EM showed that cells overexpressing Bcl-2 displayed near-normal morphology and viability in response to vincristine or etoposide. In contrast, DEVD did not prevent cell death. Although DEVD inhibited the chromatin condensation, PARP cleavage, release of apoptotic bodies, and release of labeled lipid, DEVD-treated cells showed accumulation of heterogeneous vesicles trapped in the condensed cytoplasm. These results suggest that inhibition of caspases arrested the maturation and release of apoptotic bodies. Our results also imply that Bcl-2 regulates processes in addition to caspase activation.
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Liedtke, Michaela, Clare Twist, Marcia Bieber, Neelima Bhat, Nelson N. H. Teng, and Steven Coutre. "A Phase I Study of a Novel Human Monoclonal Antibody (mAb216) with Chemotherapy for the Treatment of Patients with Relapsed or Refractory B-Lineage Acute Lymphoblastic Leukemia." Blood 110, no. 11 (November 16, 2007): 2831. http://dx.doi.org/10.1182/blood.v110.11.2831.2831.
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Abstract BACKGROUND: Despite improvements in front-line therapy for adult ALL, most patients eventually relapse and do not tolerate or respond to reinduction therapy. Novel targeted therapies are needed that have both activity against adult ALL and a toxicity profile distinct from conventional chemotherapy. MAb216 is a naturally occurring human IgM monoclonal antibody derived from the VH4-34 (variable heavy chain) gene. It has shown promise as a novel therapy for B-ALL in preclinical studies. In vitro, mAb216 specifically binds and is cytotoxic to normal human B-lymphocytes and B-progenitor lymphoblasts from patients with ALL. Binding of mAb216 to its linear lactosamine ligand leads to formation of large membrane pores resulting in cell lysis. This non-classical apoptosis occurs in the absence of complement fixation but the cytotoxicity is enhanced by complement. The membrane pores may also facilitate entry of chemotherapeutic drugs into the leukemic blast providing an explanation for the enhanced cell killing that is seen when mAb216 is combined with vincristine. METHODS: The primary aims of the study are to determine the maximum-tolerated dose, and dose-limiting toxicities of mAb216 as a single agent and in combination with vincristine in patients with relapsed or refractory B-ALL. Secondary aims are to characterize the pharmacokinetic behavior of mAb216 and to preliminarily assess clinical efficacy. Binding of mAb216 to the patient’s leukemic blasts is confirmed prior to enrollment. Two treatment courses of mAb216 are given with the same dose of antibody administered on days 0 and 7. In case of a suboptimal response (< 75% reduction in peripheral blood blasts) after the first dose of mAb216, the second dose is given in combination with vincristine. Five mAb216 dose levels are planned using a starting dose of 1.25 mg/kg and a standard 3+3 dose-escalation design. Clinical response is assessed by measuring the peripheral blood blast count weekly and by bone marrow biopsy if no blasts are present in the peripheral blood. RESULTS: Nine of 10 patients screened exhibited binding of mAb216 to their blasts and were enrolled in the study (median age 27; range 10–73). Four patients had relapsed after allogeneic bone marrow transplantation, four patients had relapsed after a median of four (range 2–5) prior therapies, and one patient had primary refractory disease. In these patients, doses up to 2.5 mg/kg of mAb216 have been well tolerated. At a dose of 1.25 mg/kg one patient experienced vomiting and grade 3 epistaxis three days after the infusion. At 2.5 mg/kg one patient developed hives during the infusion that resolved with diphenhydramine and hydrocortisone. MAb216 has not induced immune complex formation. The median half-life is 1.76 h (range 0.78–9.3 h) and strongly correlates with the binding affinity of mAb216 to the blasts. 7/9 patients experienced a reduction of their peripheral blast count between 8–61% after infusion of mAb216 alone. 7/9 patients received the second dose of mAb216 in combination with vincristine on day 7 or earlier. All seven patients, who had failed previous treatment with regimens containing vincristine, achieved a reduction of their peripheral blast count of 50–100%. One patient had a hypocellular bone marrow with no residual blasts on day 21. CONCLUSIONS: These results indicate that mAb216 alone and in combination with vincristine is a promising treatment for relapsed/refractory B-ALL. Patient recruitment and dose-escalation is ongoing.
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Shah, Mithun Vinod, Karen S. Flatten, B. Douglas Smith, Allan D. Hess, and Scott H. Kaufmann. "MTH1 Inhibitor-Induced Cytotoxicity in Acute Myeloid Leukemia." Blood 126, no. 23 (December 3, 2015): 1273. http://dx.doi.org/10.1182/blood.v126.23.1273.1273.
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Abstract BACKGROUND: Acute myeloid leukemia (AML) is an aggressive leukemia with 5-year overall survival of 20-25%. The major reason for treatment failure in AML is resistance to chemotherapy. Thus, there is an urgent need for identification of novel therapeutic agents for AML. Neoplastic cells, including AML, have dysfunctional redox regulation that results in increased reactive oxygen species (ROS). Accumulation of ROS leads to oxidation of free and incorporated nucleotides, leading to DNA damage and cell death. MTH1 is a nudix family hydrolase that sanitizes the oxidized nucleotide pool to prevent incorporation of these damaged bases in the DNA. MTH1 is thought to be non-essential for normal cells but crucial for neoplastic cells in order to avoid incorporation of oxidized dNTPs into DNA, thereby evading DNA damage and cell death. Whether MTH1 inhibitors have any activity against AML is not known. METHODS: Neoplastic myeloid cell lines HL-60, HEL, K562, KG1A, ML1, MV-4-11, SET2, and U937 were treated with varying concentrations of TH588 for a total of 48 hours. In experiments using the pan-caspase inhibitor Q-VD-OPh (Qvd), cells were pre-treated with 5µM Qvd for 1 hour followed by TH588. Cells were washed and stained with annexin, propidium iodide (PI), or MitoTracker (Life Technologies, Carlsbad, CA) for flow cytometry. To evaluate the potential impact of MTH1 inhibition on chemorefractory AML, HL-60/VCR cells were treated with vehicle control or TH588 in culture medium with or without vincristine (1µg/ml). Percentage apoptosis was calculated by normalizing to vehicle only control. With IRB approval, bone marrow aspirate samples were obtained from patients with untreated AML or healthy controls. Mononuclear cells were analyzed using colony-forming unit (CFU) assays. The total number of erythroid (CFU-E) and myeloid (CFU-G, CFU-GM) colonies containing ≥50 cells were read on day 14 and reported as percentage colonies compared to vehicle control. RESULTS: TH588 induced dose-dependent cell death in each of the neoplastic cell lines tested except HEL. In particular, treatment with TH588 resulted in a dose-dependent increase in the number of cells undergoing apoptosis as indicated by annexin V and/or PI staining (IC50 3.1-21.3µM, Figure 1). Pre-treatment with Qvd significantly inhibited TH588-induced cell death in all the cell lines studied except KG1A and SET2, suggesting a caspase-dependent mechanism of cell death. In further studies, cells treated with TH588 exhibited decreased MitoTracker staining; and Qvd pretreatment increased the number of MitoTrackerLow cells at the same time apoptotic cells decreased, suggesting that mitochondrial damage is upstream of caspase activation in TH588-induced apoptosis. Treatment with TH588 not only induced apoptosis in HL-60/VCR cells, but also facilitated further apoptosis in cells co-treated with vincristine and TH588 (Figure 2). Treatment with TH588 also diminished colony formation in a primary AML sample (IC50 6µM, Figure 3). Analysis of additional primary AML samples is ongoing. DISCUSSION: Our results show that the MTH1 inhibitor TH588 induces apoptosis in most neoplastic myeloid cells. MTH1 causes mitochondrial damage that, in turn, leads to caspase-dependent apoptosis in these cells. In HL-60/VCR cells representing chemorefractory phenotype, TH588 induces apoptosis as a single agent and resensitizes cells to vincristine. Moreover, TH588 significantly diminished colony formation in primary AML ex vivo. Further preclinical and possible clinical study of this class of agent appears warranted. Figure 1. Induction of cell death by MTH1 inhibitor TH588 in neoplastic myeloid cell lines. Figure 1. Induction of cell death by MTH1 inhibitor TH588 in neoplastic myeloid cell lines. Figure 2. TH588 induces apoptosis in HL-60/VCR cells and resensitizes cells to vincristine. Figure 2. TH588 induces apoptosis in HL-60/VCR cells and resensitizes cells to vincristine. Figure 3. TH588 significantly diminished colony formation in primary AML ex vivo indose-dependent manner. Figure 3. TH588 significantly diminished colony formation in primary AML ex vivo indose-dependent manner. Disclosures No relevant conflicts of interest to declare.
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Fine, R. L., S. Koizumi, G. A. Curt, and B. A. Chabner. "Effect of calcium channel blockers on human CFU-GM with cytotoxic drugs." Journal of Clinical Oncology 5, no. 3 (March 1987): 489–95. http://dx.doi.org/10.1200/jco.1987.5.3.489.
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Calcium channel blockers (CCBs) such as verapamil and nitrendipine are capable of increasing drug sensitivity in resistant murine and human tumor cells. This finding has potential value in the treatment of acquired drug resistance in human malignancies. Thus, we tested the ability of CCBs of two different structural classes to enhance the toxicity of doxorubicin (DOX), vinblastine (VBL), and vincristine (VCR) for normal myeloid and macrophage colony formation (marrow colony forming units-granulocyte-monocyte [CFU-GM]). Drug effects on colony formation from 35 normal volunteer marrows and from seven patient marrows in the recovery phase after cytotoxic chemotherapy were determined. No enhancement of toxicity was mediated by verapamil or nitrendipine when these drugs were co-incubated with the cytotoxic drugs for one hour or 24 hours before plating marrow cells in a semisolid agar system.
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Ghosh, Susmita, Fan Fan, Jason Roszik, Reid Powell, Yong Park, Clifford Stephan, Lee M. Ellis, and Rajat Bhattacharya. "Abstract 1056: Determining efficacy of combining the MEK inhibitor trametinib with vincristine identified by unbiased high throughput screening in RAS-mutated colorectal cancer cells." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1056. http://dx.doi.org/10.1158/1538-7445.am2022-1056.
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Abstract Background: Colorectal cancer (CRC) is a heterogeneous disease with various driver genetic mutations. Metastatic colorectal cancer (mCRC) is the second leading cause of cancer related deaths in the US. Greater than 50% of patients with mCRC harbor mutations in the oncogenic drivers KRAS or NRAS. While direct targeting of specific mutations in RAS is in the early stages of development in patients with mCRC, targeting most mutations in RAS is technically challenging. Hence, prior efforts have been focused on targeting MEK, a downstream mediator of RAS. Unfortunately, several MEK inhibitors that have entered clinical trials have failed to exhibit clinical efficacy as a monotherapy or in combination with select agents in patients with mCRC. Thus, identifying combination therapies with unbiased screening methods has the potential to improve the efficacy of MEK targeting in patients with mCRC. Aims: We aimed to perform unbiased high throughput screening (HTS) to identify drugs that, when combined with the MEK inhibitor trametinib, would enhance its efficacy. Methods: We performed unbiased HTS with KRAS mutated CRC cells grown in 3D using the MEK inhibitor trametinib as the base drug, and two different “clinically ready” compound libraries; 1) the NCI oncology set V, and, 2) a custom clinical compound set composed of drugs either approved by the FDA or in clinical trials. Using the Bliss model of synergy, vincristine was identified to be synergistic with trametinib. Effects of combining trametinib with vincristine were analyzed in vitro by 1) cell growth assays, and 2) measuring changes in cell signaling and apoptosis mediators by RPPA and western blotting. The efficacy of this combination was also examined in vivo using KRAS mutated patient derived xenografts (PDXs). Results: HTS studies demonstrated that combining trametinib with vincristine was synergistic in 3D CRC cell culture. This combination was further validated by MTT and colony formation assays. Analyses of markers for apoptosis by RPPA and western blotting demonstrated that the combination increases cell death in multiple CRC cell lines when compared to single agents. Furthermore, combining trametinib with vincristine led to significant inhibition in tumor growth when compared to the monotherapies using RAS-mutated PDXs in vivo. The combination was well tolerated by mice in vivo with minor decreases in body weight. Conclusions: Our unbiased HTS along with in vitro and in vivo validation studies demonstrated that combining trametinib with vincristine can enhance the efficacy of MEK targeted therapy in RAS mutated CRC cells. Furthermore, our in vivo studies were performed using drug doses that reflect clinically achievable doses in humans and thus serve as basis for future clinical studies to determine the efficacy of this drug combination in patients with RAS mutated mCRC. Citation Format: Susmita Ghosh, Fan Fan, Jason Roszik, Reid Powell, Yong Park, Clifford Stephan, Lee M. Ellis, Rajat Bhattacharya. Determining efficacy of combining the MEK inhibitor trametinib with vincristine identified by unbiased high throughput screening in RAS-mutated colorectal cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1056.
