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1
Kuhn, D. T., and G. Packert. "Paternal imprinting of inversion Uab1 causes homeotic transformations in Drosophila." Genetics 118, no. 1 (January 1, 1988): 103–7. http://dx.doi.org/10.1093/genetics/118.1.103.
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Abstract Paternal transmission of the bithorax-complex (BX-C) rearrangement, inversion Uab1, causes a specific dominant gain of function phenotype in most abdominal segments. This represents a case of paternal imprinting since the mutant phenotype will occur only if inversion Uab1 is paternally transmitted. The transformations in males are toward genital arch tissue. For females the transformations are to tissue found on abdominal segment 7 (Ab7) and to structures normally restricted to the genital disc. Ninety-six percent of transformed areas appear on Ab5 and Ab6 in both sexes and on Ab7 in females, coinciding with the Abd-B domain. Four percent of the transformations occurred on Ab1 through Ab4, coinciding with the abd-A domain. The mutant phenotype can be dramatically enhanced by modifying genes such as the posterior BX-C mutant tuh-3. Expressivity is modulated by maternal effect alleles interacting with tuh-3. A region of function within inversion Uab1 appears to be programmed during spermatogenesis to function in a legacy dependent manner during embryogenesis.
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&NA;. "ABT 627." Drugs in R & D 2, no. 1 (February 1999): 17–18. http://dx.doi.org/10.2165/00126839-199902010-00003.
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&NA;. "ABT-594." Inpharma Weekly &NA;, no. 1121 (January 1998): 10. http://dx.doi.org/10.2165/00128413-199811210-00018.
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&NA;. "ABT-418." Inpharma Weekly &NA;, no. 953 (September 1994): 10. http://dx.doi.org/10.2165/00128413-199409530-00017.
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Fromtling, R. A., and J. Castañer. "ABT-719." Drugs of the Future 20, no. 11 (1995): 1103. http://dx.doi.org/10.1358/dof.1995.020.11.324524.
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Merlos, M., A. Graul, and J. Castañer. "ABT-431." Drugs of the Future 22, no. 8 (1997): 821. http://dx.doi.org/10.1358/dof.1997.022.08.416901.
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Sorbera, L. A., X. Rabasseda, and J. Castañer. "ABT-773." Drugs of the Future 25, no. 5 (2000): 445. http://dx.doi.org/10.1358/dof.2000.025.05.576864.
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Sorbera, L. A., L. Revel, P. Leeson, and J. Castañer. "ABT-594." Drugs of the Future 26, no. 10 (2001): 927. http://dx.doi.org/10.1358/dof.2001.026.10.640317.
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Mealy, N. E., and J. Castañer. "ABT-492." Drugs of the Future 27, no. 11 (2002): 1033. http://dx.doi.org/10.1358/dof.2002.027.11.707859.
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Sorbera, L. A., and M. Bayés. "ABT-510." Drugs of the Future 30, no. 11 (2005): 1081. http://dx.doi.org/10.1358/dof.2005.030.11.949588.
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Wang, Y., R. Castañer, and J. Bolós. "ABT-263." Drugs of the Future 33, no. 10 (2008): 829. http://dx.doi.org/10.1358/dof.2008.33.10.1265203.
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Bordin, JO, L. Bardossy, and MA Blajchman. "Growth enhancement of established tumors by allogeneic blood transfusion in experimental animals and its amelioration by leukodepletion: the importance of the timing of the leukodepletion." Blood 84, no. 1 (July 1, 1994): 344–48. http://dx.doi.org/10.1182/blood.v84.1.344.344.
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Abstract We had reported previously (Blood 81:1880, 1993) that allogeneic blood transfusions (ABT) administered before the infusion of tumor cells in both inbred and outbred experimental animals promote tumor growth and that this effect can be ameliorated by leukodepletion. To better reproduce the human situation, we evaluated, in this present study, the effect of ABT in animals with established tumors using enumeration of pulmonary metastatic nodules as the end point. The role of allogeneic blood component transfusions in promoting tumor growth and the relative efficacy of prestorage versus poststorage leukodepletion of the ABT in preventing tumor growth enhancement were also evaluated. In an inbred murine animal model, C57Bl/6J mice were administered nonleukodepleted allogeneic (ABT), leukodepleted allogeneic (LD-ABT), or syngeneic (SBT) blood transfusions after the intravenous infusion of syngeneic methylcholanthrene-induced fibrosarcoma cells using two different protocols. A significant increase in the number of pulmonary nodules was observed in those mice that received ABT, in both protocols, compared to animals transfused with SBT or LD-ABT. Significantly higher numbers of pulmonary nodules were also seen in mice transfused with allogeneic buffy-coat leukocytes compared with mice that received either nonleukodepleted allogeneic plasma or LD-ABT. In an outbred animal (rabbit) model, recipient rabbits were administered either nonleukodepleted ABT, prestorage LD-ABT, poststorage LD-ABT, or SBT on days +4 and +9 after the infusion of syngeneic epithelial tumor cells. A significant increase in the number of pulmonary nodules was seen in rabbits that received nonleukodepleted ABT compared to animals transfused with SBT. Significantly lower numbers of pulmonary nodules were observed in rabbits that received prestorage LD-ABT compared to animals transfused with poststorage LD-ABT, but no significant difference was seen in rabbits that received poststorage LD-ABT compared with animals transfused with nonleukodepleted ABT. These studies show that ABT promote tumor growth of established animal tumors, that the ABT-induced tumor growth effect is related to the presence of donor allogeneic leukocytes, and that this effect can be ameliorated by prestorage leukodepletion. The present results also provide evidence for the lack of efficacy of poststorage leukodepletion in preventing ABT tumor growth promotion.(ABSTRACT TRUNCATED AT 400 WORDS).
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Bordin, JO, L. Bardossy, and MA Blajchman. "Growth enhancement of established tumors by allogeneic blood transfusion in experimental animals and its amelioration by leukodepletion: the importance of the timing of the leukodepletion." Blood 84, no. 1 (July 1, 1994): 344–48. http://dx.doi.org/10.1182/blood.v84.1.344.bloodjournal841344.
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We had reported previously (Blood 81:1880, 1993) that allogeneic blood transfusions (ABT) administered before the infusion of tumor cells in both inbred and outbred experimental animals promote tumor growth and that this effect can be ameliorated by leukodepletion. To better reproduce the human situation, we evaluated, in this present study, the effect of ABT in animals with established tumors using enumeration of pulmonary metastatic nodules as the end point. The role of allogeneic blood component transfusions in promoting tumor growth and the relative efficacy of prestorage versus poststorage leukodepletion of the ABT in preventing tumor growth enhancement were also evaluated. In an inbred murine animal model, C57Bl/6J mice were administered nonleukodepleted allogeneic (ABT), leukodepleted allogeneic (LD-ABT), or syngeneic (SBT) blood transfusions after the intravenous infusion of syngeneic methylcholanthrene-induced fibrosarcoma cells using two different protocols. A significant increase in the number of pulmonary nodules was observed in those mice that received ABT, in both protocols, compared to animals transfused with SBT or LD-ABT. Significantly higher numbers of pulmonary nodules were also seen in mice transfused with allogeneic buffy-coat leukocytes compared with mice that received either nonleukodepleted allogeneic plasma or LD-ABT. In an outbred animal (rabbit) model, recipient rabbits were administered either nonleukodepleted ABT, prestorage LD-ABT, poststorage LD-ABT, or SBT on days +4 and +9 after the infusion of syngeneic epithelial tumor cells. A significant increase in the number of pulmonary nodules was seen in rabbits that received nonleukodepleted ABT compared to animals transfused with SBT. Significantly lower numbers of pulmonary nodules were observed in rabbits that received prestorage LD-ABT compared to animals transfused with poststorage LD-ABT, but no significant difference was seen in rabbits that received poststorage LD-ABT compared with animals transfused with nonleukodepleted ABT. These studies show that ABT promote tumor growth of established animal tumors, that the ABT-induced tumor growth effect is related to the presence of donor allogeneic leukocytes, and that this effect can be ameliorated by prestorage leukodepletion. The present results also provide evidence for the lack of efficacy of poststorage leukodepletion in preventing ABT tumor growth promotion.(ABSTRACT TRUNCATED AT 400 WORDS).
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Touzeau, Cyrille, Carole Brosseau, Christelle Dousset, Catherine Pellat-Deceunynck, Steven Le Gouill, and Martine Amiot. "Mantle-Cell Lymphoma (MCL) Cells Are Highly Sensitive To ABT-199 But Their Sensitivity May Be Altered By The Microenvironment Via The Up-Regulation Of Bcl-Xl and Bcl2A1." Blood 122, no. 21 (November 15, 2013): 4285. http://dx.doi.org/10.1182/blood.v122.21.4285.4285.
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Abstract Despite improvement in the treatment of Mantle-cell lymphoma (MCL), relapse invariably occurs and innovative strategies are needed. Bcl-2 inhibitors such as ABT-737 and ABT-263 (navitoclax), which target both Bcl-2 and Bcl-xL, demonstrated antitumor activity in B-cell malignancies. However, the clinical development of navitoclax is limited by a deep thrombocytopenia, which is induced by inhibition of Bcl-xL in platelets. To overcome this toxicity, ABT-199, the first-in-class orally bioavailable Bcl-2-selective BH3 mimetic, has been developed and showed promising antitumor activity in B-cell lymphoma while sparing platelets. In the present study, the apoptotic efficiency of ABT-199 in comparison with that of ABT-737 was evaluated in seven MCL cell lines. We found two MCL cell lines sensitive to ABT-199 (LD50 of 100 and 200 nM), one intermediate (LD50 of 1000nM) and 4 resistant (LD50 from 5000 to 10000 nM). Surprisingly, LD50 values of the 2 sensitive cell lines (MINO, GRANTA-519) were slightly higher for ABT-199 than for ABT-737. We further demonstrated that the Bcl-2/Mcl-1 ratio determined by RT-PCR is a predictive biomarker for ABT-199 sensitivity. To further determine the role of Mcl-1 in ABT-199 resistance, Mcl-1 siRNA were transfected in Z-138 and JEKO-1 cells. Mcl-1 silencing sensitized these 2 cell lines to low dose ABT-199 confirming the importance of Mcl-1 in ABT-199 resistance as previously shown for ABT-737. Moreover, in Z-138 cells, which highly express Bcl-xL, we showed that Bcl-xL silencing sensitized them to ABT-199. These results show that in addition to Mcl-1, Bcl-xL might also confer resistance to ABT-199-induced apoptosis in MCL. This could explain the slight difference of sensitivity of MCL cells between ABT-199 and ABT-737. In contrast to MCL cell lines, we found so far that ABT-199 efficiency killed all tested circulating primary cells from MCL patients (n=7) with LD50 values inferior to 10 nM. Because MCL cells reside mainly in lymph nodes, we wondered whether mimicking the microenvironment could impact the sensitivity of MCL cells to BH3 mimetics like it was previously demonstrated for chronic lymphoid leukemia cells. Thus, the ABT-199 sensitive MINO and GRANTA-519 cells were cultured on CD40L-expressing fibroblasts L in order to mimic the lymph node microenvironment. Both cell lines and primary cells became resistant to ABT-199 within 24h. Investigation of the underlying mechanism revealed a strong up-regulation of both Bcl-xL and Bcl2A1 protein expression. By contrast, culture of MCL cells with parental CD40L- fibroblasts or in conditioned medium from CD40L+ L fibroblasts culture failed to induce ABT-199 resistance. These results highlight the implication of the CD40L pathway in ABT-199 resistance through the up-regulation of Bcl-xL and Bcl2A1 in MCL. In conclusion, while circulating primary MCL cells are highly sensitive to ABT-199, it would be important to address the impact of microenvironment on long-term survival of MCL cells within lymph nodes under ABT-199 treatment. Disclosures: No relevant conflicts of interest to declare.
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Pai, Suresh R., Kavindra V. Singh, and Barbara E. Murray. "In Vivo Efficacy of the Ketolide ABT-773 (Cethromycin) against Enterococci in a Mouse Peritonitis Model." Antimicrobial Agents and Chemotherapy 47, no. 8 (August 2003): 2706–9. http://dx.doi.org/10.1128/aac.47.8.2706-2709.2003.
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ABSTRACT Using six Enterococcus faecalis and five Enterococcus faecium strains, the ketolide ABT-773 (ABT), now known as cethromycin, was found to have in vivo efficacy against both erythromycin (ERY)-susceptible (Erys) and -intermediate (Eryi) enterococci (ABT 50% protective doses [PD50s], 0.5 to 4.1 and 10.3 to 16.2 mg/kg of body weight, respectively). Against four highly Ery-resistant (Eryr) strains for which ABT MICs were low, ABT showed much greater activity (PD50, 6.3 to 32.5 mg/kg) than ERY (PD50, >200 mg/kg) but was not protective for strains for which ABT MICs were high. In conclusion, ABT-773 showed in vivo efficacy and considerably greater activity than ERY in a mouse peritonitis model.
