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Artykuły w czasopismach na temat "Malignancy - Cytotoxicity"

1

Santos-Pirath, I. M., L. O. Walter, M. F. Maioral, P. D. Neuenfeldt, R. J. Nunes i M. C. Santos-Silva. "Apoptosis induced by synthetic compounds containing a 3,4,5-trimethoxyphenyl fragment against lymphoid immature neoplasms". Biochemistry and Cell Biology 97, nr 5 (październik 2019): 630–37. http://dx.doi.org/10.1139/bcb-2018-0316.

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T-cell acute lymphoblastic leukemia is an aggressive hematological malignancy originating from the malignant transformation of progenitor T cells at different stages of development. The treatment causes severe adverse effects and is associated with relapses and high morbidity and mortality rates. The present study aimed to evaluate the cytotoxic activity of 28 new compounds containing 3,4,5-trimethoxyphenyl analogues on hematological neoplastic cells lines. Cytotoxicity screening by the MTT method revealed that compound 1d was the most promising. Cell viability of neoplastic cells decreased in a concentration- and time-dependent manner, with compound 1d not causing hemolysis or reducing peripheral blood mononuclear cells viability, suggesting a selective cytotoxicity. We also suggested that compound 1d induced apoptotic-like cell death with mitochondrial involvement in Jurkat cells.
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Sun, Xin, Yang Yu, Li Ma, Xin Xue, Zhenkui Gao, Juan Ma i Man Zhang. "T cell cytotoxicity toward hematologic malignancy via B7-H3 targeting". Investigational New Drugs 38, nr 3 (3.07.2019): 722–32. http://dx.doi.org/10.1007/s10637-019-00819-y.

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Smyth, Mark J., Kevin Y. T. Thia, Shayna E. A. Street, Duncan MacGregor, Dale I. Godfrey i Joseph A. Trapani. "Perforin-Mediated Cytotoxicity Is Critical for Surveillance of Spontaneous Lymphoma". Journal of Experimental Medicine 192, nr 5 (5.09.2000): 755–60. http://dx.doi.org/10.1084/jem.192.5.755.

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Immune surveillance by cytotoxic lymphocytes against cancer has been postulated for decades, but direct evidence for the role of cytotoxic lymphocytes in protecting against spontaneous malignancy has been lacking. As the rejection of many experimental cancers by cytotoxic T lymphocytes and natural killer cells is dependent on the pore-forming protein perforin (pfp), we examined pfp-deficient mice for increased cancer susceptibility. Here we show that pfp-deficient mice have a high incidence of malignancy in distinct lymphoid cell lineages (T, B, NKT), indicating a specific requirement for pfp in protection against lymphomagenesis. The susceptibility to lymphoma was accentuated by simultaneous lack of expression of the p53 gene, mutations in which also commonly predispose to human malignancies, including lymphoma. In contrast, the incidence and age of onset of sarcoma was unaffected in p53-deficient mice. Pfp-deficient mice were at least 1,000-fold more susceptible to these lymphomas when transplanted, compared with immunocompetent mice in which tumor rejection was controlled by CD8+ T lymphocytes. This study is the first that implicates direct cytotoxicity by lymphocytes in regulating lymphomagenesis.
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Banerjee, Kaushik, Satyajit Das, Pritha Choudhury, Sarbari Ghosh, Rathindranath Baral i Soumitra Kumar Choudhuri. "A Novel Approach of Synthesizing and Evaluating the Anticancer Potential of Silver Oxide Nanoparticles in vitro". Chemotherapy 62, nr 5 (2017): 279–89. http://dx.doi.org/10.1159/000453446.