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O'Neill, MA, M. Mayer, KE Murray, HML Rolim-Santos, NS Santos-Magalhães, AM Thompson, and VCL Appleyard. "Does usnic acid affect microtubules in human cancer cells?" Brazilian Journal of Biology 70, no. 3 (April 2, 2010): 659–64. http://dx.doi.org/10.1590/s1519-69842010005000013.
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Usnic acid, a lichen metabolite, is known to exert antimitotic and antiproliferative activities against normal and malignant human cells. Many chemotherapy agents exert their activities by blocking cell cycle progression, inducing cell death through apoptosis. Microtubules, protein structure involved in the segregation of chromosomes during mitosis, serve as chemotherapeutical targets due to their key role in cellular division as well as apoptosis. The aim of this work was to investigate whether usnic acid affects the formation and/or stabilisation of microtubules by visualising microtubules and determining mitotic indices after treatment. The breast cancer cell line MCF7 and the lung cancer cell line H1299 were treated with usnic acid 29 µM for 24 hours and two positive controls: vincristine (which prevents the formation of microtubules) or taxol (which stabilizes microtubules). Treatment of MCF7 and H1299 cells with usnic acid did not result in any morphological changes in microtubules or increase in the mitotic index. These results suggest that the antineoplastic activity of usnic acid is not related to alterations in the formation and/or stabilisation of microtubules.
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Tonn, Jörg-Christian, Hans Kristian Haugland, Jaakko Saraste, Klaus Roosen, and Ole Didrik Laerum. "Differential effects of vincristine and phenytoin on the proliferation, migration, and invasion of human glioma cell lines." Journal of Neurosurgery 82, no. 6 (June 1995): 1035–43. http://dx.doi.org/10.3171/jns.1995.82.6.1035.
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✓ The aim of this study was to investigate the antimigratory and antiinvasive potential of vincristine sulfate (VCR) on human glioma cells and to analyze whether phenytoin (5,5-diphenylhydantoin; DPH) might act synergistically with VCR. Vincristine affects the cytoplasmic microtubules; DPH has been reported to enhance VCR cytotoxicity in murine cells. In two human glioma cell lines, GaMG and D-37MG, we found VCR to reduce monolayer growth and colony formation in a dose-dependent fashion at concentrations of 10 ng/ml and above. Phenytoin increased the cytotoxic and cystostatic effects of VCR in monolayer cells but not in spheroids. Multicellular spheroids were used to investigate directional migration. A coculture system of GaMG and D-37MG spheroids with fetal rat brain aggregates was used to analyze and quantify tumor cell invasion. A dose-dependent inhibition of migration and invasion by VCR was observed in both cell lines without further enhancement by DPH. Immunofluorescence microscopy with antibodies against α-tubulin revealed dose-dependent morphological alterations in the microtubules when the cells were exposed to VCR but not after incubation with DPH. Based on the combination of standardized in vitro model systems currently in use and the present data, the authors strongly suggest that VCR inhibits migration and invasion of human glioma cells. This is not altered by DPH, which inhibits cell proliferation in combination with VCR.
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Liu, Hui-wen, Chadwick B. Smith, Mark S. Schmidt, Xiaolu A. Cambronne, Michael S. Cohen, Marie E. Migaud, Charles Brenner, and Richard H. Goodman. "Pharmacological bypass of NAD+ salvage pathway protects neurons from chemotherapy-induced degeneration." Proceedings of the National Academy of Sciences 115, no. 42 (September 26, 2018): 10654–59. http://dx.doi.org/10.1073/pnas.1809392115.
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Axon degeneration, a hallmark of chemotherapy-induced peripheral neuropathy (CIPN), is thought to be caused by a loss of the essential metabolite nicotinamide adenine dinucleotide (NAD+) via the prodegenerative protein SARM1. Some studies challenge this notion, however, and suggest that an aberrant increase in a direct precursor of NAD+, nicotinamide mononucleotide (NMN), rather than loss of NAD+, is responsible. In support of this idea, blocking NMN accumulation in neurons by expressing a bacterial NMN deamidase protected axons from degeneration. We hypothesized that protection could similarly be achieved by reducing NMN production pharmacologically. To achieve this, we took advantage of an alternative pathway for NAD+ generation that goes through the intermediate nicotinic acid mononucleotide (NAMN), rather than NMN. We discovered that nicotinic acid riboside (NAR), a precursor of NAMN, administered in combination with FK866, an inhibitor of the enzyme nicotinamide phosphoribosyltransferase that produces NMN, protected dorsal root ganglion (DRG) axons against vincristine-induced degeneration as well as NMN deamidase. Introducing a different bacterial enzyme that converts NAMN to NMN reversed this protection. Collectively, our data indicate that maintaining NAD+ is not sufficient to protect DRG neurons from vincristine-induced axon degeneration, and elevating NMN, by itself, is not sufficient to cause degeneration. Nonetheless, the combination of FK866 and NAR, which bypasses NMN formation, may provide a therapeutic strategy for neuroprotection.
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Leven, RM, and MK Yee. "Megakaryocyte morphogenesis stimulated in vitro by whole and partially fractionated thrombocytopenic plasma: a model system for the study of platelet formation." Blood 69, no. 4 (April 1, 1987): 1046–52. http://dx.doi.org/10.1182/blood.v69.4.1046.1046.
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Abstract Isolated guinea pig megakaryocytes were cultured in the presence of plasma from normal or thrombocytopenic rabbits. Thrombocytopenic but not normal plasma stimulated formation of long cytoplasmic processes and cytoplasmic fragmentation. Activity was found in the 60% to 80% ammonium sulfate fraction of thrombocytopenic plasma but not in the 0% to 60% fraction. The 60% to 80% fraction of normal plasma contained a small amount of activity. Both colchicine and vincristine inhibited the morphogenesis stimulated by thrombocytopenic plasma. Cytochalasin B and D both mimicked the thrombocytopenic plasma-induced morphological change and affected more megakaryocytes than did the thrombocytopenic plasma. Cytochalasin and thrombocytopenic plasma together had a synergistic effect, causing many megakaryocytes to form processes and break into cytoplasmic fragments 3 to 6 microns in diameter. Immunofluorescence staining with antitubulin antiserum showed that cytoplasmic processes formed in the presence of thrombocytopenic plasma contain microtubules and that fragments released by the megakaryocytes contain microtubule rings. A model for the cytoskeletal basis of platelet formation is proposed.
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Leven, RM, and MK Yee. "Megakaryocyte morphogenesis stimulated in vitro by whole and partially fractionated thrombocytopenic plasma: a model system for the study of platelet formation." Blood 69, no. 4 (April 1, 1987): 1046–52. http://dx.doi.org/10.1182/blood.v69.4.1046.bloodjournal6941046.
Full textAbstract:
Isolated guinea pig megakaryocytes were cultured in the presence of plasma from normal or thrombocytopenic rabbits. Thrombocytopenic but not normal plasma stimulated formation of long cytoplasmic processes and cytoplasmic fragmentation. Activity was found in the 60% to 80% ammonium sulfate fraction of thrombocytopenic plasma but not in the 0% to 60% fraction. The 60% to 80% fraction of normal plasma contained a small amount of activity. Both colchicine and vincristine inhibited the morphogenesis stimulated by thrombocytopenic plasma. Cytochalasin B and D both mimicked the thrombocytopenic plasma-induced morphological change and affected more megakaryocytes than did the thrombocytopenic plasma. Cytochalasin and thrombocytopenic plasma together had a synergistic effect, causing many megakaryocytes to form processes and break into cytoplasmic fragments 3 to 6 microns in diameter. Immunofluorescence staining with antitubulin antiserum showed that cytoplasmic processes formed in the presence of thrombocytopenic plasma contain microtubules and that fragments released by the megakaryocytes contain microtubule rings. A model for the cytoskeletal basis of platelet formation is proposed.
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Willingham, M. C. "Apoptosis And Resistance To Anti-Microtubule Agents." Microscopy and Microanalysis 4, S2 (July 1998): 1036–37. http://dx.doi.org/10.1017/s1431927600025307.
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Several clinically important anti-cancer agents exert their effects on tumor cells through interference with the function of microtubules. In addition to the Vinca alkaloids, such as vinblastine and vincristine, the taxanes, such as paclitaxel (Trade Name: Taxol), kill tumor cells through a microtubular target. Treatment with taxol leads to the inability of microtubules to depolymerize, leading to the formation of large intracellular microtubular bundles. In tumor cells that progress through the cell cycle, this leads to the inability of these cells to disassembly interphase microtubule networks and a failure to form functional mitotic spindles. These cells arrest in M phase, from which they eventually progress, either by the induction of apoptotic cell death, or by micronucleation and the formation of tetraploid cells. There is also the possibility that taxol has other effects on the regulation of genes or other systems to enhance cell killing, perhaps through lowering the threshold of cells to the induction of apoptotic cell death.
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Bobrova, N. F., T. A. Sorochinskaya, S. A. Tronina, and A. Y. Bratishko. "New method of salvage retinoblastoma treatment." Modern technologies in ophtalmology, no. 1 (May 29, 2021): 215–20. http://dx.doi.org/10.25276/2312-4911-2021-1-215-220.
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Purpose. Elaboration of the new method of salvage retinoblastoma (RB) treatment, combining local and systemic chemotherapy. Material and methods. Salvage treatment using the new method was carried out in 71 children aged 2 months – 7 years on 102 eyes with RB in T1–T3 stages. At the Department of Pediatric Ophthalmopathology of SI «The Filatov Institute of Eye Diseases and Tissue Therapy of NAMS of Ukraine» the method of combined polychemotherapy (CPCT) was developed in 2010: primary IViC – injection of 0,01 µg (0,1 µg) Melphalan through pars plana; a course of CEV-protocol (drugs combination: Carboplatin + Etoposide Phosphate + Vincristine Sulfate) chemoreduction the next day after injection; monitoring the state of the tumor with repeated courses of SPHT every 3 weeks; addition of CPCT by focal destruction methods according to indications. In order to increase the ablasticity of IVi injections, we have developed the antireflux method of their implementation: to reduce IOP the diuretic injection is preliminarily performed in age-related dosage; puncture of the conjunctiva at the distance of 1–1,5 mm from the intended sclera puncture and its displacement above the IVi injection site; puncture of the sclera with obliquely perpendicular injection channel formation; IViC by cytostatic Melphalan in a volume of 0,1 ml in various dilutions depending on the indications; in repeated IViC – in different meridians; removing the needle with one-step tamponade of the injection site by cotton swab, antibiotic solution injecting under the conjunctiva with roller formation. Results. Ten-year experience of using the developed algorithm of salvage RB treatment by combined polychemotherapy, based on primary intravitreal melphalan chemotherapy (using the proposed antireflux injection method) with simultaneous systemic chemoreduction, proves its safety and effectivity – 77.5% regression of the tumors. Conclusion. Simultaneous action on the tumor of various cytostatics – one (melphalan) intraocular directly on the tumor and its vitreal clones, others – (carboplatin, etoposide, vincristine) – from the peripheral blood – creates the effect of «double blow» on RB cells. Key words: retinoblastoma, salvage treatment, combined polychemotherapy.
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Pui, C. H., C. M. Chesney, J. Weed, and C. W. Jackson. "Altered von Willebrand factor molecule in children with thrombosis following asparaginase-prednisone-vincristine therapy for leukemia." Journal of Clinical Oncology 3, no. 9 (September 1985): 1266–72. http://dx.doi.org/10.1200/jco.1985.3.9.1266.
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Eleven consecutive leukemia patients with thrombosis induced by asparaginase-prednisone-vincristine therapy were studied to gain insight into the pathogenesis of this complication. Measurement of anti-thrombin III, plasminogen, factor V, and fibrin degradation products as well as platelet aggregation sensitivity to adenosine diphosphate disclosed no consistent abnormalities that would explain pathologic thrombus formation. A decrease in platelet counts observed in nine of 11 patients, prompted us to investigate the possible involvement of factor VIII in this disorder. Levels of factor VIII procoagulant activity, von Willebrand factor (vWF) and ristocetin cofactor were similar to findings for an identically treated comparison group who remained free of thrombotic complications. However, qualitative examination of vWF by crossed immunoelectrophoresis (CIE) revealed a distinct right shift of the immunoprecipitin lines in each of three thrombotic patients tested, whereas a normal profile was found in three similarly treated patients without the complication. This altered pattern had reverted to normal when CIE was repeated 2 to 7 months later. We postulate that the abnormal vWF is related to the development of thrombosis.