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Gan, Hui Kong, Matthew E. Burge, Benjamin J. Solomon, Kyle D. Holen, Yumin Zhang, Marika Ciprotti, Thomas Merdan, et al. "A phase I and biodistribution study of ABT-806i, an 111indium-labeled conjugate of the tumor-specific anti-EGFR antibody ABT-806." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 2520. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.2520.
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2520 Background: ABT-806 is a humanized antibody targeting a conformationally exposed epitope only available when tumor Epidermal Growth Factor Receptor (EGFR) is overexpressed or (EGFRvIII) mutated. A prior trial treated 8 patients (pts) with a chimeric homologue (single-dose 5-40 mg/kg), with a minor response in one squamous cell carcinoma of skin pt. A prior phase 1A study of ABT-806 treated 26 pts (2-24 mg/kg IV q2w), with prolonged SD in one head and neck (H&N) cancer pt. No pt had a typical EGFR-inhibitor rash. The current study gathers further ABT-806 clinical data, assesses ABT-806i dosimetry in normal and malignant tissues and examines its relationship to clinical and PK/PD data. Methods: Pts with advanced tumors likely to express EGFR, ECOG 0-2, measurable disease and adequate organ function were enrolled. ABT-806i scans comprised ABT-806i 5-7mCi injection followed by whole body and regional SPECT scans over one week. Cohort (C) 1 pts (n=6) had ABT-806i scans alone. C2 pts (n=12) had ABT-806i scans at baseline and at week 6 (after 3 fortnightly doses of ABT-806; 6 pts at 18 mg/kg and 6 at 24 mg/kg). Subjects with PR/SD could receive ABT-806 on an extension study until progression. Results: 18 pts (M:F 11:7; median age 57 yrs) with tumors of H&N (6), colon (3), lung (2), brain (2), bladder (1), cervical (1) and other (3) were treated. An H&N pt had a confirmed PR whilst 5 pts had SD (lasting 37 and 24 wks in an adrenal carcinoma and H&N pt respectively). Two potential toxicities were seen at 24mg/kg on the extension study: equivocal rash (G1; three transient lesions on nose) and allergic reaction (Sweet’s syndrome, G2). Dosimetry in C1 pts confirmed safe radiation exposure levels to normal tissues. Many pts showed high, specific tumor uptake of ABT-806i, including 1 pt with an intracranial tumor. ABT-806i uptake was not significantly affected by concurrent ABT-806 treatment. Ongoing analyses of how ABT-806i uptake correlates with tumor EGFR and clinical response may inform the recommended phase 2 dose of ABT-806. Conclusions: The high therapeutic index and specificity of ABT-806 merits further investigation as monotherapy or an antibody-drug conjugate. ABT-806i may have utility as a bioimaging agent. Clinical trial information: NCT01472003.
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Hsin, I.-Lun, Ying-Hsiang Chou, Wei-Li Hung, Jiunn-Liang Ko, and Po-Hui Wang. "The Application of Arsenic Trioxide in Ameliorating ABT-737 Target Therapy on Uterine Cervical Cancer Cells through Unique Pathways in Cell Death." Cancers 12, no. 1 (December 31, 2019): 108. http://dx.doi.org/10.3390/cancers12010108.
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ABT-737, a B cell lymphoma-2 (Bcl-2) family inhibitor, activates apoptosis in cancer cells. Arsenic trioxide is an apoptosis activator that impairs cancer cell survival. The aim of this study was to evaluate the effect of a combination treatment with ABT-737 and arsenic trioxide on uterine cervical cancer cells. MTT (3-(4,5-dimethylthiazol-2-yl)-25-diphenyltetrazolium bromide) assay revealed that ABT-737 and arsenic trioxide induced a synergistic effect on uterine cervical cancer cells. Arsenic trioxide enhanced ABT-737-induced apoptosis and caspase-7 activation and the ABT-737-mediated reduction of anti-apoptotic protein Mcl-1 in Caski cells. Western blot assay revealed that arsenic trioxide promoted the ABT-737-mediated reduction of CDK6 and thymidylate synthetase in Caski cells. Arsenic trioxide promoted ABT-737-inhibited mitochondrial membrane potential and ABT-737-inhibited ANT expression in Caski cells. However, ABT-737-elicited reactive oxygen species were not enhanced by arsenic trioxide. The combined treatment induced an anti-apoptosis autophagy in SiHa cells. This study is the first to demonstrate that a combination treatment with ABT-737 and arsenic trioxide induces a synergistic effect on uterine cervical cancer cells through apoptosis. Our findings provide new insights into uterine cervical cancer treatment.
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Wang, Li, Zhou, Gao, Liu, Li, Niu, et al. "Association of Twelve Candidate Gene Polymorphisms with the Intramuscular Fat Content and Average Backfat Thickness of Chinese Suhuai Pigs." Animals 9, no. 11 (October 23, 2019): 858. http://dx.doi.org/10.3390/ani9110858.
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The present study aimed to identify the molecular markers for genes that influence intramuscular fat content (IFC), but not average backfat thickness (ABT). A total of 330 Suhuai pigs were slaughtered, and measurements of IFC and ABT were obtained. Phenotypic and genetic correlations between IFC and ABT were calculated. Thirteen single nucleotide polymorphisms (SNPs) among 12 candidate genes for IFC were analyzed, including FABP3, LIPE, IGF1, IGF2, LEP, LEPR, MC4R, PHKG1, RETN, RYR1, SCD, and UBE3C. Associations of the evaluated SNPs with IFCIFC and ABT were performed. Our results showed that the means of IFC and ABT were 1.99 ± 0.03 % and 26.68 ± 0.28 mm, respectively. The coefficients of variation (CVs) of IFC and ABT were 31.21% and 19.36%, respectively. The phenotypic and genetic correlations between IFC and ABT were moderate. Only the FABP3 (rs1110770079) was associated with IFC (p < 0.05) but not with ABT. Besides, there was a tendency for associations of RYR1 (rs344435545) and SCD (rs80912566) with IFC (p < 0.1). Our results indicated that the FABP3 (rs1110770079) SNP could be used as a marker to improve IFC without changing ABT in the Suhuai pig breeding system.
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Chauhan, Dharminder, Mohan Brahmandam, Teru Hideshima, Klaus Podar, Nikhil Munshi, Noopur Raje, and Kenneth C. Anderson. "Bcl-2, Mcl-1 and p53 Expression Confer Sensitivity to Bcl-2 Inhibitor ABT-737 in Multiple Myeloma." Blood 108, no. 11 (November 16, 2006): 3474. http://dx.doi.org/10.1182/blood.v108.11.3474.3474.
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Abstract Bcl-2 family of proteins confers resistance to chemotherapy in multiple myeloma (MM). Identification of BH3-mimetic drugs that inactivate pro-survival targets by interfering with the interaction of Bcl-2 proteins may therefore be therapeutically useful. A recent study identify ABT-737, a potent small-molecule inhibitor of anti-apoptotic proteins Bcl-2, Bcl-xL, and Bcl-w with an affinity 2–3 orders of magnitude more potent than any previously reported compounds (Nature2005, 435:672–681). Here we show that ABT-737 triggers apoptosis in MM cells resistant to conventional therapies. The functional specificity of ABT-737 binding to Bcl-2 or Bcl-xL was confirmed by using the less active enantiomer of ABT-737, which had no significant effect on viability of cells, even at higher concentration. Washout experiments show that exposure of MM cells to ABT-737 for 3h is sufficient to cause an early and irreversible commitment to cell death. Given that ABT-737 binds Bcl-2, Bcl-xL, and Bcl-w with high affinity but has far lower affinity for Mcl-1, we asked whether the anti-MM activity of ABT-737 is regulated by the relative expression of Bcl-2, Bcl-xL, or Mcl-1. For these studies, we selected MM.1S (sensitive to ABT-737: IC50-2 μM) and OPM-1 (least sensitive to ABT-737; IC50: 10–15 μM) and examined the basal expression levels of Bcl-2, Bcl-xL, and Mcl-1. MM.1S cells, in contrast to OPM-1 cells, express high basal levels of both Bcl-2 and Bcl-xL, but low Mcl-1 protein; conversely, OPM-1 cells express high Mcl-1 and low Bcl-2 levels. Since ABT-737 cannot neutralize Mcl-1, it is likely that the high Mcl-1 and low Bcl-2/Bcl-xL expression profile in OPM-1 renders these cells less sensitive to ABT-737; whereas low Mcl-1 and high Bcl-2/Bcl-xL expression in MM.1S cells allows for efficient killing by ABT-737. Importantly, treatment of MM.1S MM cells with ABT-737 and proteasome inhibitor Bortezomib induces additive cytotoxicity (combination index = 1.0). The mechanism underlying additive anti-MM activity of ABT-737 with Bortezomib includes downregulation of Mcl-1 along with targeting Bcl-2. Our findings have clinical implications: Bortezomib is FDA approved for the treatment of MM, but prolonged treatment can be associated with toxicity (Chauhan et al. Cancer Cell2005, 8:407–419); importantly, combining ABT-737 with Bortezomib would allow for the use of lower doses of Bortezomib. Another mechanism whereby MM cells evades the cytotoxic effects of chemotherapy is via p53 mutations. Bcl-2 is linked to p53-mediated signaling, and we therefore examined whether ABT-737 is able to overcome the tumorigenic effects conferred via p53 mutations. Co-precipitations experiments show that MM.1S cells (ABT-737-sensitive) predominantly carry wild type p53, whereas OPM-1 cell line (less sensitive to ABT-737) has mutant p53. Taken together, these finding suggest that 1) sensitivity to ABT-737 correlates with Bcl-2 expression in MM cells, 2) higher expression of Mcl-1 reduces sensitivity to ABT-737 whereas other anti-MM agents that block Mcl-1 may synergize with ABT-737, and 3) ABT-737 induces apoptosis in MM with p53 (wt) or p53 (mt), albeit with differential sensitivity. A report that ABT-737 enhances the apoptotic activity of chemotherapeutic agents (Olterdorf et al. Nature2005, 435:672–681), together with our present findings, provides the framework for clinical trials of ABT-737, either alone or in combination with other anti-MM agents, to enhance efficacy, reduce toxicity, and overcome drug resistance in MM patients.
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Vogler, Meike, Aneela Majid, Renata Walewska, Martin J. S. Dyer, and Gerald M. Cohen. "Marked Sensitivity of Chronic Lymphocytic Leukemia (CLL) to Apoptosis Induced by BCL2 Antagonist ABT-737." Blood 110, no. 11 (November 16, 2007): 3105. http://dx.doi.org/10.1182/blood.v110.11.3105.3105.
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Abstract Most cases of CLL express BCL2 constitutively at levels comparable to those seen in follicular lymphoma with t(14;18)(q32;q21) and BCL2 is considered to play a pivotal role in the suppression of apoptosis in this disease. The BCL2 antagonist ABT-263 has recently entered phase I/IIa clinical trials for potential treatment of CLL. ABT-263 and ABT-737 are rationally designed BH3 mimetics that are thought to act by displacing pro-apoptotic BIM from BCL2 and thus activating the apoptotic cascade. While being resistant towards some commonly used apoptotic stimuli like etoposide or TRAIL, we found that all primary CLL cells are highly and rapidly sensitive to ABT-737, with an average EC50 in 60 patients of only 6.7 nM and after only 4 h of treatment. ABT-737 induced BAX/BAK oligomerization followed by rapid and extensive cytochrome c release, caspase activation and chromatin condensation. Incubating unfractionated samples in a whole blood assay did not significantly alter sensitivity. Notably, sensitivity of CLL cells to ABT-737 was independent of the patient’s stage of disease, p53 mutation or function, cytogenetics, or IGVH mutational status. Furthermore, ABT-737-induced apoptosis was observed irrespective of previous treatment or in vivo resistance to fludarabine, suggesting that ABT-737 might induce apoptosis even in patients with highly progressive and otherwise resistant disease. We also analyzed expression levels of BCL2 and MCL1 in CLL patients by western blot, since MCL1 is considered to be the most important factor for resistance towards ABT-737. Interestingly, sensitivity to ABT-737 was independent of BCL2 and MCL1 levels in CLL, indicating that expression of MCL1 was not sufficient to render CLL resistant to ABT-737. In addition, we further induced expression of MCL1 by either IL4 or interferon γ treatment, which resulted only in a minor delay of apoptosis that was easily overcome by treatment with slightly higher concentrations of ABT-737. Hence, our data suggest that in contrast to previous reports obtained in a variety of cell lines, MCL1 upregulation is not sufficient to induce resistance to ABT-737 in primary CLL cells. Next, we investigated whether exposure to ABT-737 resulted in a displacement of BH3-only proteins from BCL2. Surprisingly, we could not detect a significant displacement of BIM from BCL2. In contrast, we found that the multidomain proapoptotic protein BAK is directly bound to BCL2 in CLL and this interaction is abrogated by ABT-737, indicating that ABT-737 can directly displace BAK but not BIM from BCL2. Taken together, our results indicate that targeting BCL2 with ABT-263 or ABT-737 may be a highly promising strategy for treatment of CLL.