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Background: Development of novel strategies to kill cancer by sparing normal cells is of utmost importance. Apart from their known antimicrobial activity, only limited information has been recorded regarding the antitumor potential of biocompatible silver oxide nanoparticles (AgONPs). There is a need to evaluate the anticancer potential of biocompatible AgONPs in vitro. Methods: A new approach of utilizing the leaf extract of Excoecaria agallocha was used to synthesize AgONPs. This was then characterized by ultraviolet-visible spectrophotometry, nanoparticle-tracking analysis, and ζ-potential analysis. Cytotoxicity and apoptotic potential were evaluated with an MTT assay and an annexin V-binding assay against the murine melanoma (B16F10), murine colon cancer (CT26), murine lung adenocarcinoma (3LL), and murine Ehrlich ascites carcinoma (EAC) cell lines. Cellular localization of AgONPs was evaluated on fluorescence microscopy. Results: UV peaks at 270 and 330 nm indicated the formation of nanoparticles (NPs) and the NP-tracking analyzer revealed them to have a size of 228 nm. AgONPs exerted initial cytotoxicity, specifically against all the experimental malignant cells by sparing the normal cell lines. Moreover, AgONPs exert apoptosis equally on all the malignant cells in vitro and ex vivo. This cytotoxicity possibly occurs via the nuclear translocation of AgONPs as analyzed in B16F10 cells. Conclusions: AgONPs utilizing natural sources would be a new medicinal approach against a broad spectrum of malignancy.
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Wang, Jiaan-Der, Ya-Yu Wang, Shih-Yi Lin, Cheng-Yi Chang, Jian-Ri Li, Shi-Wei Huang, Wen-Ying Chen, Su-Lan Liao i Chun-Jung Chen. "Exosomal HMGB1 Promoted Cancer Malignancy". Cancers 13, nr 4 (19.02.2021): 877. http://dx.doi.org/10.3390/cancers13040877.

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Reciprocal crosstalk between platelets and malignancies underscores the potential of antiplatelet therapy in cancer treatment. In this study, we found that human chronic myeloid leukemia K562 cell-differentiated megakaryocytes and murine platelets produced bioactive substances and these are released into the extracellular space, partly in their exosomal form. High-mobility group box 1 (HMGB1) is a type of exosomal cargo, and the antiplatelet drugs aspirin and dipyridamole interfered with its incorporation into the exosomes. Those released substances and exosomes, along with exogenous HMGB1, promoted cancer cell survival and protected cells from doxorubicin cytotoxicity. In a tumor-bearing model established using murine Lewis lung carcinoma (LLC) cells and C57BL/6 mice, the tumor suppressive effect of dipyridamole correlated well with decreased circulating white blood cells, soluble P-selectin, TGF-β1 (Transforming Growth Factor-β1), exosomes, and exosomal HMGB1, as well as tumor platelet infiltration. Exosome release inhibitor GW4869 exhibited suppressive effects as well. The suppressive effect of dipyridamole on cancer cell survival was paralleled by a reduction of HMGB1/receptor for advanced glycation end-products axis, and proliferation- and migration-related β-catenin, Yes-associated protein 1, Runt-related transcription factor 2, and TGF- β1/Smad signals. Therefore, exosomes and exosomal HMGB1 appear to have roles in platelet-driven cancer malignancy and represent targets of antiplatelet drugs in anticancer treatment.
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Gottlieb, DJ, HG Prentice, HE Heslop, C. Bello-Fernandez, AC Bianchi, AR Galazka i MK Brenner. "Effects of recombinant interleukin-2 administration on cytotoxic function following high-dose chemo-radiotherapy for hematological malignancy". Blood 74, nr 7 (15.11.1989): 2335–42. http://dx.doi.org/10.1182/blood.v74.7.2335.2335.

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Abstract Activated killer cells, unrestricted by major histocompatibility (MHC) antigens circulate in the peripheral blood of patients who have undergone autologous and allogeneic bone marrow transplant (BMT) and may contribute to the reduced risk of leukemic relapse observed after these procedures. Interleukin-2 (IL-2) in vitro augments this cytotoxicity and used therapeutically might thereby promote the eradication of minimal residual disease. In order to assess whether these effects on cytotoxicity can be reproduced in vivo, we studied changes in number, phenotype, and MHC unrestricted cytotoxicity of peripheral blood mononuclear cells obtained from patients with hematologic malignancy receiving IL-2 infusions. Patients with acute myeloid leukemia and multiple myeloma were treated after cytotoxic chemotherapy or autologous BMT. IL-2 infusions produced an initial lymphopenia, followed by a progressive recovery in mononuclear cell numbers and a rebound lymphocytosis after the termination of treatment. This affected all lymphocyte subsets; in particular CD25 (IL-2 receptor) positive cell numbers rose sevenfold. Cells with the ability to kill a natural killer (NK)-resistant, lymphokine activated killer cell (LAK)-sensitive target appeared in the circulation during 16 of 19 infusions and mean LAK activity rose from 5.9% to 15.5% during infusion (E:T ratio, 50:1; P less than .001). During IL-2 infusion, cells present in the peripheral blood inhibited the growth of myeloid leukemia blasts in agar after overnight co-culture. Depletion experiments showed that LAK activity was mediated by cells of both CD3- CD16+ (NK derived) and CD3+ CD16- (T derived) subsets. LAK precursor activity in peripheral blood also significantly increased during IL-2 infusion. Increases in major histocompatibility complex (MHC) unrestricted cytotoxicity can be produced by IL-2 infusions in vivo and may result in improved relapse-free survival following chemotherapy or BMT.
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Gottlieb, DJ, HG Prentice, HE Heslop, C. Bello-Fernandez, AC Bianchi, AR Galazka i MK Brenner. "Effects of recombinant interleukin-2 administration on cytotoxic function following high-dose chemo-radiotherapy for hematological malignancy". Blood 74, nr 7 (15.11.1989): 2335–42. http://dx.doi.org/10.1182/blood.v74.7.2335.bloodjournal7472335.