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Qu, Yang, Michael L. A. E. Easson, Jordan Froese, Razvan Simionescu, Tomas Hudlicky, and Vincenzo De Luca. "Completion of the seven-step pathway from tabersonine to the anticancer drug precursor vindoline and its assembly in yeast." Proceedings of the National Academy of Sciences 112, no. 19 (April 27, 2015): 6224–29. http://dx.doi.org/10.1073/pnas.1501821112.
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Antitumor substances related to vinblastine and vincristine are exclusively found in the Catharanthus roseus (Madagascar periwinkle), a member of the Apocynaceae plant family, and continue to be extensively used in cancer chemotherapy. Although in high demand, these valuable compounds only accumulate in trace amounts in C. roseus leaves. Vinblastine and vincristine are condensed from the monoterpenoid indole alkaloid (MIA) precursors catharanthine and vindoline. Although catharanthine biosynthesis remains poorly characterized, the biosynthesis of vindoline from the MIA precursor tabersonine is well understood at the molecular and biochemical levels. This study uses virus-induced gene silencing (VIGS) to identify a cytochrome P450 [CYP71D1V2; tabersonine 3-oxygenase (T3O)] and an alcohol dehydrogenase [ADHL1; tabersonine 3-reductase (T3R)] as candidate genes involved in the conversion of tabersonine or 16-methoxytabersonine to 3-hydroxy-2,3-dihydrotabersonine or 3-hydroxy-16-methoxy-2,3-dihydrotabersonine, which are intermediates in the vindorosine and vindoline pathways, respectively. Biochemical assays with recombinant enzymes confirm that product formation is only possible by the coupled action of T3O and T3R, as the reaction product of T3O is an epoxide that is not used as a substrate by T3R. The T3O and T3R transcripts were identified in a C. roseus database representing genes preferentially expressed in leaf epidermis and suggest that the subsequent reaction products are transported from the leaf epidermis to specialized leaf mesophyll idioblast and laticifer cells to complete the biosynthesis of these MIAs. With these two genes, the complete seven-gene pathway was engineered in yeast to produce vindoline from tabersonine.
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Taya, Yuji, Astushi Sato, Kaori Sato, and Takaaki Aoba. "Morphological changes in rat incisor ameloblasts after a single injection of vincristine. Sub-ameloblastic cyst formation at the late-maturation stage." Japanese Journal of Oral Biology 37, no. 1 (1995): 50–57. http://dx.doi.org/10.2330/joralbiosci1965.37.50.
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GAO, Lei, Li CHEN, Xin-hong FEI, Hui-ying QIU, Hong ZHOU, and Jian-min WANG. "STI571 combined with vincristine greatly suppressed the tumor formation of multidrug-resistant K562 cells in a human-nude mice xenograft model." Chinese Medical Journal 119, no. 11 (June 2006): 911–18. http://dx.doi.org/10.1097/00029330-200606010-00006.
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Sedeeq, Mohammed, Ahmed Maklad, Nuri Gueven, and Iman Azimi. "Development of a High-throughput Agar Colony Formation Assay to Identify Drug Candidates against Medulloblastoma." Pharmaceuticals 13, no. 11 (November 5, 2020): 368. http://dx.doi.org/10.3390/ph13110368.
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Medulloblastoma (MB) is the most common malignant childhood brain cancer. High-risk MB tumours have a high incidence of metastasis and result in poor patient survival. Drug screens, commonly used to identify potential novel therapeutic agents against MB, focus on 2D cell proliferation and viability assays given that these assays are easily adaptable to high-throughput regimes. However, 2D models fail to address invasive characteristics that are crucial to MB metastasis and are thus not representative of tumour growth in vivo. In this study, we developed a 3D 384-well agar colony formation assay using MB cells of molecular subgroup 3 that is associated with the highest level of metastasis. Two fluorescence substrates, resazurin and glycyl-phenylalanyl-aminofluorocoumarin (GF-AFC) that measure cell viability via distinct mechanisms were used to assess the growth of MB cells in the agar matrix. The assay was optimised for seeding density, growth period, substrate incubation time and homogeneity of the fluorescent signals within individual wells. Our data demonstrate the feasibility to multiplex the two fluorescent substrates without detectable signal interference. This assay was validated by assessing the concentration-dependent effect of two commonly used chemotherapeutic agents clinically used for MB treatment, vincristine and lomustine. Subsequently, a panel of plasma membrane calcium channel modulators was screened for their effect on the 3D growth of D341 MB cells, which identified modulators of T-type voltage gated and ORAI calcium channels as selective growth modulators. Overall, this 3D assay provides a reproducible, time and cost-effective assay for high-throughput screening to identify potential drugs against MB.
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Moreira, Thaís de Almeida, Talita Cristina Modesto, Ana Carla da Silva Corrêa, Luciano Francisco de Maria, Rafael Rocha de Souza, and Marcio de Barros Bandarra. "Subcutaneous transmissible venereal tumor – case report." Clínica Veterinária XXI, no. 122 (May 1, 2016): 46–54. http://dx.doi.org/10.46958/rcv.2016.xxi.n.122.p.46-54.
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Transmissible venereal tumor (TVT) is a specific cancer of the canine species that usually affects the genital region. Metastases occur by hematogenous or lymphatic routes. The extragenital form is rare and the cutaneous form is reported to be a warty proliferative lesion of ulcerated and friable surface, which usually presents itself concomitantly to the genital form of the disease. We hereby report a case of subcutaneous TVT in a mixed-breed neutered female, in order to contribute clinical and cytopathological data, as well as prognosis, due to unusual presentation of this neoplasm. The formation was disseminated as multiple nodule located on the inner face of the hind limbs. Diagnosis was achieved by cytological examination, which revealed the presence of round cells with predominantly eccentric nuclei, loose chromatin and large and intensely vacuolated cytoplasm, features of plasmacytoid TVT. Four courses of chemotherapy with vincristine sulfate were conducted, yielding complete remission of the tumor. The subcutaneous appearance of TVT is unusual, especially when no genital lesions that might suggest metastasis are found.
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Benning, V. M., M. B. Maratrat, E. C. Fournier, C. P. Melcion, and A. C. Cordier. "Flow cytometric detection of erythropoietic cytotoxicity in mouse bone marrow." Journal of Histochemistry & Cytochemistry 39, no. 1 (January 1991): 15–21. http://dx.doi.org/10.1177/39.1.1701186.
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Erythroblast proliferation and maturation in bone marrow are the processes leading to the formation of polychromatic erythrocytes (PE) and normochromatic erythrocytes (NE), respectively. PE contain RNA but no DNA, and can therefore be distinguished both from NE (which lack both RNA and DNA) and from nucleated cells (which contain both DNA and RNA). Cytotoxic agents that induce impairment of the maturation process change the PE:NE ratio. We have developed a simple and rapid method of determining the PE:NE ratio, based on flow cytometric analysis of formaldehyde-fixed, acridine orange (AO)-stained cells. The effects of cyclophosphamide (CP), mitomycin C (MMC), and vincristine (VC) were tested and the PE:NE ratio was evaluated over 7 days of treatment. In this study we monitored the kinetics of these compounds and were able to demonstrate both a time- and a dose-dependent effect. We detected a difference between the effects of the alkylating agents tested and those induced by the spindle inhibitor tested. Flow cytometry of fixed bone marrow samples stained with AO provides more information, better and more rapid statistical analysis, than conventional microscopic methods for counting the PE:NE ratio.
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Zhang, Yu, Masuo Goto, Akifumi Oda, Pei-Ling Hsu, Ling-Li Guo, Yan-Hui Fu, Susan Morris-Natschke, Ernest Hamel, Kuo-Hsiung Lee, and Xiao-Jiang Hao. "Antiproliferative Aspidosperma-Type Monoterpenoid Indole Alkaloids from Bousigonia mekongensis Inhibit Tubulin Polymerization." Molecules 24, no. 7 (March 31, 2019): 1256. http://dx.doi.org/10.3390/molecules24071256.
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Monoterpenoid indole alkaloids are structurally diverse natural products found in plants of the family Apocynaceae. Among them, vincristine and its derivatives are well known for their anticancer activity. Bousigonia mekongensis, a species in this family, contains various monoterpenoid indole alkaloids. In the current study, fourteen known aspidosperma-type monoterpenoid indole alkaloids (1–14) were isolated and identified from a methanol extract of the twigs and leaves of B. mekongensis for the first time. Among them, compounds 3, 6, 9, and 13 exhibited similar antiproliferative activity spectra against A549, KB, and multidrug-resistant (MDR) KB subline KB-VIN cells with IC50 values ranging from 0.5–0.9 μM. The above alkaloids efficiently induced cell cycle arrest at the G2/M phase by inhibiting tubulin polymerization as well as mitotic bipolar spindle formation. Computer modeling studies indicated that compound 7 likely forms a hydrogen bond (H-bond) with α- or β-tubulin at the colchicine site. Evaluation of the antiproliferative effects and SAR analysis suggested that a 14,15-double bond or 3α-acetonyl group is critical for enhanced antiproliferative activity. Mechanism of action studies demonstrated for the first time that compounds 3, 4, 6, 7, and 13 efficiently induce cell cycle arrest at G2/M by inhibiting tubulin polymerization by binding to the colchicine site.
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Sayani, Farzana A., and Charles S. Abrams. "How I treat refractory thrombotic thrombocytopenic purpura." Blood 125, no. 25 (June 18, 2015): 3860–67. http://dx.doi.org/10.1182/blood-2014-11-551580.
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Abstract Acquired thrombotic thrombocytopenic purpura (TTP) is characterized by thrombocytopenia and microangiopathic hemolytic anemia (MAHA) without an obvious cause, and may include fever, mild renal failure, and neurologic deficits. It is characterized by a deficiency of the von Willebrand factor (VWF) cleaving enzyme, ADAMTS13 (a disintegrin and metalloproteinase, with a thrombospondin type 1 motif, member 13), resulting in formation of microthrombi in the high sheer environment of the microvasculature. This causes microvascular occlusion, MAHA, and organ ischemia. Diagnosis is based on the presence of clinical symptoms, laboratory aberrations consistent with MAHA, decreased ADAMTS13 activity, and possibly presence of anti-ADAMTS13 autoantibodies. Upfront treatment of acute TTP includes plasma exchange and corticosteroids. A significant number of patients are refractory to this treatment and will require further interventions. There are limited data and consensus on the management of the refractory TTP patient. Management involves simultaneously ruling out other causes of thrombocytopenia and MAHA, while also considering other treatments. In this article, we describe our management of the patient with refractory TTP, and discuss use of rituximab, increased plasma exchange, splenectomy, and immunosuppressive options, including cyclophosphamide, vincristine, and cyclosporine. We also review recent evidence for the potential roles of bortezomib and N-acetylcysteine, and explore new therapeutic approaches, including recombinant ADAMTS13 and anti-VWF therapy.
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Ariad, Samuel, Daniel Benharroch, Lilliana Lupu, Batya Davidovici, Nicolas Dupin, and Chris Boshoff. "Early Peripheral Lymph Node Involvement of Human Herpesvirus 8–Associated, Body Cavity–Based Lymphoma in a Human Immunodeficiency Virus–Negative Patient." Archives of Pathology & Laboratory Medicine 124, no. 5 (May 1, 2000): 753–55. http://dx.doi.org/10.5858/2000-124-0753-eplnio.
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Abstract Human herpesvirus 8 (HHV-8), or Kaposi sarcoma–associated herpesvirus , is a gamma herpesvirus first detected in a specimen of Kaposi sarcoma from a human immunodeficiency virus (HIV)–positive patient. Human herpesvirus 8 is also found in an unusual clinicopathologic form of body cavity–based B-cell lymphoma, which has been named primary effusion lymphoma (PEL) and occurs primarily in HIV-positive patients. PEL is characterized by the formation of lymphomatous effusions, without obvious lymphadenopathy, tumor masses, or bone marrow involvement. Only a few cases of PEL in HIV-seronegative patients have been reported. We describe a case of an HHV-8–associated lymphoma, with ascites, pleural effusion, and axillary lymphadenopathy in an HIV-negative patient. The patient was a 68-year-old Jewish man of North African extraction, with a previous history of coronary bypass surgery and multiple blood transfusions. The pleural fluid contained large atypical lymphoid cells and was suggestive of lymphoma but could not provide a conclusive diagnosis of PEL. The lymph node contained groups of large anaplastic lymphoid cells. Polymerase chain reaction for HHV-8 performed on the lymph node specimen was positive, establishing the diagnosis of PEL. Polymerase chain reaction for Epstein-Barr virus was negative. Results of a gallium scan were normal. The patient did not respond to combination chemotherapy with cyclophosphamide, doxorubicin, vincristine sulfate, and prednisone and progressively developed, massive intra-abdominal solid tumor formation. To our knowledge, this is the first report of a case of PEL that demonstrates peripheral lymph node involvement at diagnosis and the first report of PEL in an Israeli patient.