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Pan, Rongqing, LaKeisha Debose, Juliana M. Benito, Leonard S. Golfman, Patrick A. Zweidler-McKay, Lina Han, Karine G. Harutyunyan, et al. "BCL-2-Selective BH3 Mimetic ABT-199 Is a Potent Agent For Acute Myeloid Leukemia." Blood 122, no. 21 (November 15, 2013): 1456. http://dx.doi.org/10.1182/blood.v122.21.1456.1456.
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Abstract Evasion of apoptosis is a key hallmark of cancer. BCL-2 family proteins, the central regulators of apoptosis, are often aberrantly expressed in tumors. Pro-apoptotic BCL-2 members bind and sequester anti-apoptotic BCL-2 proteins via their BH3 domains. Thus, BH3 mimetics represent a promising direction in cancer drug development. ABT-263, designed as a BH3 mimetic to inhibit BCL-2, BCL-XL, and BCL-W, has demonstrated efficacy in preclinical and clinical studies. However, thrombocytopenia is common in patients treated with ABT-263 due to the inhibition of BCL-XL, which is indispensable for platelet survival. ABT-199 (GDC-0199), a second-generation BH3 mimetic, has higher affinities for BCL-2 protein (Ki < 0.01 nM), which enhances the specificity of this agent to kill cancer cells without provoking unwanted thrombocytopenia (Souers, et al, Nature Med, 2013). Since BCL-2 is often overexpressed in hematological malignancies including acute myeloid leukemia (AML), we evaluated the anti-cancer effects of ABT-199 on AML cells. As a measure of BCL-2 specificity, BCL-XL overexpression in sensitive HL-60 cells resulted in complete resistance to ABT-199, while BCL-2 overexpression in these cells conferred moderate resistance to apoptosis induction. Moreover, OCI-AML3 cells with high MCL-1 levels were highly resistant to ABT-199, while knockdown of this protein greatly sensitized cells to this BH3 mimetic. Among 12 genetically diverse AML cell lines tested, seven were sensitive to ABT-199-induced apoptosis with 48-h EC50 ranging from 1.5 nM to 145 nM. In these seven sensitive, BCL-2 dependent cell lines, ABT-199 was uniformly more potent than ABT-737 (another BCL-2 inhibitor with a spectrum similar to ABT-263, p = 0.016). Next, we tested ABT-199 in 15 primary samples from relapsed/refractory AML patients. Twelve patient samples showed high sensitivity to apoptosis induction following 48-h exposure to ABT-199 (EC50 < 10 nM). In a larger set of 23 cryopreserved AML patient samples, including AML cells with diploid cytogenetics and mutations in FLT3, NRAS, and NPM1 genes, 18 (78%) were sensitive to ABT-199 (100 nM). However, samples from patients with complex cytogenetics, t(8;21) and JAK2 mutation (n = 12) were largely insensitive to ABT-199 (17% response rate). Interestingly, in five of six primary AML samples with high blast counts, ABT-199 induced marked apoptosis in CD34+/CD38- AML stem/progenitor cells compared to bulk AML blasts (p = 0.01). Quantitative Western blot was used to determine BCL-2 protein levels in AML cell lines. Spearman analysis showed that EC50 of ABT-199 correlated negatively with BCL-2 protein expression (r = -0.605, p = 0.0143) and correlated positively with BCL-XL protein expression (r = 0.633, p = 0.0101). Similar correlations were also observed in primary AML samples, suggesting that pre-treatment cellular BCL-2 and BCL-XL levels might have utility as predictive markers of ABT-199 sensitivity. We next examined the in vivo anti-leukemic efficacy of ABT-199 in NOD SCID gamma (NSG) mice injected with luciferase-labeled MOLM-13 cells. The mice were treated with ABT-199 by daily oral gavage (a 2-wk treatment at dose of 100 mg/kg). Bioluminescence imaging showed that ABT-199 treatment significantly inhibited leukemia burden, which was also manifested by smaller spleen size and prolonged overall survival (p = 0.0004) when compared to the vehicle-treated mice. Furthermore, a 2-wk ABT-199 treatment significantly reduced leukemia burden (> 50%) in bone marrows of NSG mice engrafted with primary FLT3-mutated AML cells (i.e., a mean of 70 ± 16% human CD45+ cells in bone marrow of control mice (n = 9) versus 32.7 ± 12% in ABT-treated mice (n = 11), p = 0.00002). Conclusions: the in vitro and in vivo efficacy data indicates that ABT-199 is a selective BCL-2 inhibitor, a potent apoptogenic agent, and hence a promising candidate for AML BCL-2-targeted therapy. Disclosures: Leverson: AbbVie, Inc.: Employment, Equity Ownership. Konopleva:AbbVie: Research Funding.
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Zhou, J., M. Pan, S. Loh, Z. Xie, Y. Lim, M. Lilly, K. Glaser, D. Albert, S. Davidsen, and C. S. Chen. "ABT-869, a novel multi-target receptor tyrosine kinase inhibitor (RTKI), combined with chemotherapy is synergistic in the therapy of acute myeloid leukemia cells with FLT3-ITD mutation (FLT3-AML)." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 13064. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.13064.
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13064 Background: Internal tandem duplications (ITDs) of fms-like tyrosine kinase 3 (FLT3) receptor are identified in 20–25% of adult AML patients associated with poor prognosis. ABT-869 is active in FLT3-AML and is currently under clinical investigaton. We hypothesize that the combination of ABT-869 with chemotherapy can improve the therapeutic index in FLT3-AML. Methods: Using Calcusyn software, the additive, synergistic or antagonistic effect of ABT-869 with concurrent or sequential cytosine arabinoside (Ara-C) or doxorubicin (Dox) was measured in MV4–11 and MOLM-14 cells. The synergistic combination sequence was further tested in a MV4–11 xenograft model in four groups (10 mice/group) including control, Ara-C, ABT-869, and combination (Ara-C first for 4 days, then daily ABT-869). Cell cycle analysis and apoptosis and signal pathway assays were performed in vitro and in vivo. Results: ABT-869 induced dose- and time-dependent apoptosis on FLT3-AML cells resulting in down regulation of p-FLT3, p-STAT5, Bcl-XL and up regulation of p53 and BID. ABT-869 caused G1-phase arrest and the removal of cells in the S- and G2/M-phase mediated by reduction of cyclins D and E. We observed significant synergistic effect with Ara-C or Dox first, followed by ABT-869, as well as in concurrent treatment with ABT-869 and Dox. Simultaneous treatment with ABT-869 and Ara-C only achieved additive effect. Conversely, we found an antagonistic effect in the sequence of pretreatment of ABT-869 followed by chemotherapy. In a MV4–11 xenograft model, all mice succumbed to leukemia in the control and Ara-C groups (median survival = 53 and 55.5 days respectively). Combination therapy gave a faster reduction of tumor volume compared to ABT-869 treatment alone (p=0.03) without recurrence of leukemia in either group by day 67. In vivo immunohistochemistry (IHC) analysis revealed ABT-869 potently inhibited VEGF and phosphor-ERK. Conclusions: ABT-869 can be given after Ara-C or Dox to act synergistically. Our study suggests that combinations of RTKIs with chemotherapy should be carefully tested prior to clinical protocol development. A clinical trial of such combination therapy in FLT3-AML is warranted. No significant financial relationships to disclose.
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Bodo, Juraj, Xiaoxian Zhao, Mitchell R. Smith, and Eric D. Hsi. "Activity of ABT-199 and Acquired Resistance in Follicular Lymphoma Cells." Blood 124, no. 21 (December 6, 2014): 3635. http://dx.doi.org/10.1182/blood.v124.21.3635.3635.
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Abstract ABT-199, a platelet-sparing pro-apoptotic BH3 mimetic shows promise in the treatment of B-cell malignancy such as chronic lymphocytic leukemia (CLL). Given the central role of BCL2 expression in follicular lymphoma (FL), we studied the effects of ABT-199 on proliferation, induction of apoptosis, and signaling pathways in the t(14;18)+ FL cell lines WSU-FSCCL and FC-TxFL2 and in primary FL cells. We also developed an ABT-199-resistant FC-TxFL2 cell line by continuous treatment with ABT-199. The growth of tested cell lines and primary FL cells was significantly inhibited with nanomolar concentrations of ABT-199. FC-TxFL2 cells (IC50 = 7 nM) were more sensitive to ABT-199 treatment than WSU-FSCCL cells (IC50 = 110 nM). The increased sensitivity was associated with higher levels of BIM pro-apoptotic protein. ABT-199 induced rapid phosphorylation of JNK kinase and substantial decrease of mitochondrial potential in FC-TxFL2 cells. Inhibition of JNK activation further augmented the apoptosis induced with ABT-199. All other tested anti-apoptotic (such as BCL-2, BCL-xL, MCL-1) and pro-apoptotic proteins (such as Bax, Puma, Bak, Bad, Noxa, Bid, Bok) were similarly expressed in both cell lines and did not change upon ABT-199 treatment. Surprisingly, cleavage of Bid was observed, which points also to activation of extrinsic apoptotic pathway. In cells with acquired resistance after continuous ABT-199 exposure, we identified increased levels of MCL-1, and elevated phosphorylation of BCL-2 on T56 and of AKT on S473, but also evidence for increased autophagy, as assessed by LC3BI/II expression, compared to parental cells. These cells remained resistant several weeks after omitting ABT-199 from culture medium. In a FL murine xenograft model, ABT-199 showed anti-tumor activity. Treatment significantly decreased tumors volumes compared to untreated mice. Subsequently isolated xenograft FC-TxFL2 cells previously exposed to ABT-199 showed increased resistance to ABT-199. However, unlike in vitro exposed cells, the resistance quickly diminished after cultivation without ABT-199. Next, the ability to overcome ABT-199 resistance with epigenetic modifiers such as decitabine and vorinostat was tested. A strong synergistic effect in potentiation of apoptosis with these therapeutics was observed. Despite the theoretic rationale for BH3 mimetic activity in FL, activity in patients with FL has not been as dramatic as has been observed for CLL. Relatively easily acquired resistance observed in our model may explain this failure. Therefore, combinations that can prevent resistance acquisition should be intensively studied and moved quickly to clinical trials. Disclosures Smith: Abbvie: Research Funding.
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Sham, Hing L., Dale J. Kempf, Akhteruzammen Molla, Kennan C. Marsh, Gondi N. Kumar, Chih-Ming Chen, Warren Kati, et al. "ABT-378, a Highly Potent Inhibitor of the Human Immunodeficiency Virus Protease." Antimicrobial Agents and Chemotherapy 42, no. 12 (December 1, 1998): 3218–24. http://dx.doi.org/10.1128/aac.42.12.3218.
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ABSTRACT The valine at position 82 (Val 82) in the active site of the human immunodeficiency virus (HIV) protease mutates in response to therapy with the protease inhibitor ritonavir. By using the X-ray crystal structure of the complex of HIV protease and ritonavir, the potent protease inhibitor ABT-378, which has a diminished interaction with Val 82, was designed. ABT-378 potently inhibited wild-type and mutant HIV protease (Ki = 1.3 to 3.6 pM), blocked the replication of laboratory and clinical strains of HIV type 1 (50% effective concentration [EC50], 0.006 to 0.017 μM), and maintained high potency against mutant HIV selected by ritonavir in vivo (EC50, ≤0.06 μM). The metabolism of ABT-378 was strongly inhibited by ritonavir in vitro. Consequently, following concomitant oral administration of ABT-378 and ritonavir, the concentrations of ABT-378 in rat, dog, and monkey plasma exceeded the in vitro antiviral EC50 in the presence of human serum by >50-fold after 8 h. In healthy human volunteers, coadministration of a single 400-mg dose of ABT-378 with 50 mg of ritonavir enhanced the area under the concentration curve of ABT-378 in plasma by 77-fold over that observed after dosing with ABT-378 alone, and mean concentrations of ABT-378 exceeded the EC50 for >24 h. These results demonstrate the potential utility of ABT-378 as a therapeutic intervention against AIDS.
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Xie, Xiaoyun, Zongyang Yu, Aiwen Huang, Guoxiang Lai, Deling Liu, and Shumei Zou. "Role of Smooth Muscle Cells Regulated by Vitamin D in Bronchial Asthma Airway Remodeling and Efficacy of Nanomedicine on Bronchial Asthma." Journal of Biomedical Nanotechnology 18, no. 7 (July 1, 2022): 1837–43. http://dx.doi.org/10.1166/jbn.2022.3387.