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Activated killer cells, unrestricted by major histocompatibility (MHC) antigens circulate in the peripheral blood of patients who have undergone autologous and allogeneic bone marrow transplant (BMT) and may contribute to the reduced risk of leukemic relapse observed after these procedures. Interleukin-2 (IL-2) in vitro augments this cytotoxicity and used therapeutically might thereby promote the eradication of minimal residual disease. In order to assess whether these effects on cytotoxicity can be reproduced in vivo, we studied changes in number, phenotype, and MHC unrestricted cytotoxicity of peripheral blood mononuclear cells obtained from patients with hematologic malignancy receiving IL-2 infusions. Patients with acute myeloid leukemia and multiple myeloma were treated after cytotoxic chemotherapy or autologous BMT. IL-2 infusions produced an initial lymphopenia, followed by a progressive recovery in mononuclear cell numbers and a rebound lymphocytosis after the termination of treatment. This affected all lymphocyte subsets; in particular CD25 (IL-2 receptor) positive cell numbers rose sevenfold. Cells with the ability to kill a natural killer (NK)-resistant, lymphokine activated killer cell (LAK)-sensitive target appeared in the circulation during 16 of 19 infusions and mean LAK activity rose from 5.9% to 15.5% during infusion (E:T ratio, 50:1; P less than .001). During IL-2 infusion, cells present in the peripheral blood inhibited the growth of myeloid leukemia blasts in agar after overnight co-culture. Depletion experiments showed that LAK activity was mediated by cells of both CD3- CD16+ (NK derived) and CD3+ CD16- (T derived) subsets. LAK precursor activity in peripheral blood also significantly increased during IL-2 infusion. Increases in major histocompatibility complex (MHC) unrestricted cytotoxicity can be produced by IL-2 infusions in vivo and may result in improved relapse-free survival following chemotherapy or BMT.
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8

Lee, Han Bi, Jae-Ho Yoon, Gi June Min, Sung-Soo Park, Silvia Park, Sung-Eun Lee, Ki-Seong Eom i in. "Natural-Killer Cell Cytotoxicity Is a Diagnostic and Prognostic Marker in Adult Patients with Secondary Hemophagocytic Lymphohistiocytosis: Results from a Prospective Phase II Observational Study". Blood 134, Supplement_1 (13.11.2019): 2331. http://dx.doi.org/10.1182/blood-2019-129676.