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Wollina, Uwe, Gesina Hansel, Dana Langner, André Koch, Jacqueline Schönlebe, and Georgi Tchernev. "Rapid Evolving Unilateral Indurated Oozing Facial Plaques in a Patient with Head-and-Neck Cancer: Peripheral T-Cell Lymphoma Not Otherwise Specified (NOS)." Open Access Macedonian Journal of Medical Sciences 5, no. 4 (July 20, 2017): 476–79. http://dx.doi.org/10.3889/oamjms.2017.085.
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BACKGROUND: The sudden development of facial plaques and nodules may be an alarming clinical sign for underlying malignancies. Nevertheless, a broad range of inflammatory and infectious diseases must be considered as well in the differential diagnosis.CASE REPORT: We report on a 53-year-old male patient with a left-sided cheek infiltration with oozing but no lymphadenopathy. He had a medical history of head-and-neck cancer. The primary differential diagnosis was herpes zoster with secondary impetiginization or pyoderma facial. About eight weeks later, the patient presented with progressive formation of nodules and plaques on the face and isotretinoin was stopped. Skin biopsy suggested mycosis fungoid and an oral treatment with bexarotene was started. After limited response for another eight weeks, he returned later with massive facial swelling, nodules and impetiginization. Another skin biopsy was performed to exclude diagnostic error or investigate possible disease progression. Microscopic evaluation and multiplex-polymerase chain reaction confirmed the diagnosis of peripheral T-cell lymphoma, not otherwise specified (PTL-NOS), stage Ia (T1 N0 M0). Imaging techniques excluded metastatic spread. By interdisciplinary tumour board, R-CHOP (rituximab, cyclophosphamide, hydroxyl-doxorubicin, vincristine, and prednisolone) was recommended and initiated by hemato-oncologists.CONCLUSIONS: PLT-NOS confirmed in the present patient has a poor prognosis with a 5-year survival rate of less than 20%.
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Kaneko, Rena, Hiroyuki Mitomi, Natsuko Nakazaki, Yuichiro Yano, Masazumi Ogawa, and Yuzuru Sato. "Primary Hepatic Lymphoma Complicated by a Hepatic Inflammatory Pseudotumor and Tumor-Forming Pancreatitis." Journal of Gastrointestinal and Liver Diseases 26, no. 3 (September 1, 2017): 299–304. http://dx.doi.org/10.15403/jgld.2014.1121.263.eko.
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Background: Hepatic inflammatory pseudotumor (IPT) is considered to be benign in biological behavior, and its malignant transformation is extremely rare. There has only been one published case of primary hepatic lymphoma complicated by hepatic IPT.Case presentation: A 73-year-old man presented with obstructive jaundice and a pancreatic head mass. Histology of the mass revealed chronic pancreatitis with lymphoid follicle formation, leading to a diagnosis of a suspicion of follicular pancreatitis. After a choledochojejunostomy, a hepatic tumor was detected, and a biopsy revealed lymphoplasmacytic infiltration. Immunohistochemistry confirmed the polyclonal nature of lymphoplasma cells, indicative of an IPT. The hepatic tumor disappeared during follow-up, but the patient exhibited a high fever related to tumor recurrence. A biopsy revealed the co-existence of a diffuse large B-cell lymphoma and an IPT. IgG4-related disease was excluded because storiform fibrosis, obliterative phlebitis, and a significant increase in IgG4-immunoreactive cells were absent in all investigated tissues. The tumor completely disappeared after chemotherapy.Conclusion: Careful observation is necessary in this kind of situation because the presence of a hepatic IPT may represent an increased risk of malignant transformation.Abbreviations: IPT: inflammatory pseudotumor; DLBCL: diffuse large B-cell lymphoma; CT: computed tomography; LDH: lactate dehydrogenase; sIL-2R: soluble interleukin-2 receptor; EBER: Epstein-Barr virus-encoded small RNA; R-CHOP: rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone
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Ignjatovic, Mile, Mihailo Bezmarevic, and Snezana Cerovic. "Solitary extramedullary plasmacytoma of the duodenum and pancreas: A case report and review of the literature." Vojnosanitetski pregled 73, no. 4 (2016): 402–7. http://dx.doi.org/10.2298/vsp141031142i.
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Introduction. The extramedullary plasmacytomas (EMPs) are rare tumors of plasma cell disorders which are rarely found in the duodenum. We presented a case of solitary EMPs involving the duodenum and pancreas successfully treated by surgical resection after failure of chemotherapy. Case report. A 55-year-old female with previously diagnosed solitary EMP of the duodenum was admitted to our institution after failure of three cycles of vincristine, adriablastine, dexamethasone (VAD) chemotherapy regimen with an upper gastrointestinal obstruction. On admission computed tomography of the abdomen showed tumor in the region of the second part of duodenum and uncinate process of the pancreas with a complete duodenal obstruction. Intraoperatively a tumor formation was in the region of the second duodenal part, originated from the wall of duodenum with the total diameter of 7 x 5 cm, covering the entire circumference of duodenal wall leaded to a narrowing of duodenal lumen to the thigh gap with an upper gastrointestinal obstruction. Infiltration in the head of the pancreas and uncinate process were also found. The Whipple?s procedure was performed but postoperative course was complicated by rapidly refilling chylous ascites which was resolved 4 days after the surgery. Conclusion. Each patient with gastrointestinal EMPs should be considered separately and in timely manner, thus adequate treatment could provide local disease control.
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Dai, Guang Zhi, Wen Bo Han, Ya Ning Mei, Kuang Xu, Rui Hua Jiao, Hui Ming Ge, and Ren Xiang Tan. "Pyridoxal-5′-phosphate–dependent bifunctional enzyme catalyzed biosynthesis of indolizidine alkaloids in fungi." Proceedings of the National Academy of Sciences 117, no. 2 (December 27, 2019): 1174–80. http://dx.doi.org/10.1073/pnas.1914777117.
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Indolizidine alkaloids such as anticancer drugs vinblastine and vincristine are exceptionally attractive due to their widespread occurrence, prominent bioactivity, complex structure, and sophisticated involvement in the chemical defense for the producing organisms. However, the versatility of the indolizidine alkaloid biosynthesis remains incompletely addressed since the knowledge about such biosynthetic machineries is only limited to several representatives. Herein, we describe the biosynthetic gene cluster (BGC) for the biosynthesis of curvulamine, a skeletally unprecedented antibacterial indolizidine alkaloid from Curvularia sp. IFB-Z10. The molecular architecture of curvulamine results from the functional collaboration of a highly reducing polyketide synthase (CuaA), a pyridoxal-5′-phosphate (PLP)-dependent aminotransferase (CuaB), an NADPH-dependent dehydrogenase (CuaC), and a FAD-dependent monooxygenase (CuaD), with its transportation and abundance regulated by a major facilitator superfamily permease (CuaE) and a Zn(II)Cys6 transcription factor (CuaF), respectively. In contrast to expectations, CuaB is bifunctional and capable of catalyzing the Claisen condensation to form a new C–C bond and the α-hydroxylation of the alanine moiety in exposure to dioxygen. Inspired and guided by the distinct function of CuaB, our genome mining effort discovers bipolamines A−I (bipolamine G is more antibacterial than curvulamine), which represent a collection of previously undescribed polyketide alkaloids from a silent BGC in Bipolaris maydis ATCC48331. The work provides insight into nature’s arsenal for the indolizidine-coined skeletal formation and adds evidence in support of the functional versatility of PLP-dependent enzymes in fungi.
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ZHANG, Jiandi, Timothy A. DRISCOLL, Yusuf A. HANNUN, and Lina M. OBEID. "Regulation of membrane release in apoptosis." Biochemical Journal 334, no. 2 (September 1, 1998): 479–85. http://dx.doi.org/10.1042/bj3340479.
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Apoptosis is a fundamental process of cell regulation whereby cells execute one or more biochemical programs leading to cell death. Several mechanisms have been evaluated and suggested to play roles in the regulation of apoptosis, including the activation of phospholipase A2 (PLA2), usually measured as release of 3H-labelled arachidonic acid (AA) from prelabelled cells. The current study was aimed at examining the role of PLA2 in regulating apoptosis in response to several inducers (such as vincristine and etoposide) in lymphoid cell lines. Cells were labelled with [3H]fatty acids and the released radioactivity was characterized. These studies indicated that the AA release assay did not reflect release of non-esterified fatty acid via activation of the PLA2 pathway. Rather, studies using TLC and electron microscopy showed that AA release reflected a previously unsuspected shedding of a heterogeneous population of membrane vesicles and fragments, probably as components of apoptotic bodies. Further studies demonstrated that this process is an integral part of apoptosis. Overexpression of Bcl-2 or the addition of caspase peptide inhibitor benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethane prevented the characteristic morphological changes of cell death, and completely inhibited the release of membrane vesicles and fragments. On the other hand, release of membrane vesicles and fragments was caused by various inducers of apoptosis, as measured by release of either 3H-labelled AA or palmitic acid. Thus the present study demonstrates that the release of membrane lipids during apoptosis defines a new assay for apoptosis and has allowed the investigation of the mechanisms regulating formation of apoptotic bodies.
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Rys, Ryan N., Maanasa Venkataraman, Jibin Zeng, Koren Kathleen Mann, and Nathalie Johnson. "Fas Mutations in Non-Hodgkin's Lymphoma (NHL): Implications for Disease Progression and Therapeutic Resistance." Blood 134, Supplement_1 (November 13, 2019): 1520. http://dx.doi.org/10.1182/blood-2019-130602.
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Introduction: Diffuse large B cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma and standard frontline treatment is carried out with R-CHOP chemotherapy. However, DLBCL remains an extremely heterogenous disease and refractory/relapse events are common. Recent sequencing experiments have found 18% of relapsed DLBCL contains Fas mutations, an increase from mutations seen at initial diagnosis. Fas receptor (FasR) is a transmembrane protein encoded by the Fas gene that is critical for the induction of extrinsic apoptosis. Once FasR is bound by Fas Ligand expressed on cytotoxic T cells, it initiates the formation of the death-inducing signaling complex and subsequent programmed cell death. Downregulation of FasR expression on B cells has also been a proposed method by which B cell lymphomas are able to evade immune surveillance. Therefore, we hypothesized that dysfunction in Fas signaling contributes to chemotherapy resistance and disease relapse in DLBCL. We used an immune-competent mouse model that can generate aggressive B cell lymphomas (Eμ-Myc) to investigate the role of Fas mutations in lymphomagenesis and response to chemotherapy. Methods: We designed a breeding program, in which we crossed heterozygous Lpr mice, which harbor a germline mutation in Fas, with Eμ-Myc mice. This led to the development of mice that grow spontaneous Eμ-Myc lymphomas with either FasWT or Fasmut gene alterations, hereafter designated WT and MUT. These mice were analyzed for disease progression and their lymphoma cells were intravenously injected into C57BL/6 mice to create 2nd generation lymphomas. A 3rd generation cohort was developed similarly from injecting 2nd generation lymphoma cells into another group of C57BL/6 mice. 3rd generation mice were treated with components of R-CHOP chemotherapy, namely doxorubicin, vincristine, and cyclophosphamide. Overall and disease-related survival were monitored for all cohorts, and lymph node and spleen tissues were preserved from all 3 generations as formalin-fixed paraffin-embedded (FFPE) blocks. A tissue microarray was created to analyze the tumor microenvironment and elements of extrinsic apoptosis/immune response. Immunohistochemistry staining of the microarray using T cell and lymphoma-related markers is currently ongoing (CD3, CD4, CD8, CD25, FoxP3, TP53, Nfkb, Bcl2). Results: In the 1st generation, 21/37 WT and 11/18 MUT mice developed lymphoma, with the time to lymphoma death being similar in both groups (170 days versus 140 days, respectively, p =0.32). Of the 32 primary NHLs generated, 3 didn't have sufficient viable cells to perform subsequent experiments. The remaining 29 NHLs were injected into at least two different C57BL/6 mice, with the exception of one who only had enough cells to inject into one mouse. Thus, the second generation included 57 mice transplanted with 29 primary NHLs. Lymphoma development was higher in the MUT cohort (12/37 WT and 14/20 MUT, p=0.011). The all-cause overall survival was not different between both genotypes (p=0.152), but lymphoma specific survival was significantly shorter in the MUT mice (67 days for MUT and 136 days for WT, p=0.026). In the 3rd generation, 93 mice developed lymphoma (54 WT and 39 MUT), of which 15 were used as untreated controls and 78 were treated with components of R-CHOP. Overall, WT mice appeared to have durable responses to therapy, as shown by increased survival when compared to controls across doxorubicin, vincristine, and cyclophosphamide groups (p=0.0147, 0.0406, 0.0321 respectively). However, no difference in survival was seen in the MUT cohort between treated and untreated controls. Conclusion: Fas mutations may provide survival advantages to lymphoma cells implanted into immune-competent mice. They may also promote resistance to R-CHOP, particularly vincristine, doxorubicin, and cyclophosphamide, but the exact mechanism by which this occurs is unclear. The immune-tumor cell interactions are being investigated by IHC and will be presented. Disclosures Johnson: Roche: Consultancy, Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, gifts, and others, Research Funding; Abbvie: Consultancy, Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Honoraria; BMS: Consultancy, Honoraria; BD Biosciences: Other: Provided a significant proportion of the antibodies used in this project free of cost.; Seattle Genetics: Honoraria; Lundbeck: Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, gifts, and others, Research Funding.