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This study aimed to analyze the therapeutic effect of nanomedicine on bronchial asthma and the effect of vitamin 1,25-(OH)2D3 on airway remodeling. The four groups of Z1 (1,25-(OH)2D3+RNPEG-ABT-199), Z2 (RNPEG-ABT-199), Z3 (ABT-199), and Z4 (normal Control) were designed in this study. The prepared acid-responsive mitochondrial targeting nanomedicine (RNPEG-ABT-199) and non-responsive mitochondrial targeting nanomedicine (PEG-ABT-199) were applied to the treatment of asthma mouse models. The results showed the PU value of caspase-3 in Z4 was lower than Z1, Z2, and Z3 groups; and in Z3 was higher than Z1 and Z2 groups. IL-4, IL-5, and TNF-α levels in Z3 were obviously higher than Z1, Z2, and Z4 groups, while those in the Z1 were obviously lower than the Z2 and Z4 groups; the proliferation activity of airway smooth muscle cells (ASMCs) of Z3 was obviously higher than the Z1, Z2, and Z4 groups, and that of the Z1 was obviously lower than the Z2 group. In short, RNPEG-ABT-199 has stronger lysosomal escape ability and mitochondrial targeting than PEG-ABT-199. RNPEG-ABT-199 can cause apoptosis of inflammatory cells and decrease pro-inflammatory cytokines, which is better than PEG-ABT-199. Vitamin1,25-(OH)2D3 can obviously inhibit the proliferation activity of ASMCs cells, and be used in the treatment of asthma along with RNPEG-ABT-199.
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Vollmer, Timothy L., Daniel R. Wynn, M. Shamsul Alam, and Joaquin Valdes. "A phase 2, 24-week, randomized, placebo-controlled, double-blind study examining the efficacy and safety of an anti-interleukin-12 and -23 monoclonal antibody in patients with relapsing–remitting or secondary progressive multiple sclerosis." Multiple Sclerosis Journal 17, no. 2 (December 6, 2010): 181–91. http://dx.doi.org/10.1177/1352458510384496.
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Background: Interleukins 12 and 23 (IL-12/23) have been implicated in multiple sclerosis (MS) pathogenesis. This study assessed the efficacy and safety of ABT-874, a monoclonal anti-IL-12/23 antibody, in active relapsing–remitting MS (RRMS) or secondary progressive MS (SPMS). Methods: In this 24-week study, patients with RRMS or SPMS received ABT-874 200 mg every other week (EOW), ABT-874 200 mg every week (EW), or placebo. The cumulative number of gadolinium-enhanced lesions, relapse rate, disability progression, and adverse events were measured. Results: 215 patients were randomized (ABT-874 200 mg EOW, N = 76; ABT-874 200 mg EW, N = 70; placebo, N = 69). At week 24, gadolinium-enhanced lesions were statistically significantly reduced with ABT-874 200 mg EOW vs. placebo (mean number [SD]: 5.4 [8.1] vs. 7.6 [14.4], p = 0.003), but not with ABT-874 200 mg EW (6.8 [11.3], p = 0.134). Mean relapse rate (relapses/y) was significantly lower for ABT-874 200 mg EW vs. placebo (0.1 [95% CI −0.0, 0.3] vs. 0.5 [0.2, 0.8], p = 0.007). Changes from baseline in disability scores and incidences of adverse events were not significantly different across treatment groups, although a numerically greater percentage of serious adverse events was reported for ABT-874 treatment groups. Conclusions: Although rates of adverse events were not significantly different between ABT-874 treatment groups and placebo, the magnitude of ABT-874 efficacy was less than that observed with other agents currently in development for MS treatment. Anti-IL-12/23 monotherapy does not appear to warrant further testing as monotherapy treatment for MS.
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Grobman, Arnold, and Hulda Grobman. "ABT Authors Praised." American Biology Teacher 57, no. 3 (March 1, 1995): 133. http://dx.doi.org/10.2307/4449946.
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Wiedemann, H. R. "Isaac Arthur Abt." European Journal of Pediatrics 152, no. 3 (March 1993): 177. http://dx.doi.org/10.1007/bf01956138.
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Ko, Tun Kiat, Charles Chuah, John Huang, King-Pan Ng, and S. Tiong Ong. "The BCL-2 Inhibitor ABT-199 Enhances Imatinib-Induced Cell Death In Chronic Phase CML Progenitors." Blood 122, no. 21 (November 15, 2013): 3978. http://dx.doi.org/10.1182/blood.v122.21.3978.3978.
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Abstract The advent of tyrosine kinase inhibitors (TKI) that specifically target BCR-ABL has significantly prolonged the life of patients with CML. We and others have previously shown that the BH3 mimetic ABT-737 or its clinical equivalent, ABT-263, can significantly enhance TKI-induced cell death in both CML cell lines and primary cells (Ng et al. Nature Medicine, 18: 521-528, 2012). ABT-737 and ABT-263 are BH3 mimetics that have broad specificity against anti-apoptosis regulators such as BCL-2 and its related proteins (BCL-XL & BCL-W). However, in clinical trials employing ABT-263, a dose-limiting toxicity is thrombocytopenia. This is due to the inhibitory effect of ABT-263 on BCL-XL that is pivotal for platelet survival. As a result, a new BH3 mimetic, ABT-199, has been developed that binds with high affinity to BCL-2 but not BCL-XL, and thus does not harm platelets. Here, we evaluated the effectiveness of ABT-199, as a single agent or in combination with imatinib, in reducing the viability of CD34+ cells from the different phases of CML (chronic, accelerated and blast). We also assessed the cytotoxic effect of ABT-199 on normal cord blood CD34+ cells. The number of samples used in this study was: (1) chronic phase CML (CP, n=4), (2) accelerated phase CML (AP, n=2), (3) blast phase CML (BP, n=1), and (4) normal cord blood (NCB, n=3). We evaluated the viability of progenitor cells by colony formation assay. A broad concentration range of ABT-199 (in nM: 0, 1, 2, 5, 10, 20, 50, 100, 200, 500, 2000) was used in this study. The concentration of imatinib used was 2uM, which is in line with the plasma concentrations achievable in most patients with CML. Below are three tables that summarize the results obtained from this study.Table 1Treatment with 2uM imatinib only.CP (n=4)AP & BC (n=3)NCB (n=3)Average CFU reduction65%23%20%(Relative to DMSO control)Table 2Treatment with ABT-199 only: concentration required to achieve the following CFU reduction.Average CFU reductionCP (n=4)AP & BC (n=3)NCB (n=3)50%500nM2000nM10nM90%2000nMNot achieved within the concentration range used500nMTable 3Combined treatment with ABT-199 and 2uM imatinib (IM): concentration required to achieve the following CFU reduction.Average CFU reductionCP (n=4)AP & BC (n=3)NCB (n=3)50%Not achieved within the concentration range used2nM ABT-199 + 2uM IM10nM ABT-199 + 2uM IM90%10nM ABT-199 + 2uM IM200nM ABT-199 + 2uM IM100nM ABT-199 + 2uM IM In summary, we found that: (1) Compared to CML, NCB progenitors were very sensitive to ABT-199, with a reduction of average cell viability to 50% at just 10nM (with or without imatinib); (2) When the dose-limiting cytotoxic effect of ABT-199 on NCB was taken into consideration, we were able to discover an ABT-199 concentration (10nM) that significantly enhanced imatinib-induced cell death of CP CML progenitors without causing NCB viability to fall below 50%; and (3) The inferior efficacy of the combination on AP/BC vs CP progenitors suggests that BCL2-independent mechanisms contribute to the survival of advanced phase CML progenitors. Finally, our in vitro data may also explain some of the adverse hematologic effects observed in clinical trials that employ ABT-199, including neutropenia and thrombocytopenia. Nevertheless, our data suggest that ABT-199, when used at a concentration that is not cytotoxic to normal progenitors and in combination with imatinib, can be beneficial in treating patients with chronic phase CML. Disclosures: Chuah: Novartis: Honoraria; Bristol-Myers Squibb: Honoraria.
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Bojarczuk, Kamil, Binu K. Sasi, Stefania Gobessi, Idanna Innocenti, Luca Laurenti, and Dimitar G. Efremov. "Inhibition of SYK More Effectively Overcomes MCL-1 Mediated ABT-199 Resistance of BCR-Stimulated CLL Cells Than Inhibition of BTK or PI3Kdelta." Blood 126, no. 23 (December 3, 2015): 489. http://dx.doi.org/10.1182/blood.v126.23.489.489.
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Abstract The selective Bcl-2 antagonist ABT-199 has demonstrated promising clinical activity in patients with CLL. This drug is strongly cytotoxic against unstimulated peripheral blood CLL cells in vitro, but is much less effective against CLL cells that have received signals mimicking interactions with the lymph node microenvironment. In particular, stimulation of peripheral blood CLL cells with CD40L and IL-4 results in substantial resistance, which is mediated by induction of the antiapoptotic Bcl-2 family proteins Bcl-XL and Bfl-1. In the present study, we investigated whether resistance to ABT-199 can be conferred by engagement of the BCR, which is another stimulus that CLL cells receive primarily in the lymph nodes. Sustained engagement of the BCR with immobilized anti-IgM antibody, which is commonly used as a surrogate for a membrane-bound antigen, significantly protected CLL cells from ABT-199-mediated apoptosis (n=28; % viable CLL cells after 24 hours in culture without ABT-199: 52.2±14.8; with 2nM ABT-199: 28.3±15.1, with 2nM ABT-199 and immobilized anti-IgM: 43.0±19.5, P <0.001). Resistance of BCR-stimulated CLL cells from ABT-199 mediated apoptosis directly correlated with induction of the antiapoptotic Bcl-2 family protein Mcl-1 (n=14, Pearson correlation coefficient 0.675, P =0.008), whereas no significant changes were observed in the levels of Bcl-XL, Bcl-2 and Bim. Downregulation of Mcl-1 by RNA interference completely reversed resistance of anti-IgM stimulated CLL cells to ABT-199, suggesting that induction of this antiapoptotic protein is primarily responsible for BCR-mediated protection (n=5; % viable after nucleofection with control siRNA: 39.0±15.9; control siRNA and ABT-199: 14.2±4.1; control siRNA, ABT-199 and anti-IgM: 27.4±13.9; Mcl-1 siRNA, ABT-199 and anti-IgM: 14.6 ±6.0; P =0.022 for the comparison between the last two conditions). In line with this possibility, nucleofection of primary CLL cells with in vitro -transcribed Mcl-1 mRNA resulted in almost complete protection from ABT-199 induced apoptosis (n=3, % viable cells after nucleofection with control mRNA: 47.0±12.7; control mRNA and ABT-199: 27.5±16.2; Mcl-1 mRNA and ABT-199: 46.5±6.0). To investigate whether clinically tested BCR pathway inhibitors can prevent anti-IgM-mediated Mcl-1 induction and consequent ABT-199 resistance, we pretreated CLL cells with the SYK inhibitors R406 and GS-9973, the BTK inhibitor ibrutinib or the PI3Kδ inhibitor idelalisib (all used at 1μM concentration) and evaluated changes in Mcl-1 expression. Although all four inhibitors reduced Mcl-1 expression in anti-IgM stimulated CLL cells, the effect of SYK inhibitors was considerably more profound. In addition, only SYK inhibitors were capable of reducing Mcl-1 expression below basal levels. To understand the reasons for the greater activity of SYK inhibitors, we compared the capacity of R406, GS-9973, ibrutinib and idelalisib to inhibit the kinases AKT and GSK3, which are both important regulators of Mcl-1. Activated AKT increases Mcl-1 expression through post-transcriptional mechanisms, whereas activated GSK3 downregulates Mcl-1 by targeting it for proteasomal degradation. All four BCR pathway inhibitors efficiently blocked anti-IgM induced activation of AKT, but BCR-induced phosphorylation and inactivation of GSK3 was blocked only by R406 and GS-9973. These data suggest that all four drugs can prevent de novo Mcl-1 synthesis, but only SYK inhibitors can increase the rate of Mcl-1 turnover. The capacity of SYK inhibitors to overcome BCR-mediated ABT-199 resistance was further confirmed by investigating the viability of anti-IgM stimulated CLL cells (n=22) cultured in the presence or absence of ABT-199, R406 and GS-9973. Both R406 and GS-9973 significantly reduced protection of anti-IgM-stimulated CLL cells from ABT-199-induced apoptosis (ABT-199 and anti-IgM: 52.0±14.0; ABT-199, anti-IgM and R406: 41.7±12.0; ABT-199, anti-IgM and GS-9973: 43.5±13.5, P <0.001). In conclusion, these data demonstrate that BCR signals induce resistance of CLL cells to ABT-199 by upregulating Mcl-1. Resistance to ABT-199 can be effectively overcome by SYK inhibitors, which target Mcl-1 by preventing AKT activation and GSK3 inactivation. Altogether, these data suggest that SYK inhibitors should be the most appropriate BCR pathway inhibitors to test in combination with ABT-199 in the clinic. Disclosures No relevant conflicts of interest to declare.