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Background: Hemophagocytic lymphohistiocytosis (HLH) can be life-threatening if not detected and treated appropriately. Diagnosing HLH can be confusing due to other similar febrile diseases that present with cytopenia. Although a decrease in natural-killer cell (NK)-cytotoxicity is an important diagnostic parameter for primary HLH, the role in adult HLH has not been well-defined. Aim: To identify the diagnostic relevance and the significant cut-off values for NK cytotoxic function, we focused on patients that presented with fever with either cytopenia or evidence of hemophagocytosis. NK cytotoxicity was calculated at the time of diagnosis and we tried to identify significant differences between the causes of disease. Finally, the overall treatment response and survival outcomes were also evaluated based on the level of NK cytotoxicity in several subgroup analyses. Methods: We prospectively enrolled 123 adult patients that presented with fever accompanied by either cytopenia in at least two lineages or marrow hemophagocytosis. A diagnosis of HLH was based on HLH-2004 criteria and treated based on HLH-94 protocol. HLH-suspected patients were initially treated with 10mg/BSA of dexamethasone, and etoposide was considered if clinical improvement was not observed within 7 days after dexamethasone. Patients other than HLH were treated with disease-specified therapy. NK-cytotoxicity was calculated at diagnosis by K562-cell direct lysis using flow-cytometry. Results: HLH (n=60) was determined to be caused by Epstein-Barr virus (EBV, n=11), infection other than EBV (n=16), malignancies (n=19), and unknown (n=14). Febrile diseases other than HLH (n=63) were diagnosed as rheumatologic disease (n=22), malignancies (n=21), infection (n=12), non-malignant hematological diseases (n=6), and unknown (n=2). The results revealed that an HLH diagnosis was significantly correlated with lower NK-cytotoxicity, compared to other diseases (12.1% vs. 26.2%, p<0.001), and a value less than 22% was a relevant cut-off for diagnosing HLH. Additionally, lower NK-cytotoxicity showed inferior 2-year overall survival in the non-malignancy subgroup (72.2% vs. 88.8%, p=0.038). Multivariate analysis showed that low NK-cytotoxicity, splenomegaly, and marrow hemophagocytosis were independent diagnostic parameters for HLH, and low NK-cytotoxicity and EBV-association were related with poor survival outcomes in non-malignant febrile diseases. Conclusion: We determined that decreased NK-cytotoxicity is a relevant marker that can be used for diagnosis of adult HLH compared with several similar febrile diseases and is also related to poor OS in non-malignant febrile diseases. Based on these results and other prospective studies, we hope that additional relevant diagnostic criteria for adult HLH can be identified in the near future. Disclosures Kim: Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Hanmi: Consultancy, Honoraria; AGP: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SL VaxiGen: Consultancy, Honoraria; Novartis: Consultancy; Amgen: Honoraria; Chugai: Honoraria; Yuhan: Honoraria; Sanofi-Genzyme: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Honoraria; Janssen: Honoraria; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka: Honoraria; BL & H: Research Funding. Lee:Alexion: Consultancy, Honoraria, Research Funding; Achillion: Research Funding.
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Soiffer, RJ, MJ Robertson, C. Murray, K. Cochran i J. Ritz. "Interleukin-12 augments cytolytic activity of peripheral blood lymphocytes from patients with hematologic and solid malignancies". Blood 82, nr 9 (1.11.1993): 2790–96. http://dx.doi.org/10.1182/blood.v82.9.2790.2790.

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Abstract Interleukin-12 (IL-12) is a heterodimeric 70-kD cytokine that can enhance the activity of cytotoxic effector cells. Although IL-12 shares some functional properties with interleukin-2 (IL-2), it appears to act via a distinct mechanism. In this report, we examined the effects of IL- 12 on the cytolytic activity and proliferation of peripheral blood mononuclear cells (PBMC) obtained from patients with malignant disease. PBMC from two groups of patients were evaluated. The first group consisted of 12 individuals with metastatic solid tumors. PBMC from these patients demonstrated a marked defect in their ability to lyse natural killer (NK)-sensitive targets (K562) compared with normal volunteers. Overnight incubation with IL-12 (35 pmol/L) corrected this defect. The effect of 35 pmol/L of IL-12 on cytotoxicity was similar to that of 3 nmol/L of IL-2. In contrast, this concentration of IL-12 had little effect on cytolytic activity against an NK-resistant cell line (COLO 205). When IL-12 was added to PBMC obtained from cancer patients who were being treated with low-dose IL-2 in vivo, a dramatic increase in cytolytic activity against both NK-sensitive and -resistant tumor targets was observed. Unlike IL-2, IL-12 failed to stimulate proliferation of resting PBMC from cancer patients significantly. The second group of patients we studied comprised 13 patients who had recently undergone allogeneic bone marrow transplantation (BMT) for hematologic malignancy. In resting PBMC from these transplant recipients, IL-12 was capable of enhancing cytotoxicity against both NK- sensitive and -resistant tumor targets. Our findings indicate that IL- 12 can restore defective NK activity of PBMC from patients with metastatic cancer, as well as enhance cytolytic function of PBMC from patients after allogeneic BMT. The clinical use of IL-12 as an immunomodulator in patients with malignancy merits further consideration.
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Soiffer, RJ, MJ Robertson, C. Murray, K. Cochran i J. Ritz. "Interleukin-12 augments cytolytic activity of peripheral blood lymphocytes from patients with hematologic and solid malignancies". Blood 82, nr 9 (1.11.1993): 2790–96. http://dx.doi.org/10.1182/blood.v82.9.2790.bloodjournal8292790.