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Ma, Jing-Xin, Hong Li, Xiao-Xin Cheng, Mo-Li Wu, Li-Jun Yu, Qing-You Kong, Ming Liu, and Jia Liu. "Inhibition of SIRT1 Transcription in Resveratrol-differentiated Medulloblastoma Cells." Functional Foods in Health and Disease 3, no. 5 (May 31, 2013): 154. http://dx.doi.org/10.31989/ffhd.v3i5.56.
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Backgrounds: Medulloblastoma (MB) is the commonest brain malignancy in childhood with poor prognosis, because of its rapid aggressive growth and frequent occurrence. The current chemotherapeutic regimens for medulloblastoma patients involve a combination of lomustine, cisplatin, carboplatin, vincristine or cyclophosphamide, which have distinct short- and long-term side-effects. It is therefore in urgent need to explore safer and more effective adjuvant approach(s). Resveratrol, a polyphenol rich in numerous plants, has multiple biological activities including anticancer effects. Our previous data confirmed that resveratrol inhibited proliferation and induced differentiation and apoptosis of medulloblastoma cells. SIRT1 is a deacetylase of class III HDACs and the supposed molecular effecter of resveratrol. SIRT1 involves in aging prevention and cancer formation in a cell-context specific manner. Nevertheless, the datum concerning the role(s) of SIRT1 in formation and prognosis of medulloblastoma is still missing.Objective: The present study aimed to address the expression patterna of SIRT1 in medulloblastoma tissues and non-cancerous counterparts and to explore whether resveratrol exerts its anti-medulloblastoma effects via regulating SIRT1 expression and bioactivity.Methods: The expression of SIRT1 in medulloblastoma and non-cancerous counterparts was elucidated by immunohistochemical ataining (IHC). To clarify the function of SIRT1 in medulloblastomas, SIRT1 expression in UW228-3 medulloblastoma cells were suppressed by RNA interference (RNAi). The influence of resveratrol in SIRT1 expressions in UW228-3 cells was analyzed by reverse transcription-polymerase chain reaction (RT-PCR), immunocytochemistry (ICC) and Western blotting (WB). The catalytic activity of deacetylase SIRT1 was examined by measuring the acetylation of the main substrate p53.Results: IHC staining revealed that SIRT1 was expressed in 64.17% of MB tissues, which was higher than that in noncancerous cerebellum tissues (14.29%). The frequencies of SIRT1 expression in the nodular MB (22.22%) with better prognosis is lower than that in anaplastic MB (79.07% ) and classic MB (60.29 %; P<0.05). The proliferation of UW228-3 cells was remarkably suppressed after being transfected with SIRT1 siRNA, accompanied with extensive cell death. The results of RT-PCR and WB showed that after 48 hours 100 M resveratrol treatment, SIRT1 expression in UW228-3 cells was down-regulated at both transcriptional and translational levels. However, resveratrol has no effect on the deacetylase activity of SIRT1.Conclusion: The above findings suggested that SIRT1 expression is corrected with the formation and prognosis of human MB. Resveratrol influences SIRT1 functioning in human MB cells through inhibiting SIRT1 expression rather than modulating its acetylation activity.Keywords: resveratrol, SIRT1, RNA interference, deacetylase, medulloblastoma
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Kovtun, O. P., O. V. Koryakina, V. V. Bazarnyi, and L. G. Fechina. "CLINICAL AND DIAGNOSTIC VALUE OF THE CYTOKINE PROFILE IN BLOOD PLASMA AND CEREBROSPINAL FLUID IN CHILDREN WITH VINCRISTIN-INDUCED PERIPHERAL NEUROPATHY IN ACUTE LYMPHOBLASTIC LEUKEMIA." Pediatria. Journal named after G.N. Speransky 101, no. 3 (June 17, 2022): 134–42. http://dx.doi.org/10.24110/0031-403x-2022-101-3-134-142.
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Vincristine-induced peripheral neuropath (VIPN) is the main neurotoxic complication in the treatment of acute lymphoblastic leukemia (ALL) in children. The mechanisms for peripheral nerve system injury are not fully understood, rand recent studies have shown the involvement of the immune system. Objective of the study: to determine the cytokine profiles in blood plasma and cerebrospinal fluid in children with ALL and determine their relationship with the formation of VIPN. Materials and methods of research: 65 patients aged 3–17 years with ALL participated in a single-center prospective observational cohort study who underwent chemotherapy treatment according to the ALL-MB-2015 protocol. The patients were divided into two groups based on the severity of VIPN: the 1st group (n=44) – patients with ALL, having neurological manifestations of VIPN, and the 2nd group (n=21) – children with ALL without clinical symptoms of peripheral neuropathy. Levels of cytokines were observed in children’s blood plasma and cerebrospinal fluid by the multiparametric immunofluorescence assay. Results: Comparison of cytokines levels in blood plasma and cerebrospinal fluid represented an increase in CXCL10 (IP-10), CXCL12 (SDF-1α) and stem cells factor (SCF) in the group of children with clinical signs of VIPN. Results suggested statistically significant twofold increase in CXCL10 (IP-10) in blood plasma (p<0,001), an increase in CXCL12 (SDF-1α) in blood plasma and cerebrospinal fluid (p<0.01 and p=0.05, respectively) and SCF in the cerebrospinal fluid (p=0.03). In addition, it was established that a mixed detection of the levels of CXCL10 (IP-10) and CXCL12 (SDF-1α) in blood plasma is highly informative. Conclusion: the results obtained allow us to consider the indications of CXCL10 (IP-10), CXCL12 (SDF-1α) and SCF as biological markers for early diagnosis of VIPN.
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Herrera-Gonzalez, Sarahi, Dema Shamoon, Tingliang Shen, Simon Badin, and Yatinder Bains. "A Unique Case of Mantle Cell Lymphoma Masquerading as a Cecal Mass." Case Reports in Gastrointestinal Medicine 2021 (September 10, 2021): 1–5. http://dx.doi.org/10.1155/2021/5581043.
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Mantle cell lymphoma (MCL), a type of B-cell non-Hodgkin’s lymphoma, is a rare and aggressive disease with a poor prognosis due to its advanced presentation at diagnosis. It is characterized by a translocation in the Bcl-1 gene, which results in overexpression of cyclin D1. MCL is frequently seen in the form of multiple lymphomatous polyposis (MLP) in which innumerable polyps are observed in the gastrointestinal (GI) tract. In rare instances, MCL presents a single mass. The most common presentation involves male patients in their sixties, with generalized lymphadenopathy, extranodal involvement, and B symptoms (night sweats, fever, and weight loss). Endoscopic findings of MLP include cerebroid folding of the gastric mucosa and innumerable polyps extending from the duodenum to the large intestine and are reported in approximately 9% of all GI lymphomas. Less commonly, only 2–4% of GI malignancies present as a primary GI MCL as a single mass, usually in the stomach and ileocecal region in the intestine. Radiologic findings include lymphadenopathy, splenomegaly, multiple polyposis, or wall thickening with ulceration or mass formation. In most instances, advanced disease is found at diagnosis, for which 5-year survival ranges only from 26 to 46%, even when appropriate treatment is initiated. High mitotic rate, or Ki-67 index, is of prognostic value and is associated with poor prognosis. Treatment involves conventional chemo-immunotherapy consisting of R CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) or RB (rituximab and bendamustine), with the latter being better tolerated and associated with longer progression-free survival. Surgical resection is usually limited to patients in which complications are seen such as bleeding, perforation, or bowel obstruction. We present a unique case of a 70-year-old male with nonbilious, nonbloody emesis, and symptomatic anemia who was found to have a cecal mass consistent with MCL.
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Shimizu, Naomi, Shouko Nakamura, Naoyuki Kawagoe, Rena Oka, Yasuhiro Watanabe, Sho Tanaka, Yuta Sato, et al. "Rituximab (R)-CHOP Therapy Has Progressed Arteriosclerosis with an Elevation of Von Willebrand Factor (vWF) in Patients with Malignant Lymphoma." Blood 132, Supplement 1 (November 29, 2018): 5380. http://dx.doi.org/10.1182/blood-2018-99-112326.
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Abstract Introduction : An increased incidence of arteriosclerosis has been noted in cancer survivors. Until now, only a few reports have been reported on relationship between arteriosclerosis and chemotherapy. As a mechanism for developing arteriosclerosis by chemotherapy, reduction of nitric oxide from endothelial cells has been reported. We have reported a case who was 68-year-old female with follicular lymphoma, clinical stage IVA showing the plaque formation of carotid artery and the elevation of cardio-ankle vascular index (CAVI) after eight courses of R-CHOP therapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) without complication of diabetes mellitus and hyperlipidemia (2017, JCMR). In this study, we evaluated the incidence of developing arteriosclerosis with chemotherapy using CAVI as an arterial stiffness parameter, carotid artery ultrasonography and the value of von Willebrand factor (vWF) as an endothelial damage in patients with malignant lymphoma who were treated with R-CHOP therapy. Materials and methods: Between March 2017 and February 2018, thirteen patients with B-cell malignant lymphoma who were treated with R-CHOP chemotherapy were enrolled after obtaining written informed consent. We evaluated the arteriosclerosis with CAVI index, carotid artery ultrasonography and the value of vWF during each chemotherapy. This study was approved by the Ethics Committee of Toho University. Results: Twelve men and one woman were registered (the median age, 73 years old, range, 59 - 82). One patient was treated with 4 courses of R-CHOP followed by irradiation and the remaining 12 patients were treated with 6-8 courses of R-CHOP. All patients achieved complete remission. The mean value of vWF was significantly elevated from 147 ± 40.0 % to 192 ± 39.8 % after one course of R-CHOP (p = 0.001). Then, the value of vWF was elevated significantly at the each time point compared with the pretreatment value (after 3 cycles; 190 ± 53.5, p = 0.0017, 6 cycles; 198 ± 32.5, p = 0.0024) (Figure 1). The value at after the final chemotherapy (175 ± 41.3) decreased significantly comparing the value of final treatment (207 ± 38.9, p = 0.0112). Nine patients showed the progression of arteriosclerosis with new plaque formation or progression of intima-media thickness by carotid artery ultrasonography. Plaque score after completing the therapy was elevated significantly from 6.4 ± 4.33 to 6.8 ± 4.65 (p = 0.0313) as shown in Figure 2. Some patients showed the elevation of CAVI index with the progression of treatment. However, there was no significant elevation of the index during the treatment. Conclusions: We reported that malignant lymphoma patients showed the significant elevation of vWF and new plaque formation in carotid artery during the R-CHOP therapy. vWF elevation might have progressed the arteriosclerosis in the patients with R-CHOP therapy. Further study will be required to clarify the relationship between chemotherapy and arteriosclerosis. Disclosures No relevant conflicts of interest to declare.