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Lever, John R., and Emily A. Fergason-Cantrell. "Allosteric modulation of sigma receptors by BH3 mimetics ABT-737, ABT-263 (Navitoclax) and ABT-199 (Venetoclax)." Pharmacological Research 142 (April 2019): 87–100. http://dx.doi.org/10.1016/j.phrs.2019.01.040.
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Müller, Bernd. "Energie gepaart mit Emotionen." VDI-Z 162, no. 07-08 (2020): 54–55. http://dx.doi.org/10.37544/0042-1766-2020-07-08-54.
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Audi Sport ABT Schaeffler ist in der sechsten Saison wieder einer der Titelfavoriten in der ABB FIA Formel-E-Meisterschaft – dies auch dank der Technologiepartnerschaft mit Zeiss. Die erste rein elektrische Rennserie der Welt stellt ganz neue Anforderungen an die Messtechnik.
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Musselman, Kristin E., Kristen Walden, Vanessa K. Noonan, Hope Jervis-Rademeyer, Nancy Thorogood, Laurent Bouyer, Brian Chan, et al. "Development of priorities for a Canadian strategy to advance activity-based therapies after spinal cord injury." Spinal Cord 59, no. 8 (June 7, 2021): 874–84. http://dx.doi.org/10.1038/s41393-021-00644-2.
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Abstract Study Design Participatory design. Objectives Activity-based therapies (ABT) have physical and psychosocial benefits for individuals with spinal cord injury (SCI). A Canadian ABT summit was held to: (1) identify methods used in stroke rehabilitation that may be appropriate for SCI; (2) understand the current state of ABT activities in Canada; and (3) identify priorities for ABT research and care for the next five years. Setting Stakeholder-engaged meeting at a tertiary rehabilitation hospital. Methods Thirty-nine stakeholders, including individuals with SCI, frontline clinicians, healthcare administrators, researchers, funders and health policy experts, attended. Two participants were note-takers. Priority identification occurred through input from stakeholder groups, followed by individual voting. Conventional content analysis was used to synthesize the information in the meeting notes. Results The strengths of ABT in stroke rehabilitation included clear and clinically feasible definitions, measurements and interventions, and recognized requirements for implementation (e.g. behavior change, partnerships). Knowledge gaps concerning ABT activities in Canada were identified for acute and community settings, non-traumatic populations, and the interventions, equipment and standardized measures (i.e. upper limb, activity levels) used. Five priorities for ABT across the continuum of care were identified: (1) Identify current ABT activities; (2) Create a network to facilitate dialog; (3) Track engagement in ABT activities; (4) Develop and implement best practice recommendations; and (5) Study optimal timing, methods, and dose of ABT. Working groups were formed to address priorities 1–3. Conclusions The priorities will guide SCI research and care activities in Canada over the next five years. Sponsorship Praxis Spinal Cord Institute.
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Joyce, D. E., G. Mulji, L. S. Gutierrez, and F. J. Castellino. "Evaluation of the thrombospondin-1 analogue ABT-510 in the APCMin/+ mouse intestinal adenoma model." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 13545. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.13545.
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13545 Background: The extracellular matrix protein Thrombospondin-1 (TSP-1) affects the angiogenic balance in cancer to suppress tumor growth. Exogenous TSP-1 or the peptide derivative ABT-510 (Abbott, Chicago, IL) can reverse this angiogenic switch from adenoma to carcinoma. We evaluated treatment effects of ABT-510 in the APCMin/+ mouse spontaneous intestinal adenoma model. This study determined reduction in intestinal adenoma number after ABT-510 or the combined treatment of ABT-510/bevacizumab (Genentech) compared to no treatment in APCMin/+. Proliferation, vascularity, and dysplasia were also compared. Methods: 90 day old APCMin/+ mice (familial adenomatous polyposis, 5q21 termination), Jackson Laboratory (Bar Harbor, ME)) received drug for three weeks: 1.) ABT-510, 60 mg/Kg/day s.c. pump for 2 weeks then i.p. daily for the last 7 days, 2.) Anti-VEGF antibody bevacizumab 10 mg/Kg i.p. twice per week in combination with ABT-510, and 3.) untreated controls. After 21 days mice were sacrificed, intestines harvested and adenomas enumerated. Immunohistochemistry (PCNA, vWF/CD31) was performed. Studies were IACUC approved. Wilcoxon signed-rank test was used to compare results. Results: Twenty one mice were evaluated with no adverse effects. Comparisons were made to untreated APCMin/+ controls. Untreated controls (N=7) demonstrated a mean of 7.7±1.25 polyps. ABT-510 treated APCMin/+ (N=8) demonstrated a mean of 3.4±1.8 polyps, significantly different from controls (p<0.004). Combined bevacizumab and ABT-510 treatment demonstrated a mean of 4.7 ±3.0 polyps (p<0.008). There was no significant difference between the ABT-510 and combined ABT-510/bevacizumab treated groups. Immunohistochemistry for tumor vascularity (anti-CD31/anti-vWF) and for proliferation (PCNA) demonstrated enhanced vascular and PCNA staining in polyps, but no differences were detected in tumor dysplasia or immunohistochemistry compared across control and treatment groups. Conclusions: Significant reduction in APCMin/+ polyp number was seen with ABT-510 and the combination ABT-510/bevacizumab treatment groups compared to untreated controls. Tumor-specific vascularity and proliferation was characteristically no different across control and treated groups. [Table: see text]
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McCarthy, Aine, Vincent Yeung, John G. Gribben, and Li Jia. "Inhibition of Autophagy by Chloroquine Sensitises Lymphoma Cells to ABT-737-Induced Apoptosis." Blood 120, no. 21 (November 16, 2012): 1625. http://dx.doi.org/10.1182/blood.v120.21.1625.1625.
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Abstract Abstract 1625 Diffuse large B-cell lymphoma (DLBCL) is characterised by overexpression of the anti-apoptotic protein Bcl-2. It has been recently observed that Bcl-2 also inhibits autophagy by binding and sequestering Beclin-1, an essential autophagy protein, but it is unclear whether Bcl-2 inhibits both apoptosis and autophagy in DLBCL cells. We aimed to determine the dual role of Bcl-2 in both apoptosis and autophagy in Bcl-2 positive cell lines (Su-DHL4 and CRL) and Bcl-2 negative cell lines (Su-DHL8 and Su-DHL10) using the BH3 mimetic compound ABT-737. The sensitivity of Bcl-2 positive and Bcl-2 negative cell lines to ABT-737-mediated mitochondrial depolarization (ΔΨmLOW) and cell death (DAPI positive) was assessed by flow cytometry. Treatment of the Bcl-2 positive cell lines Su-DHL4 and CRL with ABT-737 significantly increased (p<0.01) the percentage of both ΔΨmLOW cells, indicating mitochondrial damage as well as DAPI positive cells indicating cell death. Treatment with ABT-737 increased Bax activation and PARP cleavage in Bcl-2 positive cells, indicating that as expected, ABT-737-induced cell death is via apoptosis. ABT-737-induced cell death was not detected in Bcl-2 negative cell lines Su-DHL8 and Su-DHL10, demonstrating that, as expected, the sensitivity of DLBCL cell lines to ABT-737-induced apoptosis is Bcl-2 dependent. Treatment of Bcl-2 positive cells with ABT-737 also resulted in a decreased cellular co-localisation of Bcl-2 and Beclin-1 as detected by immunofluorescent staining. Degradation of p62 and LC3-II, selective substrates of autophagy, was detected by Western blotting in Bcl-2 positive but not in Bcl-2 negative cell lines after treatment with ABT-737 for 15 hours. LC3-I is a diffuse cytoplasmic protein which upon activation of autophagy becomes cleaved and lipidated to LC3-II which becomes punctate within cells. Punctuate LC3-II is a widely used marker of active autophagy. ABT-737-induced autophagosome formation was determined at an earlier time point (3 hours after ABT-737 treatment) using immune-fluorescent microscopy. ABT-737 induced increased numbers of larger punctate LC3-II in Bcl-2 positive Su-DHL4 and CRL cell lines but not in Bcl-2 negative cells, indicating that inhibition of Bcl-2 induces autophagy in Bcl-2 positive cells. We then determined whether autophagy affects ABT-737-induced apoptosis by blocking autophagy using an autophagy inhibitor chloroquine (CQ). Co-treatment with ABT-737 and CQ resulted in an increase in the percentage of ΔΨmLOW cells, DAPI positive cells and PARP cleavage compared to cells treated with ABT-737 alone in Bcl-2 positive cell lines. Combined, these results indicate that inhibition of autophagy by chloroquine further sensitises Bcl-2 positive cells to ABT-737-induced apoptosis. In summary, our results indicate that Bcl-2 inhibits autophagy in lymphoma cells by sequestering Beclin-1. Disruption of this interaction by ABT-737 induces autophagy which in turn inhibits apoptosis. Inhibition of autophagy results in increased sensitivity of Bcl-2 positive cells to ABT-737-induced apoptosis, suggesting a role for autophagy inhibitors in lymphoma treatment. Disclosures: No relevant conflicts of interest to declare.
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Thijssen, Rachel, Christian R. Geest, Martin FM de Rooij, Nora Liu, Bogdan I. Florea, Katinka Weller, Hermen S. Overkleeft, et al. "Possible Mechanisms Of Resistance To The Novel BH3-Mimetic ABT-199 In In Vitro Lymph Node Models Of CLL – The Role Of Abl and Btk." Blood 122, no. 21 (November 15, 2013): 4188. http://dx.doi.org/10.1182/blood.v122.21.4188.4188.
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Abstract The new BH3-mimetic ABT-199 antagonizes Bcl-2 and avoids the thrombocytopenia associated with clinical application of its predecessor ABT-263 (navitoclax). Chronic lymphocytic leukemia (CLL) cells are highly sensitive to ABT-199 and the first clinical results show clear reductions in peripheral and bone marrow CLL cells and in lymph node size. In the lymph node, CLL cells receive pro-survival signals that upregulate Bcl-XL, Mcl-1 and Bfl-11. These Bcl-2 family members are not targeted by ABT-199, which poses the potential risk of remaining clones with residual viability. Here, we aimed to define the signals that determine sensitivity for ABT-199 and ABT-737 in an in vitro lymph node model of CLL. We applied CD40 and cytokine stimulation in combination with kinase inhibitors that are known to change microenviroenmental signals and increase drug resistance in CLL. Stimulation via CD40 plus IL-4 or IL-21 differentially affected the expression of Mcl-1, Bcl-XL, Bfl-1 and Noxa and this correlated with strong alterations in sensitivity to ABT-737 and ABT-199 (see table 1 for LC 50 values). As reported before2, in vitro CD40 stimulation reduced sensitivity to ABT-737 by 100-fold, and this was further decreased by IL-4. Strikingly, CD40+IL-4 stimulation in primary CLL cells resulted in full resistance to 10 μM ABT-199, probably due to very high levels of Bcl-XL.Table 1The LC50 of ABT-737 or ABT-199 for CLL cells stimulated with CD40L and IL-21 or IL-4 (averaged values n=8)StimulationLC50 (μM)ABT-737ABT-1993T3 (control)0.0050.0013T40L0.781> 103T40L + IL-210.1950.210 3T40L + IL-46.772> 103T40L + IL-21 + IL-40.4269.121 We next sought ways to circumvent resistance against ABT-199 induced in our in vitro model. We showed previously that the broad spectrum kinase inhibitor dasatinib prevented CD40-mediated resistance to various drugs, including ABT-7373. We therefore first characterized the targets of dasatinib in primary CLL by solid-phase pull-down, mass-spectrometry and competition binding. Abl and Btk were identified as dominant and specific interactors of dasatinib. Importantly, resistance for BH3-mimetics could be overcome by dasatinib (see table 2) and the Abl inhibitor imatinib, but not by the more selective Btk inhibitor ibrutinib. Conversely, BCR- and chemokine-controlled adhesion could be abolished by dasatinib and ibrutinib, but not by imatinib. Thus, Abl and Btk function in two key pro-survival arms; chemoresistance and localization in the protective environment.Table 2The LC50 of ABT-737 or ABT-199 for CLL cells stimulated with CD40L in combination with Dasatinib (averaged values n=4)StimulationLC50 (μM)ABT-737ABT-1993T30.0050.0013T40L0.781> 103T40L + 100 nM Dasatinib0.0810.066 3T40L + 1000 nM Dasatinib0.0370.020 The observed resistance to ABT-199 induced in our in vitro a co-culture system designed to simulate the CLL microenvironment does not reflect the observations from clinical trials in patients. Nevertheless, long-term clinical application of ABT-199 in CLL might select for resistant clones at protective niches. Our data suggest that this may be overcome by combination treatment with kinase inhibitors that either directly abrogate anti-apoptotic signals or cause egress from lymph node sites and prevent the resistance mechanism from coming into play. 1. Smit LA, Hallaert DY, Spijker R et al. Differential Noxa/Mcl-1 balance in peripheral versus lymph node chronic lymphocitic leukemia cells correlates with survival capacity. Blood 2007;109:1660-1668. 2. Vogler M, Butterworth M, Majid A et al. Concurrent up-regulation of BCL-XL and BCL2A1 induces approximately 1000-fold resistance to ABT-737 in chronic lymphocytic leukemia. Blood 2009;113:4403-4413. 3. Hallaert DY, Jaspers A, van Noesel CJ et al. c-Abl kinase inhibitors overcome CD40-mediated drug resistance in CLL; Implications for therapeutic targeting of chemoresistant niches. Blood 2008;112:5141-5149. Disclosures: No relevant conflicts of interest to declare.