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Interleukin-12 (IL-12) is a heterodimeric 70-kD cytokine that can enhance the activity of cytotoxic effector cells. Although IL-12 shares some functional properties with interleukin-2 (IL-2), it appears to act via a distinct mechanism. In this report, we examined the effects of IL- 12 on the cytolytic activity and proliferation of peripheral blood mononuclear cells (PBMC) obtained from patients with malignant disease. PBMC from two groups of patients were evaluated. The first group consisted of 12 individuals with metastatic solid tumors. PBMC from these patients demonstrated a marked defect in their ability to lyse natural killer (NK)-sensitive targets (K562) compared with normal volunteers. Overnight incubation with IL-12 (35 pmol/L) corrected this defect. The effect of 35 pmol/L of IL-12 on cytotoxicity was similar to that of 3 nmol/L of IL-2. In contrast, this concentration of IL-12 had little effect on cytolytic activity against an NK-resistant cell line (COLO 205). When IL-12 was added to PBMC obtained from cancer patients who were being treated with low-dose IL-2 in vivo, a dramatic increase in cytolytic activity against both NK-sensitive and -resistant tumor targets was observed. Unlike IL-2, IL-12 failed to stimulate proliferation of resting PBMC from cancer patients significantly. The second group of patients we studied comprised 13 patients who had recently undergone allogeneic bone marrow transplantation (BMT) for hematologic malignancy. In resting PBMC from these transplant recipients, IL-12 was capable of enhancing cytotoxicity against both NK- sensitive and -resistant tumor targets. Our findings indicate that IL- 12 can restore defective NK activity of PBMC from patients with metastatic cancer, as well as enhance cytolytic function of PBMC from patients after allogeneic BMT. The clinical use of IL-12 as an immunomodulator in patients with malignancy merits further consideration.
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Rozprawy doktorskie na temat "Malignancy - Cytotoxicity"

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Padilla, Roberto. "Discovering the Potential of Photoluminescent Ruthenium(II) Complexes as Photodynamic Therapy Agents". Diss., Virginia Tech, 2016. http://hdl.handle.net/10919/78190.

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Anthracene was attached to light activated, ruthenium-based DNA disruptors to probe their distribution in cancer cells. The objective of this research is to understand the photophysical properties (Chapter 2), photoreactivity toward DNA and proteins (Chapter 3), and localization within cancer cells (Chapter 4) of ruthenium complexes that demonstrate promise as photodynamic therapy (PDT) agents. [(AnthbpyMe)(bpy)Ru(dpp)]2+ (1) and [(AnthbpyMe)2Ru(dpp)]2+ (2) absorb visible light with metal-to-ligand charge transfer (MLCT) transitions at 459 nm (16,000 M-1 cm-1 ) and 461 nm (21,000 M-1 cm-1 ), respectively. These species exhibit 3 MLCT emissions at λem = 661 nm and λem = 663 nm for 1 and 2, respectively, while the anthracene show emissions at 450 – 560 nm. The anthracene unit(s) quench the 3 MLCT to give quantum yields (lifetime) of Φem = 0.0059 [398(1) ns] and Φem = 0.0011 [414(1) ns] for 1 and 2, respectively. Voltammetry shows an irreversible anthracene oxidation at 1.23 – 1.28 V, RuIII/II oxidation at 1.53 – 1.55 V, and quasi-reversible reduction couples attributed to dpp0/-1 at 0.98 V. DNA gel shift assays demonstrate that complexes 1 and 2 modify DNA in the presence and absence of 3 O2 upon light activation to convert supercoiled DNA to a mixture of open circular (OC) DNA and a species that exhibit sa distinctly different migration rate than either OC and linear DNA. Binding constants, Kb, for complexes 1 and 2, toward DNA are 3.50 × 105 (3.50 × 104 ) and 4.50 × 103 (4.50 × 102 ) respectively. SDS-PAGE assays show that the complexes 1 and 2 modify bovine serum albumin (BSA) through an 3 O2-dependent mechanism upon light iii activation. The localization and PDT potency of the anthracene-Ru-dpp complexes are tested against F98 cells, which are rat glioma cells that simulate the infiltrative patterns of growth in cancer. Confocal microscopy demonstrates that complexes 1 and 2 internalize and localize primarily along the cell membrane and associate with dot-like vesicles within the cytoplasm. Complexes 1 and 2 show IC50 values of 107 µM and 85 µM, respectively, after 15 min of drug exposure and 1 h of PDT-treatment (λPDT = 455 nm).
Ph. D.
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Craperi, Delphine. "Thérapie génique des gliomes : caractérisation des voies cytotoxiques déclenchées par le système thymidine kinase herpétique/ganciclovir". Université Joseph Fourier (Grenoble ; 1971-2015), 1998. http://www.theses.fr/1998GRE10073.