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Ali, Shamsher, Eric Hénon, Ritchy Leroy, and Georges Massiot. "Addition of Vindoline to p-Benzoquinone: Regiochemistry, Stereochemistry and Symmetry Considerations." Molecules 26, no. 21 (October 22, 2021): 6395. http://dx.doi.org/10.3390/molecules26216395.
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Vindoline and catharanthine are the major alkaloids of Catharanthus roseus and are extracted in large quantities to prepare the pharmaceutically important Vinca type alkaloids vincaleukoblastine, vincristine and navelbine. The higher yield of vindoline relative to catharanthine makes it an attractive substrate for developing new chemistry and adding value to the plant. In this context, we have reacted vindoline with a selection of electrophiles among which benzoquinone. Conditions were developed to optimize the synthesis of a mono-adduct, of five bis-adducts, and of tri-adducts and tetra-adducts, several of these adducts being mixtures of conformational isomers. Copper(II) was added to the reactions to promote reoxidation of the intermediate hydroquinones and simplify the reaction products. The structures were solved by spectroscopic means and by symmetry considerations. Among the bis-isomers, the 2,3-diadduct consists of three unseparable species, two major ones with an axis of symmetry, thus giving a single set of signals and existing as two different species with indistinguishable NMR spectra. The third and minor isomer has no symmetry and therefore exhibits nonequivalence in the signals of the two vindoline moieties. These isomers are designated as syn (minor) and anti (major) and there exists a high energy barrier between them making their interconversion difficult. DFT calculations on simplified model compounds demonstrate that the syn-anti interconversion is not possible at room temperature on the NMR chemical shift time scale. These molecules are not rigid and calculations showed a back-and-forth conrotatory motion of the two vindolines. This “windshield wiper” effect is responsible for the observation of exchange correlations in the NOESY spectra. The same phenomenon is observed with the higher molecular weight adducts, which are also mixtures of rotational isomers. The same lack of rotations between syn and anti isomers is responsible for the formation of four tri-adducts and of seven tetra-adducts. On a biological standpoint, the mono adduct displayed anti-inflammatory properties at the 5 μM level while the di-adducts and tri-adducts showed moderate cytotoxicity against Au565, and HeLa cancer cell lines.
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Romagnoli, Mathilde, Regis Bataille, and Sophie Barillé-Nion. "The Critical Role of Survivin in the Survival and Proliferation of Human Myeloma Cells." Blood 106, no. 11 (November 16, 2005): 110. http://dx.doi.org/10.1182/blood.v106.11.110.110.
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Abstract Multiple myeloma (MM) is characterized by the accumulation of malignant plasma cells with an enhanced proliferation and survival capacity within the bone marrow. Myeloma cells often develop drug resistance leading to treatment failure in the patients. Survivin is a member of the inhibitors of apoptosis (IAP) gene family that has been implicated in both cell viability and cell cycle regulation and described as overexpressed in most cancers. We have observed that survivin is expressed in human myeloma cell lines (HMCL) from moderate level in both HMCL XG-6 and MM1S to strong level in U266. Survivin was also detectable in primary myeloma cells. Moreover, survivin expression peaked at G2/M phase and was induced by IL-6 and IGF-1 through JAK/STAT and PI3K/AKT signalling pathways. In order to elucidate the role of survivin in myeloma cells, MM1S and XG-6 HMCL were transfected with human survivin cDNA. First, The survivin transient transfectants MM1S were significantly less sensitive to different drugs (dexamethasone, melphalan, paclitaxel, vincristine, doxorubicin) than the control vector transfectants MM1S. Secondly survivin stable transfected clones established from the HMCL XG-6 that is dependent on IL-6 for its growth, could be maintained in culture without IL-6 longer than control stable clones. Moreover these survivin clones proliferated without exogenous IL-6 in contrast to control clones that kept their IL-6 dependent growth. Furthermore, in vivo preliminary data suggest that survivin overexpressing clones could develop tumor in the SCID-human MM model in contrast to control clones. These data tend to prove that survivin participates in drug sensitivity, escape from IL-6 dependence and tumor formation capacity of HMCL. In summary, our findings suggest that survivin plays an important role in the pathogenesis of MM. A more defined understanding of survivin biology should enhance the rational development of drugs to inhibit its function in myeloma cells.
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Ma, Xiao-Tong, Ya-Kun Mou, Yang-Yang Zhao, Nan Wang, Xiao-Yan Liu, Jing Yin, Yan-Ping Ma, and Dan Guo. "Set7 Is Highly Expressed in B-Lineage Acute Lymphoblastic Leukemia Cells and Overexpression of Set7 Exhibits Antileukemia Effect." Blood 128, no. 22 (December 2, 2016): 5088. http://dx.doi.org/10.1182/blood.v128.22.5088.5088.
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Abstract Set7 is a member of protein lysine methyltransferase family that is highly conserved in vertebrates. Set7 can regulate the maintenance of chromosome structure, cell cycle and apoptosis, and plays an important role in many kinds of cancer, metabolism and inflammatory process. However, studies concerning its pathogenic role in leukemia are scarce. We analyzed the expression of Set7 in different types of leukemia and healthy human bone marrow cells or peripheral blood from the Oncomine databases (http://www.oncomine.org), and showed that Set7 was highly expressed in acute lymphoid leukemia (ALL) patients, especially in patients with B-ALL. In this study, we examined the expression of Set7 in various hematopoietic tumor cell lines, bone marrow samples from patients and healthy volunteers. We found that Set7 was highly expressed in B-ALL cell lines Nalm6 and REH compared with other hematopoietic malignant cell lines. Furthermore, Set7 was overexpressed in bone marrow mononuclear cells of adult and pediatric patients with B-ALL than in healthy human bone marrow samples, and sorted CD19+ cells, as well (P<0.001). To investigate Set7 gene function, retroviral-mediated overexpression or removal experiments were performed. Gain-of-function and loss-of-function analyses in Nalm6 and REH cells demonstrated that Set7 inhibited cell growth, colony formation and enhanced the chemosensitivity of B-ALL cells to Vincristine (VCR), Arabinocytidine (Ara) and Daunorubicin (DNR). Protein sequence analysis showed that Ebf1 might be a potential substrate for Set7. The expression of Rad51 and Tnsf11, the downstream target genes of Ebf1, were changed as expected when Set7 was overexpressed in Nalm6 and REH. Our study shows for the first time that overexpression of Set7 has an inhibitory effect on B-ALL. These findings suggest that Set7 may be a promising molecular therapy target for B-ALL treatment and provide new clues for understanding the molecular mechanisms of the leukemogenesis of B-ALL. Disclosures No relevant conflicts of interest to declare.
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Kiso, Tetsuo, Ken-Ichi Fujita, Xu Ping, Toshio Tanaka, and Makoto Taniguchi. "Screening for Microtubule-Disrupting Antifungal Agents by Using a Mitotic-Arrest Mutant of Aspergillus nidulans and Novel Action of Phenylalanine Derivatives Accompanying Tubulin Loss." Antimicrobial Agents and Chemotherapy 48, no. 5 (May 2004): 1739–48. http://dx.doi.org/10.1128/aac.48.5.1739-1748.2004.
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ABSTRACT The microtubule, which is one of the major targets of anthelmintics, anticancer drugs, and fungicides, is composed mainly of α- and β-tubulins. We focused on a unique characteristic of an Aspergillus nidulans benA33 mutant to screen for microtubule-disrupting antifungal agents. This mutant, which has a β-tubulin with a mutation of a single amino acid, undergoes mitotic arrest due to the formation of hyperstable microtubules at 37°C. The heat sensitivity of the mutant is remedied by some antimicrotubule agents. We found that an agar plate assay with the mutant was able to distinguish three types of microtubule inhibitors. The growth recovery zones of the mutant were formed around paper disks containing microtubule inhibitors, including four benzimidazoles, ansamitocin P-3, griseofulvin, and rhizoxin, on the agar plate at 37°C. Nocodazole, thiabendazole, and griseofulvin reversed the mitotic arrest of the mutant and promoted its hyphal growth. Ansamitocin P-3 and rhizoxin showed growth recovery zones around the growth-inhibitory zones. Benomyl and carbendazim also reversed mitotic arrest but produced weaker growth recovery than the aforementioned drugs. Other microtubule inhibitors, such as colchicine, Colcemid, paclitaxel, podophyllotoxin, TN-16, vinblastine, and vincristine, as well as some cytoskeletal inhibitors tested, did not show such activity. In our screening, we newly identified two mycotoxins, citrinin and patulin, two sesquiterpene dialdehydes, polygodial and warburganal, and four phenylalanine derivatives, arphamenine A, l-2,5-dihydrophenylalanine (DHPA), N-tosyl-l-phenylalanine chloromethylketone, and N-carbobenzoxy-l-phenylalanine chloromethyl ketone. In a wild-type strain of A. nidulans, DHPA caused selective losses of microtubules, as determined by fluorescence microscopy, and of both α- and β-tubulins, as determined by Western blot analysis. This screening method involving the benA33 mutant of A. nidulans is useful, convenient, and highly selective. The phenylalanine derivatives tested are of a novel type of microtubule-disrupting antifungal agents, producing an accompanying loss of tubulins, and are different from well-known tubulin inhibitors affecting the assembly of tubulin dimers into microtubules.
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Lovi, N. K., D. Koffie, E. K. Antiri, E. Abole, J. E. Tawiah, F. Amihere, and I. Ekem. "Aggressive Plasma Cell Myeloma as an Underlying Cause of Paraparesis In an Unusually Young Male Patient." Postgraduate Medical Journal of Ghana 7, no. 2 (July 12, 2022): 115–18. http://dx.doi.org/10.60014/pmjg.v7i2.177.
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Plasma Cell Myeloma, also called multiple Myeloma, is a haematological malignancy characterised by the proliferation of malignant plasma cells with an associated monoclonal paraproteinemia. The disease is described to have a median age of diagnosis in the 7thdecade of life and rare below the 4th decade. We report a case in which the patient was first diagnosed as having Multiple Myeloma at the age of 29 years. The patient had been having symptoms for at least 5 months prior to the diagnosis being arrived at. His earliest symptoms were non-specific: malaise, low grade fever, easy fatigability. These were followed by palpitations, recurring bipedal swelling, polyuria and two months later gnawing lower back pain. Shortly after, he experienced sudden inability to walk without support. The patient reported to us that he had visited a number of primary care facilities where he had full blood counts done as well as x-rays of the lumbosacral spine but was apparently told that apart from having moderate anaemia, his lumbo-sacral X-ray findings were not significant. At the last facility he visited before presenting to our hospital, he was told that he had severe anaemia due tochronic kidney disease. At presentation, a careful review of his history together with his laboratory investigations which included a FBC, blood film comment, BUE/Cr, and X- ray of the thoracolumbosacral spine was suggestive of Multiple Myeloma. Hence with his first blood film comment which showed mild rouleaux formation a bone marrow aspirate was requested. An ESR had not been done. Themarrow showed plasma cell infiltration of 65%. Serum protein electrophoresis showed an M component of 8g/L while a serum free light chain assay revealed an increase of the lambda component of 8480 mg/L (normal: 5.71- 26.30). A repeat x ray showed lytic lesions in the pelvic girdle, spine, shoulders and sternum. Patient was started on oral and intravenous hydration, renal dialysis, Zoledronic acid, chemotherapy with Vincristine, Adriamycin, Dexamethasone and Thalidomide, physiotherapy and thoracolumbar bracing. Patientresponded well to treatment.
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Seideman, Jonathan H., and David A. Scheinberg. "Multi-Drug Resistance Phenotype in Myeloid Leukemia Cells Confers Radiation Resistance Via DNA Damage Sensor Uncoupling." Blood 114, no. 22 (November 20, 2009): 4243. http://dx.doi.org/10.1182/blood.v114.22.4243.4243.