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Konopleva, Marina, Juliana M. Benito, Karine G. Harutyunyan, Isabel Marzo, LaKiesha Debose, Oscar Gonzalo, Ping Zhou, et al. "Acute Lymphoblastic Leukemia Is a Bcl-2 Dependent Disease: Proteomic Profiling and Pre-Clinical Efficacy Of a Selective Bcl-2 Antagonist ABT-199." Blood 122, no. 21 (November 15, 2013): 3919. http://dx.doi.org/10.1182/blood.v122.21.3919.3919.
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Abstract The expression of Bcl-2 family proteins is perturbed in multiple types of cancers, including leukemias, and is associated with disease progression and resistance to chemotherapy. ABT-199 (GDC-0199) is a new BH3 mimetic that was developed to specifically target Bcl-2 while sparing Bcl-XL, hence avoiding thrombocytopenia intrinsic to 1st generation BH3 mimetics like ABT-737 (Souers et al., Nat Med, 2013). In this study, we report proteomic profiling of Bcl-2 family members in a large series of ALL patients (pts) and pre-clinical activity of ABT-199. Expression of 20 pro- and anti-apoptotic proteins was studied in 186 newly diagnosed ALL using reverse phase protein arrays (RPPA). Supervised clustering demonstrated distinct differences in 11 proteins in ALL with different cytogenetic and FAB characteristics (Fig. 1, p<0.005, false discovery rate <0.2%). Among these, pts with Burkitt's leukemia/lymphoma (n=9) expressed low levels of Bcl-2 and Bax while maintaining high expression of Bim, caspases and PARP. In contrast, t(4;11) pts expressed higher levels of Bcl-2, Bax and Bim. No significant differences in Bcl-XL or Mcl-1 levels were found in different ALL subtypes. Figure 1 RPPA profiling of apoptosis regulators in ALL. Heatmap of differentially expressed proteins based on cytogenetics and immunophenotype. Black box, Burkitt's leukemia; red box, t(4;11). Figure 1. RPPA profiling of apoptosis regulators in ALL. Heatmap of differentially expressed proteins based on cytogenetics and immunophenotype. Black box, Burkitt's leukemia; red box, t(4;11). The potential of ABT-199 to disrupt interactions between Bcl-2 and different pro-apoptotic proteins was studied using Bimolecular Fluorescence Complementation (BiFC, J Biol Chem 288:4935, 2013). The coding sequences for human Bcl-2, Bim, Bak, Bax and Noxa were subcloned into BiFC plasmids containing Venus fragments and transfected into HeLa cells. Approximately 60-70% of transfected cells were positive for Venus fluorescence due to association between Bcl-2 and Bim, Noxa, Bax or Bak. ABT-199 (2.5 µM, 24 hrs) significantly reduced Venus signal, indicating an inhibition of the interactions of Bcl-2 with these proteins, most potently with the multidomain proteins Bax and Bak (95%±18% and 85%±15% inhibition, respectively). ABT-199 rapidly induced apoptotic cell death in ALL cell lines and in primary ALL samples. Pre-B ALL cells (Nalm-6, REH, SEMK2 and RS4;11) were sensitive to ABT-199 and ABT-737 (IC50 0.007-1.4µM (199) and 0.035-0.7µM (737)). Notably, ABT-199 was more cytotoxic than ABT-737 against MLL-rearranged SEMK2 and RS4;11 cells, consistent with the notion of the greater Bcl-2 dependency of these cells. Lentiviral silencing of Bcl-XL sensitized REH cells to apoptosis by ABT-199 and ABT-737. T-ALL cells (PF-382, MOLT-4, P-12) expressed lower levels of Bcl-2 and were uniformly less sensitive to ABT-199 compared to ABT-737 (IC50 3.7±1.1µM vs 0.7±0.3µM, p=0.01). Burkitt's lymphoma cells Ramos and Raji had low Bcl-2 and high Mcl-1 expression, and were resistant to both agents (IC50>4µM). Next, the cytotoxic activity of ABT-199 was tested against a panel of 12 genetically diverse primary ALL samples, including 6 from pts with relapsed or refractory disease. Ten out of twelve samples (83%) were exquisitely sensitive to both agents, with IC50 values of 0.0001-0.14µM for ABT-199 and 0.0004-0.3µM for ABT-737. One of the four Ph+ samples was resistant to both agents, and one of the two T-ALL was less sensitive to ABT-199 compared to ABT-737. Two samples with t(4;11) were highly sensitive to ABT-199. All primary ALL samples tested (n=7) expressed high levels of Bcl-2, and no significant correlation between sensitivity and expression of Bcl-2 family members was found. Importantly, three human-derived xenografts from pediatric pre-B-ALL samples (1345, 1809, 0398) were very sensitive to ABT-199 (IC50 3nM, 0.1nM and 2.3nM, respectively). Finally, anti-leukemia activity of ABT-199 was tested in MLL-rearranged patient-derived xenograft NSG mice. Treatment with ABT-199 at 100mg/kg/d by oral gavage days 13-23 significantly reduced leukemia tumor burden as determined by bioluminescence imaging (average 70% reduction in BLI signal in 4 ABT-treated mice compared to 4 control animals at 9 weeks, p=0.03). In summary, proteomic profiling and patterns of sensitivity to Bcl-2 inhibition indicate that ALL, with exception of Burkitt's lymphoma, represents a Bcl-2 dependent disease. These results provide strong rationale for introducing ABT-199, which recently showed impressive efficacy in CLL trials, into the clinical armamentarium of ALL therapy. Disclosures: Konopleva: AbbVie, Inc: Research Funding. Leverson:AbbVie, Inc.: Employment, Equity Ownership.
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Yao, Xiaoxiao, Xiaoning Li, Dan Zhang, Yingjun Xie, Baozhen Sun, Hang Li, Liankun Sun, and Xuewen Zhang. "B-cell lymphoma 2 inhibitor ABT-737 induces Beclin1- and reactive oxygen species-dependent autophagy in Adriamycin-resistant human hepatocellular carcinoma cells." Tumor Biology 39, no. 3 (March 2017): 101042831769596. http://dx.doi.org/10.1177/1010428317695965.
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ABT-737, a B-cell lymphoma 2 homology 3 mimetic, not only induces cell apoptosis by inhibiting the interaction of B-cell lymphoma 2 and Bax but also induces cell autophagy by interrupting the interaction of B-cell lymphoma 2 and Beclin1. Several recent studies have reported that ABT-737 has antitumor efficacy in diverse cancers. However, another study showed that hepatocellular carcinoma cells with high B-cell lymphoma 2 expression were resistant to ABT-737 compared to hepatocellular carcinoma cells with low B-cell lymphoma 2 expression. It was also found that ABT-737-induced autophagy is crucial for drug resistance. Here, we observed that of B-cell lymphoma 2 expression in Adriamycin-resistant human hepatocellular carcinoma HepG2/ADM cells is higher than that in human hepatocellular carcinoma HepG2 cells. Therefore, we further confirmed the mechanism and effect of autophagy induced by ABT-737 on apoptosis in HepG2/ADM cells with high B-cell lymphoma 2 expression. Our results showed that ABT-737 induced apoptosis and autophagy in time- and dose-dependent manner in HepG2/ADM cells, and this ABT-737-induced autophagy was Beclin1-dependent. In addition, we demonstrated that ABT-737 induced reactive oxygen species-mediated autophagy, and the reactive oxygen species-inhibitor N-acetyl-l-cysteine suppressed the reactive oxygen species-induced autophagy and ABT-737-induced increase in HepG2/ADM cell apoptosis. Furthermore, autophagy inhibitors increased HepG2/ADM cell apoptosis. In conclusion, our study further confirms that Beclin1- and reactive oxygen species-dependent autophagy induced by ABT-737 also plays a protective function in HepG2/ADM cells, which show B-cell lymphoma 2 expression higher than that in HepG2 cells.
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Horton, Thomas W., Barbara A. Block, Rachel Davies, Lucy A. Hawkes, Duncan Jones, Hannah Jones, Keith Leeves, et al. "Evidence of increased occurrence of Atlantic bluefin tuna in territorial waters of the United Kingdom and Ireland." ICES Journal of Marine Science 78, no. 5 (April 17, 2021): 1672–83. http://dx.doi.org/10.1093/icesjms/fsab039.
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Abstract Atlantic bluefin tuna (ABT, Thunnus thynnus; Linneaus, 1758) is an ecologically important apex-predator with high commercial value. They were once common off the coast of the United Kingdom (UK), before disappearing in the 1960s. In regions lacking commercial fisheries for ABT, such as the UK and Ireland, spatial data can be scarce. In these cases, sightings and bycatch databases can offset information shortfalls. Here, we document the reappearance of ABT into territorial waters of the UK from 2014 onwards, and increased occurrence off Ireland. We analyse a novel, multi-source dataset comprising occurrence data (2008–2019; 989 sightings and 114 tonnes of bycatch) compiled from a range of sources (scientific surveys, ecotours and fisheries). We show an increasing trend in effort-corrected ABT occurrence in (i) the pelagic ecosystem survey in the western English Channel and Celtic Sea (PELTIC), (ii) an ecotour operator, and (iii) the Irish albacore fishery in on-shelf and off-shelf waters. Sightings of ABT by the PELTIC correlated with modelled abundance estimates of ABT and the Atlantic multidecadal oscillation. These data demonstrate that sightings of ABT have increased off the UK and Ireland since 2014, following the same increasing trend (2010 onwards) as the eastern ABT population.
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Rybka, Vladyslava, Yuichiro Suzuki, and Nataliia Shults. "Effects of Bcl-2/Bcl-xL Inhibitors on Pulmonary Artery Smooth Muscle Cells." Antioxidants 7, no. 11 (October 26, 2018): 150. http://dx.doi.org/10.3390/antiox7110150.
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Pulmonary arterial hypertension (PAH) is a fatal disease without satisfactory therapeutic options. By the time patients are diagnosed with this disease, the remodeling of pulmonary arteries has already developed due to the abnormal growth of pulmonary vascular cells. Therefore, agents that reduce excess pulmonary vascular cells have therapeutic potential. Bcl-2 is known to function in an antioxidant pathway to prevent apoptosis. The present study examined the effects of inhibitors of the anti-apoptotic proteins Bcl-2 and Bcl-xL. ABT-263 (Navitoclax), ABT-199 (Venetoclax), ABT-737, and Obatoclax, which all promoted the death of cultured human pulmonary artery smooth muscle cells. Further examinations using ABT-263 showed that Bcl-2/Bcl-xL inhibition indeed promoted apoptotic programmed cell death. ABT-263-induced cell death was inhibited by antioxidants. ABT-263 also promoted autophagy; however, the inhibition of autophagy did not suppress ABT-263-induced cell death. This is in contrast to other previously studied drugs, including anthracyclines and proteasome inhibitors, which were found to mediate autophagy to induce cell death. The administration of ABT-263 to rats with PAH in vivo resulted in the reversal of pulmonary vascular remodeling. Thus, promoting apoptosis by inhibiting anti-apoptotic Bcl-2 and Bcl-xL effectively kills pulmonary vascular smooth muscle cells and reverses pulmonary vascular remodeling.
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Hogdal, Leah, Daniel J. DeAngelo, Richard M. Stone, Verena I. Gaidzik, Donna Bucci, Konstanze Döhner, Guido Marcucci, Jeremy Ryan, and Anthony Letai. "BH3 Profiling Predicts On-Target Cell Death Due To Selective Inhibition Of BCL-2 By ABT-199 In Acute Myelogenous Leukemia." Blood 122, no. 21 (November 15, 2013): 238. http://dx.doi.org/10.1182/blood.v122.21.238.238.