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Abstract Abstract 4243 We have found that a stable multi-drug resistant (MDR) variant of the myeloid leukemia line, HL60, called RV+, which was selected for drug resistance in the presence of vincristine, is clonogenically cross-resistant to gamma radiation (RV+ Do= 0.81 Gy, HL60 Do = 0.49 Gy). At equal doses, these two different cell lines incurred equivalent DNA double strand breaks (DSBs) upon irradiation as measured by pulse-field electrophoresis, and showed nearly identical bulk DSB repair capacity and efficiency, suggesting that the resistence phenotype is not due to a reduction in DSBs. Interestingly, an early and proximal marker of DSBs, phosphorylation of the histone variant H2AX, is up to seven-fold lower in RV+ cells, despite equivalent bulk DNA damage. This discrepancy between physical damage and proximal signaling is accompanied by dramatically attenuated early and late G2/M checkpoint responses in RV+ cells, which require nearly 10 times the radiation dose of HL60 cells (2.0 Gy compared to 0.2 Gy) to elicit a full early G2/M check, and up to four times the dose (4.0 Gy compared to 1.0 Gy) for an equivalent late G2/M response. Consistent with decreased checkpoint stringency, up to eight time as many RV+ cells were found to be entering mitosis after radiation, with 62.7% unresolved DSBs as measured by micronuclei formation. Although HL60 had a comparable percentage of cells with unresolved breaks (72.6%), the total number of cells entering mitosis with intact nuclei was proportionally much lower. Moreover, in the same dose range, RV+ cells have a marked decrease in radiation-induced apoptosis compared to HL60, which has been shown to be an important clonogenic predictor in hematopoietic cells. As RV+ cells are 10-fold more sensitive to cytarabine-induced apoptosis, RV+ cell insensitivity is likely not due to a global anti-apoptotic phenotype. Increased clonogenic survival suggests that RV+ have partially decoupled sensing of extant DNA damage from checkpoint and apoptotic responses, possibly through downregulation of phospho-H2AX or its cognate upstream kinases. Current research seeks to determine a causal relationship between these unique radioresistance phenomena. Disclosures: No relevant conflicts of interest to declare.
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Guzman, Monica L., Wen Xie, Jeanne P. De Leon, Francis Burrows, Eric J. Feldman, and Gail J. Roboz. "Leukemia Stem/Progenitor Cells From AML Patients Treated With The Multi-Kinase Inhibitor TG02 Demonstrate Increased Proliferation and Are Sensitized To Chemotherapeutic Agents." Blood 122, no. 21 (November 15, 2013): 3892. http://dx.doi.org/10.1182/blood.v122.21.3892.3892.
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Abstract TG02 is a multi-kinase inhibitor that targets cyclin-dependent kinases (CDKs), ERK5, JAK2, and Flt3. In vitro studies of TG02 have shown robust induction of apoptosis in both acute myeloid leukemia (AML) cell lines and primary cells (Goh et al, 2011). Leukemia stem cells (LSCs) comprise a largely quiescent, highly chemotherapy-resistant cell population and are believed to initiate and maintain AML, as well as contribute to its poor prognosis. Thus, we sought to investigate the impact of TG02 on LSCs collected from patients with relapsed/refractory AML enrolled in a phase I dose escalation trial. Patients ≥ 18 years with advanced hematological malignancies or newly diagnosed AML pts ≥ 65 years unfit for intensive therapy were enrolled onto daily (A) and intermittent (B, 5 days on 2 days off X 2 weeks) schedules in 28-day cycles. Pts had acceptable organ function and ECOG PS 0-2. Dose levels were 10 - 70 mg on arm A and 30 - 150 mg on arm B. We evaluated immunophenotypically defined leukemia stem and progenitor cells (LSPCs) by flow cytometry, cell cycle status and colony forming assays. A total of 16 patients were evaluated with treatment doses ranging from 10-150 mg of TG02. Clinically, treatment with TG02 did not have an effect in AML tumor burden, and most patients at our center only received one cycle of treatment (Roboz et al ASCO 2012 Annual Meeting Abstract #6557, J Clin. Oncol. 30, 2012). However, we found that 8 patient samples showed increased LSPCs in both the bone marrow and peripheral blood. Interestingly, we observed an increase in LSPC cell proliferation, as determined by Ki-67 positive staining. AML colony forming assays also showed increased colony formation (n=5) after one cycle of treatment, which suggests an increase in the frequency of LSPCs. The increase in colony formation in peripheral blood samples suggests mobilization of LSPCs from the marrow into the circulation. Thus, we hypothesized that exposure to TG02 in vivo may result in sensitization to other chemotherapeutic agents, such as Ara-C. We evaluated the effects of Ara-C and other chemotherapeutics, such as vincristine, in primary AML cells obtained from patients before and after treatment with TG02. We found that in vivo exposure to TG02 resulted in significantly increased sensitivity to Ara-C in vitro in 3 out of 4 samples tested Together, our data suggest that TG02 induces an effect in LSCs resulting in increased proliferation and, thus, sensitization to other chemotherapeutic drugs, such as Ara-C. Importantly, although no patients at our center receiving single agent TG02 met the criteria for an objective response, by performing correlative studies in association with the clinical trial, we found the TG02 has a marked effect in AML LSCs that could potentially be exploited by combining it with other agents. Disclosures: Burrows: Tragara Pharmaceuticals: Employment, Equity Ownership. Feldman:Tragara Pharmaceuticals: Consultancy.
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Geng, Huimin, Jae-Woong Lee, Zhengshan Chen, Behzad Kharabi Masouleh, Christian Hurtz, Eugene Park, Gang Xiao, et al. "IL2RA (CD25) Recruits Inhibitory Phosphatases to the Cell Membrane and Mediates Negative Feedback Control of STAT5 Signaling in Acute Lymphoblastic Leukemia." Blood 124, no. 21 (December 6, 2014): 788. http://dx.doi.org/10.1182/blood.v124.21.788.788.
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Abstract Background and hypothesis: CD25 (IL2RA, interleukin 2 receptor α chain) is a transmembrane protein with a 13aa cytoplasmic tail. CD25 cooperates with β- and γ-chains in binding IL-2, but does not contribute to cytokine signaling. During normal B cell development, CD25 is specifically upregulated on the surface of IL7-dependent pre-B cells and is also expressed on the surface of a subset of human pre-B ALL cases. CD25-expressing ALL is typically associated with poor clinical outcome. For these reasons, we studied the functional significance of CD25 expression on human pre-B ALL cells. Results: Flow cytometry and immunohistochemistry staining on a large panel of patient samples (n=416; MDACC, ECOG) revealed specific cell surface expression of CD25 in Ph+ ALL and Ph-like ALL, which are both high-risk subtypes of ALL. In agreement with selective expression on high-risk subsets, high expression levels of CD25 at the time of diagnosis were predictive of poor overall clinical outcome in these studies (P=0.005). BCR-ABL1 in Ph+ ALL and related tyrosine kinases in Ph-like ALL strongly activate STAT5, which then induces transcriptional activation of the IL2RA locus. Since Stat5 is also active during normal pre-B cell differentiation, we first analyzed B cell development in Il2ra-/- mouse bone marrow. Il2ra-/- B cell development was blocked at the pre-B cell stage, consistent with specific upregulation of CD25 on pre-B cells. In human Ph+ ALL cells, we found IL2RB and IL2RG were not co-expressed with CD25, suggesting a function of CD25 in Ph+ALL that is distinct from IL2 signaling. To test the biological significance of tyrosine kinase/STAT5-induced activation of CD25, we developed an Il2ra-/- mouse model for BCR-ABL1 pre-B ALL. Interestingly, the cytoplasmic tail of CD25 includes phosphorylation sites (S268 and T271) that are known substrates for serine/threonine phosphorylation by PKCα, which was reported to regulate protein phosphatase 2A (PP2A). To investigate interacting proteins with the cytoplasmic tail of CD25, we performed immune precipitation (IP) against the flag-tagged CD25-tail in primary Ph+ ALL cells which were transduced with either a CD25-tail-flag or an EV-flag vector. 2D mass spectrometry and Western blot on the IP products confirmed strong interactions with PKCα and PP2A. Weestern blot analysis confirmed additional interactions with inhibitory phosphatases including PTEN, PTPN6 (SHP1) and Inpp5d (SHIP1) in human Ph+ALL cells. In addition, both 2D MS and Westernblot showed recruitment of the Stat5-feedback inhibitors CISH, SOCS2 and SOCS3 at the CD25 cytoplasmic tail. Studying functional parameters of Il2ra-/-BCR-ABL1 ALL cells, we found impaired proliferation and colony formation capacity and drastically increased increased phosphorylation levels of pABLY412, pSTAT5Y694, pERKT202/Y204, pAKTS473, pP38T180/Y182 and p53. Reconstitution of CD25 expression restored normal phosphorylation levels of these molecules, as well as proliferation and colony formation.In a serial transplant setting, we observed that leukemia initiation in transplant recipients from Il2ra-/- BCR-ABL1 ALL cells required 10- to 100-times higher cell numbers, suggesting that CD25 contributes to leukemia initiation. In addition, CD25 expression is associated with a higher level of drug-resistance: In patient-derived pre-B ALL cells with mixed CD25Low and CD25High populations, the standard chemotherapy agent vincristine selectively induced apoptosis of in CD25Low but not CD25High ALL cells. An anti-CD25 immunotoxin drugs efficiently eradiated CD25High leukemia cells and thereby overcame drug-resistance against vincristine. Conclusions: Our studies identified CD25 as a surface receptor that mediates membrane recruitment of PP2A and CISH, SOCS2, negative feedback regulators of STAT5. CD25 is transcriptionally activated by STAT5 and therefore specifically expressed on high-risk ALL subtypes with oncogenic activation of the Stat5 pathway (Ph+ ALL and Ph-like ALL). We propose that CD25-mediated negative feedback control stabilizes oncogenic tyrosine kinase signaling and mediates drug-resistance in Ph+ ALL and Ph-like ALL cells. Targeted inhibition using CD25-directed immunotoxins may be useful in new approaches to overcome drug-resistance in Ph+ ALL and Ph-like ALL. Disclosures No relevant conflicts of interest to declare.
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Lee, Jae-Woong, Zhengshan Chen, Huimin Geng, Gang Xiao, Eugene PARK, Samir Parekh, Steven M. Kornblau, et al. "CD25 (IL2RA) Orchestrates Negative Feedback Control and Stabilizes Oncogenic Signaling Strength in Acute Lymphoblastic Leukemia." Blood 126, no. 23 (December 3, 2015): 1434. http://dx.doi.org/10.1182/blood.v126.23.1434.1434.
Full textAbstract:
Abstract Background and hypothesis: CD25 (IL2RA) represents the α chain of the interleukin 2 receptor on T cells and plays an important role in the maintenance of regulatory T (Treg) cells, hence preventing T cell autoimmunity. In a comprehensive gene expression analysis, we found that CD25 is specifically upregulated by pre-B cell receptor (pre-BCR) signaling during early B cell development and oncogenic tyrosine kinase that mimic pre-BCR signaling (e.g. in Ph+ ALL and Ph-like ALL). In adults with Ph+ ALL (ECOG; MDACC) and children with Ph-like ALL (P9906) patients with CD25 expression at the time of diagnosis have a particularly poor outcome (n=416; P=0.005). For these reasons, we studied the function of CD25 in B cell development and leukemia in a series of genetic experiments. Results: Unlike T cells, CD25 (IL2RA) does not function as IL2 receptor chain in B cells and B-lineage ALL: CD25 expressed on B-lineage cells did not pair with IL2Rb and g-chains and was not responsive to IL2. Il2ra-/- B cells were arrested at the pre-B cell stage with hyperactive pre-BCR downstream signaling including SRC, BTK and ERK. In the presence of CD25, Il2ra+/+ B cells responded to engagement of the pre-BCR with phosphorylation of pre-BCR downstream tyrosine kinases and coordinated release of Ca2+ from cytoplasmic stores. In the absence of CD25 (Il2ra-/-), the pre-BCR signals autonomously, resulting in uncoordinated Ca2+ oscillations of variable duration. While CD25 does not function as IL2 receptor chain in B cells, it coordinates pre-BCR-dependent signal transduction and regulates its intensity. The pre-BCR related tyrosine kinase BTK is phosphorylated by BCR-ABL1 in Ph+ ALL and other tyrosine kinase oncogenes in Ph-like ALL (Chen et al., 2015). Interestingly, overexpression of a constitutively active form of BTK resulted in strong upregulation of CD25 surface expression. Conversely, the BTK-inhibitor ibrutinib abolished CD25 expression suggesting that feedback control between pre-BCR signaling and CD25 requires BTK. The ability of CD25 to stabilize oncogenic signaling strength in Ph+ ALL and Ph-like ALL was important for leukemia-initiation and development of fatal disease. In the absence of CD25, Il2ra-/- ALL cells showed impaired proliferation and colony formation. Serial transplantation experiments revealed a profound defect of Il2ra-/- ALL cells to initiate leukemia. 100-times more cells were required to cause fatal disease. In addition, CD25 expression mediated drug-resistance in ALL cells: In patient-derived pre-B ALL cells with heterogeneous CD25 expression, vincristine selectively induced apoptosis in CD25Low cells but spared CD25High ALL cells. Combination with an anti-CD25 immunotoxin efficiently eradiated CD25High leukemia cells and sensitized the ALL cell population to treatment with vincristine. To elucidate the mechanism of how CD25 coordinates negative feedback control of pre-BCR signaling or its oncogenic mimics, we focused on its short (13aa) cytoplasmic tail, which includes two phosphorylation sites (S268 and T271) that are known substrates for serine/threonine protein kinase, PKCα. To identify cytoplasmic interaction partners of CD25, we overexpressed a Flag-tagged truncated form of CD25 including a myristoylation signal for constitutive membrane localization, transmembrane domain and cytoplasmic tail. Immunoprecipitation (IP; Flag) followed by 2D mass spectrometry revealed strong interactions of PP2A with cytoplasmic tail of CD25. Western blots showed additional strong interactions of the cytoplasmic tail of CD25 with inhibitory phosphatases PTEN, SHP1 and SHIP1. Importantly, reconstitution of myristoylated CD25 tail but not a mutant construct lacking the serine/threonine motif (S268A/T271A) rescued proliferation and survival defects of Il2ra-/- ALL cells. Conclusion: We identified CD25 as a surface receptor that mediates membrane recruitment of PP2A, PTEN, SHP1 and SHIP1, which balances fluctuations in signaling output from a pre-B cell receptor or its oncogenic mimic in ALL cells (e.g. BCR-ABL1 in Ph+ ALL). We propose that CD25-mediated negative feedback control stabilizes oncogenic tyrosine kinase signaling and mediates drug-resistance in Ph+ ALL and Ph-like ALL cells. Targeted inhibition using CD25-directed immunotoxins may be useful in new approaches to overcome drug-resistance in Ph+ ALL and Ph-like ALL. Disclosures No relevant conflicts of interest to declare.
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Maier, Armin, Monika Engelhardt, Heinz-Herbert Fiebig, and Julia Schüler. "Profiling of 24 Standard of Care Drugs in a Panel of 20 Human Hematological Cell Lines Using Xenograft-Derived Three-Dimensional (3D) Cultures Ex Vivo and In Vivo." Blood 118, no. 21 (November 18, 2011): 4995. http://dx.doi.org/10.1182/blood.v118.21.4995.4995.
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Abstract Abstract 4995 Introduction: Leukemia and lymphoma account for a notable proportion of cancers worldwide. The heterogeneity and biological characteristics of hematological malignancies induce unique therapeutic challenges. It is well known that pluripotent as compared to differentiated cells possess the potential for anchorage independent growth in semisolid medium. This can be monitored via clonogenic or colony formation assays, in which cells grow in vitro in a three-dimensional (3D) manner without adherence to plastic culture material support. These assays can be utilized to evaluate growth and drug sensitivity of tumor stem and progenitor cells (Fiebig HH et al. Eur J Cancer 40:802, 2004). In addition, these 3D cell culture assays often mimic the in vivo scenario better than 2D cell culture assays with adherent tumor cells. Material and methods: For our ex vivo anti-tumor efficacy profiling using clonogenic assays, we established a panel of 20 hematological cell lines comprising different entities like acute lymphoblastic leukemia (ALL, 4 cell lines), acute myeloid leukemia (AML, 6 cell lines), chronic myeloid leukemia (CML, 5 cell lines), Hodgkin- (1 cell line) and non-Hodgkin-lymphoma (NHL, 3 cell lines), as well as multiple myeloma (MM, 3 cell lines). Tumor cells were injected into the flanks of NOD/SCID mice in order to obtain subcutaneous tumor xenografts, which were kept at low passages (n <3). These xenografts served as starting material either to prepare single cell suspensions for ex vivo analysis, or to carry out in vivo efficacy tests using either subcutaneous or disseminated growing tumor xenografts. Results: Twenty-four standard of care agents were tested in terms of their ex vivo chemosensitivity (e.g. cytarabine, cyclophosphamide, dexamethasone, doxorubicin, etoposide, melphalan, prednisolone, vincristine), including selected targeted drugs also (e.g. bortezomib, imatinib, nilotinib, sorafenib). The drugs showed diverse patterns of selectivity and potency: vincristine, doxorubicin and cytarabine, but also the proteasome inhibitor bortezomib exhibited pronounced activity with IC50 values in the nanomolar range (mean IC50 = 1 – 100nM), not only in their respective clinical application, but also in various other tumor entities, such as in ALL and AML with use of bortezomib. Differential activity was determined e.g. for prednisolone and dexamethasone, which were active in a micromolar range (mean IC50 = 22 – 58μM) in the ALL cell lines CCRF-CEM and MOLT-4, AML cell lines NOMO-1, NHL DAUDI and U-937, as well as the MM cell line IM-9. All-trans-retinoic acid (mean IC50 = 1.3μM) as well as interferon-gamma-1b (mean IC50 = 0.43 μM) showed specific activity patterns with pronounced growth inhibition in AML (3/6 tested AML cell lines: KG-1, NOMO-1, OCI-AML2), but also in CML (1/5 tested CML cell lines: EM-2) and MM (1/3 tested MM cell lines: L-363). The strong correlation of both tyrosine kinase inhibitors imatinib and nilotinib (spearman coefficient: 0.73, p <0.001) and their differential activity restricted to bcr-abl-positive cells served as a positive control for the implemented test system. In vivo follow-up testing in defined tumor xenografts confirmed the results obtained ex vivo. For example, cyclophosphamide that showed strong antitumor activity with use of the NHL cell line DAUDI via clonogenic assay (IC50 = 0.3μM), also induced tumor remissions of 80% in xenografts with subcutaneously growing DAUDI cells as compared to untreated control animals. Moreover, an exceedingly promising antitumor activity of sorafenib in AML cells assessed via clonogenic assay (mean IC50 0.84μM in AML cells vs. mean IC50 4.0μM over all tested entities) could be confirmed in the disseminated in vivo model using HL-60 cells (reduction of 99% vs. untreated control; Schueler J. et al. Blood 116 (21):2141, 2010). Conclusions: The presented panel screen using clonogenic assays is of great value for time and cost effective profiling of traditional cytotoxic as well as new targeted anti-cancer agents which can be confirmed in tumor models of hematological malignancies and can thereby guide to more effectively designed in vivo experiments. Diverse activity and resistance patterns ex vivo and in vivo also contribute to create clinical development strategies of standard and novel compounds. Disclosures: No relevant conflicts of interest to declare.
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Zukhrufan, M. Huki, and Eifel Faheri. "Diffuse large B-cell lymphoma in a patient with chronic myelogenous leukemia on accelerated phase with bilateral pleural effusion: a case report." International Journal of Research in Medical Sciences 8, no. 2 (January 27, 2020): 743. http://dx.doi.org/10.18203/2320-6012.ijrms20200266.
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Chronic Myelogenous Leukemia (CML) is a myeloproliferative disorder of pluripotent stem cells. The pathogenesis of CML is known to be related to mutations in the form of Philadelphia chromosomes. The incidence of CML constitutes 20% of all cases of leukemia in adults. The current gold standard for CML therapy is using tyrosine kinase inhibitors (TKI), Imatinib. Non-Hodgkin Lymphoma (NHL) is a malignancy that develops from lymph nodes. In NHL the formation of malignant cells is in the form of lymphocytes that are at one of the differentiation levels of either T lymphocytes or B lymphocytes. Diffuse large B cell lymphoma is the most common NHL, representing about 40% of all lymphoma cases. NHL management is targeted chemotherapy using rituximab combined with cyclophosphamide, doxorubicine, vincristine and prednisone. A Thirty-four year-old female patient has been reported with the main complaint of fatigue and pale weakness accompanied by an enlarged abdomen. Complaints are also accompanied by a lump in the right neck, fever, productive cough and shortness of breath. The patient has been known to suffer from CML with BCR-ABL (+) since five years ago and received Imatinib therapy, but then the patient stopped treatment himself. On physical examination found anemic, multiple enlargement of the neck lymph nodes, wet crackles soft and loud in the basal of both lungs and splenomegaly. On investigations found severe anemia, thrombocytopenia and blast 13%, increased d-dimer, bronchopneumonia-compliant infiltrate and bilateral pleural effusion on chest x-ray, results of exudate pleural fluid analysis with the cytology of a malignant smear metastasis of lymphoma to the pleura, histopathology of the neck lymph nodes with chest x-ray, analysis of exudate pleural fluid with the cytology of a malignant smear metastasis of lymphoma into the pleura, histopathology of the neck lymph nodes with the results of diffuse large B-Cell lymphoma, as well as enlargement of paraaortic lymph nodes, hepatosplenomegaly and chronic pancreatitis on abdominal ultrasound. Patients was given antibiotics, transfusion of packed red cells and platelets, pleural tap and chemotherapy. The patient was planned to undergo chemotherapy for 6 cycles of 21 days, and a CD20 examination was performed. The incidence of NHL in patients with good CML in imatinib therapy is not yet certain whether there is a direct relationship.
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Yongsheng, Ruan, Enzi Jiang, Hye Na Kim, Heather Ogana, Mo Yang, Deepa Bhojwani, Alan S. Wayne, and Yong-Mi Kim. "Targeting of Integrin α4/VCAM-1 with AVA4746 Modulates the Redox-Status and Metabolism in ALL and Angiogenesis." Blood 134, Supplement_1 (November 13, 2019): 3881. http://dx.doi.org/10.1182/blood-2019-132101.
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Background. Treatment of resistant or relapsed acute lymphoblastic leukemia (ALL) remains a challenge. Adhesion of ALL cells via integrin α4/VCAM-1 pathway to bone marrow stromal cells promotes cell adhesion-mediated drug resistance (CAM-DR). Previously, we have shown that AVA4746, a non-peptidic small molecule integrin α4 antagonist, functionally de-adheres patient-derived B-ALL cells from VCAM-1. Furthermore, we demonstrated that antagonizing VCAM-1 by AVA4746 in combination with traditional chemotherapy prolongs survival of B-ALL xenograft NSG mice derived from a relapsed B-ALL patient. The objective of the present study was to determine the underlying mechanism of the integrin α4/VCAM-1 pathway blockade using AVA4746. Method. The effect of AVA4746 intracellular levels of reactive oxygen species (ROS) in five primary B-ALL cells by flow cytometry using 2',7'-dichlorofluorescein diacetate (DCFDA) staining. Oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) measurement was assessed by Seahorse XF cell mito stress test in one primary ALL using Seahorse XFp Analyzer. The effect of AVA4746 on angiogenesis was analyzed by using an endothelial tube formation assay with HUVEC cells. In vivo effect of high dose of AVA4746 (30mg/kg bid p.o.) and prolonged treatment (28 days) was assessed in a murine xenograft model of primary ALL. Results. We have previously determined that the metabolic activity was markedly decreased in two of two ALL cases by AVA4746 as assessed by WST-1 assay. Therefore, we investigated further the effect of AVA4746 on metabolism of ALL cells. For this purpose, ALL cells were treated in vitro with AVA4746 (25μM) or 0.1% DMSO as control for 2 or 4 hours. A significant increase of intracellular ROS level was consistently found in presence of AVA4746 compared to DMSO at both 2h or 4hours in all five primary B-ALL cells. According to our preliminary bioenergetics assay, after 24h treatment with AVA4746 0, 25μM, AVA4746 decreased the metabolic potential of LAX7R cells as shown by the difference in stressed OCR and stressed ECAR (P=0.0036 and 0.0056, respectively). AVA4746 significantly impeded endothelial tube formation of HUVEC cells as shown by the statistically significant differences in numbers of nodes, segments, meshes and meshes area indicating an effect of AVA4746 on angiogenesis, which will be further examined in vivo. In vivo, AVA4746 (30mg/kg bid p.o.) in combination with vincristine, dexamethasone, L-asparaginase (VDL) chemotherapy treatment prolonged survival (n=5) compared with the VDL only treated group (n=5) (MST= 87 days vs MST= 77 days; P=0.0229). There was no significant difference in survival between the PBS control group (n=4) and the AVA4746 only treatment group (n=5). Conclusion. Interrupting integrin α4/VCAM-1 pathway by AVA4746 increases intracellular ROS level of B-ALL cells and downregulates metabolic potential. AVA4746 inhibits in vitro angiogenesis. The combined treatment of high dose AVA4746 and VDL prolonged survival compared to VDL alone. As the integrin α4/VCAM-1 pathway plays a critical role in CAM-DR of B-ALL, AVA4746 may be a potential candidate for therapy of drug resistant B-ALL. Disclosures Wayne: Kite, a Gilead Company: Consultancy, Research Funding; Servier: Consultancy; AbbVie: Consultancy; Spectrum Pharmaceuticals: Consultancy, Research Funding.