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Abstract Most patients with acute myeloid leukemia (AML) become resistant to chemotherapy at some point in their course and succumb to their disease. It is necessary to prevent chemo-resistance or enhance chemosensitivity in a selective fashion to lead to a higher cure rate and a lower toxic burden. The B-cell leukemia /lymphoma 2 (BCL-2) protein acts to prevent commitment to programmed cell death initiated in the mitochondrion. Inhibiting the function of this protein is an attractive approach to cancer therapy, but it remains a challenge to identify those tumors that will best be treated with such a strategy. Here, we test the sensitivity of AML cell lines and primary patient samples to the selective BCL-2 inhibitor, ABT-199, and test for correlation between ABT-199 sensitivity with BCL-2 dependence measured by BH3 profiling. We hypothesized that cells that are more dependent on BCL-2 will be more sensitive to inhibition by ABT-199. To this end, we tested the sensitivity of seven AML cell lines and 34 primary patient samples to ABT-199. We found that both cell lines and primary patient samples were sensitive to ABT-199 (Figure 1). In the case of primary patient cells, the median EC-50 was approximately 20 nM, and cell death could be seen within 2 hours. Importantly, we found that sensitivity to ABT-199 was independent of cytogenetics and NPM1 and FLT3 mutations of the primary patient cells suggesting that treatment with ABT-199 could be useful for a variety of AML patients, even those with an intrinsically poor prognosis. We also measured dependence on BCL-2-mediated apoptosis in cell lines and primary patient samples by BH3 profiling. BH3-profiling is a method to determine the mitochondrial priming level of a cell by exposing cellular mitochondria to standardized amounts of peptides derived from the BH3 domains of BH3-only proteins and determining the rate of cytochrome c release. BH3-profiling can also identify which anti-apoptotic species are critical in mediating cell death in a given cell type. For instance, the BAD BH3-only protein binds with high affinity to BCL-2, BCL-XL and BCL-W. Thus, release of cytochrome c following BAD peptide incubation suggests an anti-apoptotic dependency on BCL-2, BCL-XL or BCL-W. Therefore, we tested whether ABT-199 sensitivity correlates with functional dependence on BCL-2 in both cell lines and primary patient samples. We found that cells that released cytochrome c following incubation with the BAD peptide were more sensitive to ABT-199 treatment (Figure 2). This demonstrates that ABT-199 functions on target at the mitochondria since the ABT-199 mitochondrial activity correlates well with ABT-199 cytotoxicity data. Since ABT-199 does not inhibit MCL-1, increased expression of MCL-1 could be a potential source of upfront resistance to BCL-2 inhibition. Therefore, we asked if there was a correlation between MCL-1 dependence and ABT-199 sensitivity. We observed a weak anti-correlation between mitochondrial sensitivity to ABT-199 and sensitivity to the MCL-1 selective peptide NOXA BH3. This suggests that there is a minor tendency for MCL-1 dependent mitochondria to be less sensitive to ABT-199. The ex-vivo sensitivity of AML cells to ABT-199, which appears to be BCL-2 specific, is similar to that observed in CLL, a disease for which ABT-199 has demonstrated consistent activity in clinical trials. Moreover, the BH3 profiling studies demonstrate ABT-199 activity at the mitochondrion that correlates very well with cytotoxicity, supporting a mitochondrial mechanism of action. Our BH3 profiling studies will be undertaken to determine if the results will serve as a predictive biomarker in an upcoming phase II clinical trial of ABT-199 in AML. Disclosures: Letai: AbbVie: Consultancy; Dana-Farber Cancer Institute: Patents & Royalties.
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Shankar, Deepa B., Jenny C. Chang, Bertrand Parcells, Salemiz Sandoval, Junling Li, Ru-Qi Wei, Paul Tapang, et al. "The Multi-Targeted Receptor Tyrosine Kinase Inhibitor, ABT-869, Induces Apoptosis of AML Cells Both In Vitro and In Vivo." Blood 106, no. 11 (November 16, 2005): 616. http://dx.doi.org/10.1182/blood.v106.11.616.616.
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Abstract Children with acute myeloid leukemia (AML) have less than 60% overall survival despite aggressive chemotherapy and bone marrow transplantation. Only one third of the adult patients diagnosed with AML will be cured. AML blast cells from up to 30% of patients express a constitutively active receptor tyrosine kinase, FLT3-ITD, which contains an internal tandem duplication in the juxtamembrane domain. Patients with FLT3-ITD have a worse prognosis. ABT-869 is a novel multi-targeted small molecule inhibitor of receptor tyrosine kinases and is a potent inhibitor of FLT3, c-Kit, and all members of the VEGF and PDGF receptor families. To determine the effects of ABT-896 on AML cells, we treated AML cell lines, primary cells, and tumors in xenograft models with varying concentrations of the drug. In vitro viability assays showed that ABT-869 inhibited the growth of two different cell lines, MV-4-11 (human AML cell line that expresses FLT3-ITD) and BAF3-ITD (murine B-cell line stably transfected with the FLT3-ITD) at an IC50 of 10nM. ABT-869 was also effective against another mutation of FLT3, D835V, but at higher concentrations (IC50 of 100nM). Phosphorylation of FLT3 and activation of downstream signaling molecules, STAT5 and ERK, were inhibited by ABT-869 in a concentration-dependent manner. Cells were also stained with Annexin V-FITC and Propidium Iodide, and analyzed using FACS. ABT-869 induced apoptosis, caspase-3 activation, and PARP cleavage after 48 hours. To examine the in vitro effects of ABT-869 on normal hematopoietic progenitor cells, we performed methylcellulose-based colony assays with human bone marrow. No significant difference was observed in the number and type of colonies formed using BM cells treated with ABT-869 or control, up to a concentration of 1 micromolar. These results suggest that ABT-869 is not toxic to normal bone marrow progenitor cells at concentrations that are effective against AML cells. To examine the effects of ABT-869 in vivo, we treated SCID mice injected with MV-4-11, Baf3-ITD, Baf3-D835V, or Baf3-WT cells, with oral preparations of ABT-869. Complete regression of MV-4-11 tumors was observed in mice treated with ABT-869 at 20 and 40 mg/kg/day. No adverse effects were detected in the peripheral blood counts, bone marrow, spleen or liver. Histology of the tumors from the control-treated group showed a high degree of proliferation by Ki-67 staining, increased mitotic figures, and a well-defined tumor mass. In contrast, the tumors from mice treated with ABT-869 showed a number of apoptotic bodies by TUNEL staining and the presence of reactive, inflammatory cells. Interestingly, we also observed that mice that received ABT-869 the day after injection of AML cells remained tumor-free for over 2 months in contrast to the mice receiving the vehicle alone. Inhibition of FLT3 phosphorylation was demonstrated in the tumors from mice treated with ABT-869. We are evaluating the activity of ABT-869 treatment of SCID mice injected with Baf3-ITD, Baf3-D835V, or Baf3-WT cells. NOD-SCID mouse models are currently being used to analyze the effects of ABT-869 on primary AML cells in vivo. Our preclinical studies demonstrate that ABT-869 is effective and nontoxic, and provide rationale for the treatment and prevention of relapse in AML patients.
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Andreeff, Michael, Rooha Contractor, Peter P. Ruvolo, Xingming Deng, Ismael Samudio, Yue-Xi Shi, Teresa McQueen, et al. "Mechanisms of Apoptosis Induction by BH3 Inhibitor ABT-737 in AML." Blood 106, no. 11 (November 16, 2005): 244. http://dx.doi.org/10.1182/blood.v106.11.244.244.
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Abstract Bcl2 family proteins are key regulators of apoptosis. Aberrations in Bcl2 levels are known to promote tumorigenesis and chemoresistance. Thus, strategies to target Bcl2 will likely provide effective therapies for malignancies such as acute myeloid leukemia (AML). In this report, we investigate mechanisms of action of the novel small molecule Bcl2 inhibitor ABT-737 in AML. ABT-737 effectively killed AML patient blast cells and colony-forming cell lines at nanomolar concentrations with no effect on normal hematopoietic cells. Notably, CD34+38−123+ AML stem cells are highly sensitive to the compound. ABT-737-induced apoptosis is initiated by disruption of Bcl2:Bax dimers and activation of the intrinsic apoptotic pathway. ABT-737 works synergistically with chemotherapeutic agents such as ara-C and doxorubicin. To investigate the role of Bcl-2 phosphorylation in the sensitivity to BH3 inhibitor, we used IL-3 dependent NSF.N1/H7 mouse myeloid cells modified by site-directed mutagenesis to produce various Bcl-2 phospho-mutants. NSF.N1/H7 cells stably transfected with phosphomimetic T69E/S70E/S87E (EEE) Bcl-2 mutants were resistant to ABT-737 (IC50>500 nM) as compared to cells expressing wt-Bcl-2 or the nonphosphorylatable T69A/S70A/S87A (AAA) Bcl2 mutants (IC50s of 50 and 25 nM). Consistent with a mechanism whereby increased Bcl2 phosphorylation impedes ABT-737 suppression of Bcl2 dimerization with Bax, ABT-737 potently blocked Bcl2:Bax association in cells expressing exogenous WT Bcl2 and AAA mutant Bcl2 but not in cells expressing exogenous phosphomimetic EEE mutant Bcl2. Since the S70E phosphorylation site of Bcl-2 is a known ERK substrate, we examined combined effects of ABT-737 and MEK inhibitor PD98059 in OCI-AML3 cells resistant to ABT-737 alone. The combined activity of PD98059 and ABT-737, evaluated by isobologram analysis, revealed a striking synergistic interaction between the MEK and BH3 inhibitors, with combination indices (CI) of 0.08±0.003. OCI-AML3 cells exhibit the highest expression of Mcl-1 among the acute leukemia cell lines tested. We propose that loss of Mcl-1 expression as a result of suppression of ERK may also be involved in the ability of PD98059 to enhance ABT-737-induced apoptosis. siRNA to Mcl-1 strikingly sensitized OCI-AML3 cells to ABT-induced apoptosis (14% apoptosis in parental cells at 2.5μM ABT-737, 64% apoptosis in siRNA-transfected cells at 10-fold lower concentration of 0.25μM). We have further demonstrated that ABT-737 reduced leukemia burden and significantly (p=0.0018) prolonged survival of mice in an in vivo mouse model. These findings suggest that: 1) ABT-737 reduces apoptosis through disruption of Bcl2:Bax heterodimers; 2) its activity is limited by Bcl2 phosphorylation and Mcl-1 overexpression; 3) combination with MEK inhibition results in inhibition of Bcl2 phosphorylation, downregulation of Mcl-1 and dramatic enhancement of ABT-737-induced apoptosis in AML.
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Miegel, Annekathrin, and Philipp Lenz. "Rezension von: Lenz, Philipp, Reichsabtei und Klosterreform." Zeitschrift für Württembergische Landesgeschichte 75 (March 1, 2022): 474. http://dx.doi.org/10.53458/zwlg.v75i.2013.
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Philipp Lenz, Reichsabtei und Klosterreform – Das Kloster St. Gallen unter dem Pfleger und Abt Ulrich Rösch 1457 – 1491 (Monasterium Sancti Galli 6), St. Gallen: Verlag am Klosterhof 2014. 655 S., 16 s/w und farb. Abb. ISBN 978-3-905906-10-3. Geb. CHF 98.–
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Shoemaker, Alex R., Michael J. Mitten, Anatol Oleksijew, Jacqeuline M. O’Connor, Baole Wang, Scott Ackler, Mary Joseph, et al. "The Bcl-2 Family Inhibitor ABT-263 Shows Significant Anti-Tumor Efficacy in Models of B Cell Non-Hodgkin’s Lymphoma." Blood 108, no. 11 (November 16, 2006): 825. http://dx.doi.org/10.1182/blood.v108.11.825.825.
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Abstract ABT-263 is an orally bioavailable small molecule inhibitor of Bcl-2 family proteins with a Ki of ≤ 1 nM against Bcl-2, Bcl-XL, and Bcl-w. Non-Hodgkin’s B-cell lymphomas represent clinically relevant disease targets for this molecule due, in part, to strong expression of Bcl-2 often associated with various types of NHL (frequently involving a t(14;18) translocation including the Bcl-2 locus). ABT-263 exhibits sub-micromolar in vitro activity against a variety of NHL cell lines. DoHH-2 and WSU-DLCL2 are two B-cell NHL lines harboring the t(14;18) translocation that exhibit differential in vitro sensitivity to ABT-263. Granta-519 is a mantle cell lymphoma line with the characteristic t(11;14)(q13:q32) translocation resulting in overexpression of cyclin D1. ABT-263 has an EC50 of approximately 150 nM in the Granta-519 cell line. Here we present efficacy data evaluating the activity of ABT-263 in several NHL xenograft models. ABT-263 has significant in vivo anti-tumor efficacy in established flank tumor models both as monotherapy and in combination with cytotoxic agents. The efficacy of ABT-263 at 100 mg/kg/day, p.o., q.d. ×21 was evaluated as monotherapy and in combination with etoposide, vincristine, modified CHOP, R-CHOP, bortezomib, rapamycin, and rituximab. Results show that ABT-263 significantly inhibits tumor growth as a monotherapy (~50–60% tumor growth inhibition) and enhances the efficacy of these cytotoxic agents in combination therapy. Statistically significant enhancement of tumor growth inhibition was observed for each combination relative to monotherapy treatment. Efficacy was maintained even when therapy was initiated on larger (~500 mm3) tumors. Combinations of ABT-263 + rapamycin and ABT-263 + rituximab result in complete regression of a significant percentage of established B cell lymphoma tumors for a sustained period of time in vivo. The combination of ABT-263 + R-CHOP resulted in complete regression of 100% of the tumors in the mantle cell lymphoma model. The strong in vitro potency and tumor regressions seen in vivo suggest that ABT-263 has great potential for the oral treatment of NHL B-cell lymphomas.
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Li, J., X. Sha, and P. LoRusso. "Pharmacogenetics of a PARP inhibitor ABT-888 metabolic pathway." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): e14556-e14556. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e14556.
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e14556 Background: Poly(ADP-ribose) polymerase (PARP) is essential for single-stranded DNA break repair and repair of DNA damage can lead to radio- and chemo-resistance. Thus, inhibition of PARP activity can sensitize cells to cytotoxic therapies. ABT-888 is a potent, orally bioavailable PARP inhibitor. Preclinical studies suggest that ABT-888 potentiates multiple cytotoxic agents and its efficacy is correlated with plasma/tumor drug concentrations. The objective of this study was to determine the pharmacogenetic effect of genetic variants in the ABT-888 metabolic pathway, with the aim to better understand molecular basis of the variation in ABT-888 pharmacokinetics (PK) and therapeutic outcome. Methods: The major enzymes responsible for ABT-888 metabolism were identified by in vitro metabolism studies with specific recombinant human cytochrome P450 (CYP) enzymes. The functional significance of genetic variants of the identified enzymes was assessed by examining ABT-888 metabolic kinetics by candidate variant enzymes and microsomes. The association of the functional significant genetic variants with the PK and clinical outcome is being evaluated in the context of an ongoing phase I trial in which ABT-888 is administered in combination with irinotecan in patients with advanced solid tumors. Results: ABT-888 was metabolized predominantly by human CYP2D6, to a less extent by CYP1A1, and to a negligible extent by CYP1A2, 2C9, 2C19, 3A4, and 3A5. CYP2D6*10 exhibited markedly reduced catalytic capability in ABT-888 overall metabolism and the metabolite (A-925088) formation, with in vitro maximum clearance being 31% and 5.3%, respectively, of that estimated from the wild-type CYP2D6. In human liver microsomes carrying homozygous CYP2D6*4, the rates of parent drug disappearance and metabolite formation were significantly lower than those observed in the microsomes carrying wild-type CYP2D6, P < 0.05. Conclusions: CYP2D6 is the predominant enzyme responsible for the hepatic metabolism of ABT-888. Common allelic variants CYP2D6*10 and *4 are associated with significantly reduced metabolic activity towards ABT-888. CYP2D6 polymorphisms may influence the PK and therapeutic outcome of ABT-888. Its clinical relevance remains to be determined. No significant financial relationships to disclose.
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Wang, Youping, and Donna H. Wang. "Prevention of endothelin-1-induced increases in blood pressure: role of endogenous CGRP." American Journal of Physiology-Heart and Circulatory Physiology 287, no. 4 (October 2004): H1868—H1874. http://dx.doi.org/10.1152/ajpheart.00241.2004.
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To determine the role of endothelin-1 (ET-1) and its receptors in the regulation of calcitonin gene-related peptide (CGRP) release, male Wistar rats were divided into six groups and subjected to the following treatments for 1 wk with or without ABT-627 (an ETA receptor antagonist, 5 mg·kg−1·day−1 in drinking water) or A-192621 (an ETB-receptor antagonist, 30 mg·kg−1·day−1 by oral gavage): control (Con), ET-1 (5 ng·kg−1·min−1 iv), Con + ABT-627, Con + A-192621, ET-1 + ABT-627, and ET-1 + A-192621. Baseline mean arterial pressure (MAP, mmHg) was higher ( P < 0.05) in Con + A-192621 (122 ± 4) and ET-1 + A-192621 (119 ± 4) groups compared with Con (104 ± 6), ET1 (106 ± 3), Con + ABT-627 (104 ± 3), and ET1 + ABT-627 (100 ± 3) groups. Intravenous administration of CGRP8–37 (a CGRP receptor antagonist, 1 mg/kg) increased MAP ( P < 0.05) in ET-1 (13 ± 1), Con + A-192621 (12 ± 1), and ET-1 + A-192621 (15 ± 3) groups compared with Con (4 ± 1), Con-ABT-627 (4 ± 1), and ET-1 + ABT-627 (5 ± 1) groups. Plasma CGRP levels (in pg/ml) were increased ( P < 0.05) in ET-1 (57.5 ± 6.1), Con + A-192621 (53.9 ± 3.4), and ET-1 + A-192621 (60.4 ± 3.0) groups compared with Con (40.4 ± 1.6), Con + ABT-627 (40.0 ± 2.9), and ET-1 + ABT-627 (42.6 ± 1.9) groups. Plasma ET-1 levels (in pg/ml) were higher ( P < 0.05) in ET-1 (2.8 ± 0.2), ET-1 + ABT-627 (3.2 ± 0.4), Con + A-192621 (3.3 ± 0.4), and ET-1 + A-192621 (4.6 ± 0.3) groups compared with Con (1.1 ± 0.2) and Con-ABT-627 (1.3 ± 0.2) groups. Therefore, our data show that ET-1 infusion leads to increased CGRP release via activation of the ETA receptor, which plays a compensatory role in preventing ET-1-induced elevation in blood pressure.
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Temmoku, Jumpei, Masayuki Miyata, Eiji Suzuki, Yuya Sumichika, Kenji Saito, Shuhei Yoshida, Haruki Matsumoto, et al. "Comparing the effectiveness and safety of Abatacept and Tocilizumab in elderly patients with rheumatoid arthritis." PLOS ONE 17, no. 9 (September 19, 2022): e0274775. http://dx.doi.org/10.1371/journal.pone.0274775.
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Background The number of biological DMARDs (bDMARDs) used in elderly patients with rheumatoid arthritis (RA) has increased in recent years. We aimed to compare the drug retention rates and safety of abatacept (ABT) and tocilizumab (TCZ) in elderly patients with RA. Methods A total 125 elderly patients with RA (>65 years) who began therapy with either ABT (n = 47) or TCZ (n = 78) between 2014 and 2021 at our institute were enrolled. We compared the drug retention rate and clinical response at 24 weeks between elderly patients with RA treated with ABT and those treated with TCZ. Adverse events (AEs) and the reasons for drug discontinuation were assessed. Results There was no significant difference in demographic characteristics except for the use of glucocorticoid between the ABT and TCZ groups. There was no significant difference in the drug retention rate between the ABT and TCZ groups. Furthermore, there was no significant difference in the discontinuation rates due to the lack of effectiveness between these two groups. The proportions of the patients archiving low disease activity at 24 weeks did not differ significantly between the two groups. Whereas, the discontinuation rates due to AEs, including interstitial lung disease (ILD), seemed higher in the TCZ group than in the ABT group. In TCZ-treated group, the concomitant use of methotrexate (MTX) significantly increased the incidences of AEs leading to the discontinuation of TCZ. Whereas these was no significant impact of concomitant use of MTX on the incidences of AEs leading to discontinuation in ABT-treated group. Conclusions In elderly patients with RA treated with ABT and TCZ, drug retention rates were equivalent between the two groups. There were some differences in safety profiles between ABT and TCZ, and the rates of discontinuation due to AEs, including ILD, seem to be lower with ABT than with TCZ in elderly patients with RA.
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Faber, Anthony C., Anna F. Farago, Carlotta Costa, Anahita Dastur, Maria Gomez-Caraballo, Rebecca Robbins, Bethany L. Wagner, et al. "Assessment of ABT-263 activity across a cancer cell line collection leads to a potent combination therapy for small-cell lung cancer." Proceedings of the National Academy of Sciences 112, no. 11 (March 3, 2015): E1288—E1296. http://dx.doi.org/10.1073/pnas.1411848112.
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BH3 mimetics such as ABT-263 induce apoptosis in a subset of cancer models. However, these drugs have shown limited clinical efficacy as single agents in small-cell lung cancer (SCLC) and other solid tumor malignancies, and rational combination strategies remain underexplored. To develop a novel therapeutic approach, we examined the efficacy of ABT-263 across >500 cancer cell lines, including 311 for which we had matched expression data for select genes. We found that high expression of the proapoptotic gene Bcl2-interacting mediator of cell death (BIM) predicts sensitivity to ABT-263. In particular, SCLC cell lines possessed greater BIM transcript levels than most other solid tumors and are among the most sensitive to ABT-263. However, a subset of relatively resistant SCLC cell lines has concomitant high expression of the antiapoptotic myeloid cell leukemia 1 (MCL-1). Whereas ABT-263 released BIM from complexes with BCL-2 and BCL-XL, high expression of MCL-1 sequestered BIM released from BCL-2 and BCL-XL, thereby abrogating apoptosis. We found that SCLCs were sensitized to ABT-263 via TORC1/2 inhibition, which led to reduced MCL-1 protein levels, thereby facilitating BIM-mediated apoptosis. AZD8055 and ABT-263 together induced marked apoptosis in vitro, as well as tumor regressions in multiple SCLC xenograft models. In a Tp53; Rb1 deletion genetically engineered mouse model of SCLC, the combination of ABT-263 and AZD8055 significantly repressed tumor growth and induced tumor regressions compared with either drug alone. Furthermore, in a SCLC patient-derived xenograft model that was resistant to ABT-263 alone, the addition of AZD8055 induced potent tumor regression. Therefore, addition of a TORC1/2 inhibitor offers a therapeutic strategy to markedly improve ABT-263 activity in SCLC.
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Lawitz, Eric J., William D. O'Riordan, Armen Asatryan, Bradley L. Freilich, Terry D. Box, J. Scott Overcash, Sandra Lovell, et al. "Potent Antiviral Activities of the Direct-Acting Antivirals ABT-493 and ABT-530 with Three-Day Monotherapy for Hepatitis C Virus Genotype 1 Infection." Antimicrobial Agents and Chemotherapy 60, no. 3 (December 28, 2015): 1546–55. http://dx.doi.org/10.1128/aac.02264-15.
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ABT-493 is a hepatitis C virus (HCV) nonstructural (NS) protein 3/4A protease inhibitor, and ABT-530 is an HCV NS5A inhibitor. These direct-acting antivirals (DAAs) demonstrated potent antiviral activity against major HCV genotypes and high barriers to resistancein vitro. In this open-label dose-ranging trial, antiviral activity and safety were assessed during 3 days of monotherapy with ABT-493 or ABT-530 in treatment-naive adults with HCV genotype 1 infection, with or without compensated cirrhosis. The presence of baseline resistance-associated variants (RAVs) was also evaluated. The mean maximal decreases in HCV RNA levels from baseline were approximately 4 log10IU/ml for all ABT-493 doses ranging from 100 mg to 700 mg and for ABT-530 doses of ≥40 mg. There were no meaningful differences in viral load declines for patients with versus without compensated cirrhosis. Twenty-four (50%) of the baseline samples from patients treated with ABT-493 had RAVs to NS3/4A protease inhibitors. Among 40 patients treated with ABT-530, 6 (15%) carried baseline RAVs to NS5A inhibitors. Viral load declines in patients with single baseline NS5A RAVs were similar to those in patients without RAVs. One patient harbored baseline RAVs at 3 NS5A positions and appeared to have a slightly less robust viral load decline on day 3 of monotherapy. No serious or grade 3 (severe) or higher adverse events and no clinically relevant laboratory abnormalities were observed with either compound. ABT-493 and ABT-530 demonstrated potent antiviral activity and acceptable safety during 3-day monotherapy in patients with HCV genotype 1 infection, with or without compensated cirrhosis. Based on these results, phase II studies assessing the combination of these DAAs for the treatment of chronic HCV infection in patients with or without compensated cirrhosis have been initiated. (This study has been registered at ClinicalTrials.gov under registration no. NCT01995071.)