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La therapie genique par transfert du gene de la thymidine kinase du virus de l'herpes simplex de type 1 (hsv1-tk) suivi d'un traitement avec la prodrogue ganciclovir (gcv) a ete utilisee pour le traitement de divers cancers. L'efficacite de cette therapie est en partie due a l'existence d'un effet de toxicite de voisinage : le traitement au ganciclovir entraine non seulement la mort des cellules exprimant hsv1-tk mais aussi celle des cellules adjacentes non transfectees. Nous avons entrepris une etude in vitro des mecanismes moleculaires de la toxicite de ce systeme enzyme/prodrogue sur des lignees issues de tumeurs cerebrales. Les resultats obtenus montrent que le couple hsv1-tk/gcv declenche deux reactions cellulaires differentes au stress cytotoxique, selon les lignees utilisees. Dans un premier cas, le traitement au ganciclovir entraine un blocage du cycle cellulaire en phase s rapidement suivi d'une mort cellulaire associant des phenomenes d'apoptose et de necrose. Dans le second cas, le couple hsv1-tk/gcv declenche une mort cellulaire tardive et atypique, sans reel arret du cycle cellulaire. Ce phenomene, associe a l'apparition de cellules geantes et polyploides, est appele catastrophe mitotique et pourrait impliquer la proteine p21. Ces deux modes de mort cellulaire semblent independants de la proteine p53 et impliquent une activation de la proteine pro-apoptotique bax. Le gene represseur de la mort cellulaire bcl-2 inhibe en partie le processus apoptotique declenche par le systeme hsv1-tk/gcv ; ce gene pourrait donc jouer un role dans certaines formes de resistance observees au cours de cette etude. Ainsi, cette etude demontre que le phenotype tumoral va conditionner le destin cellulaire apres le traitement et s'avere donc un determinant critique de la sensibilite a cette approche therapeutique.
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Chen, Yi-Chen, i 陳亦禎. "Investigation of Methylation Status of FLT4 and MGMT in Cancers and Enhancement of Temozolomide-Induced Cytotoxicity for Malignant Glioma". Thesis, 2014. http://ndltd.ncl.edu.tw/handle/jj3z56.

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碩士
國立中正大學
生物醫學研究所
102
Oral cancer is the fourth most common cancer type among men in Taiwan, and about 94% of oral cancers are oral squamous cell carcinoma (OSCC). In cancer pathogenesis, epigenetic modification such as DNA methylation driven gene silencing of tumor suppressor genes is recognized as a key event. Therefore, we employed the Illumina GoldenGate Methylation array, which included 1,505 CpG sites covering 807 genes to analyze oral samples from OSCC patients. Among them, Fms-related tyrosine kinase 4 (FLT4) was highly methylated in most of the OSCC samples. In addition, we employed bisulfite pyrosequencing analysis to validate the methylation level of FLT4 in OSCC lines and patient samples. We found hyper-methylation levels were observed in OSCC lines. We also treated OSCC lines with 5-aza-dC, and found that the methylation level of FLT4 was reduced. Furthermore, we examined FLT4 methylation level in patient samples and found that FLT4 was significantly hyper-methylated in OSCC samples than in normal samples. Next, we used real-time PCR and found the expression level of FLT4 in OSCC lines and OSCC samples were low, but significantly higher expression of FLT4 was found in normal oral tissues. Taken DNA methylation and gene expression profiles together, we found FLT4 was hyper-methylated in oral cancer and thus it may hold diagnostic and predictive value as a biomarker. In addition to understanding the methylation profile of OSCC, we are also interested in exploring the methylation status of drug-resistant genes in glioblastoma multiforme (GBM). GBM is the most common form of primary brain tumor in adults and is difficult to completely resect by surgery. The chemotherapy drug temozolomide (TMZ) is often used to treat GBM, however, upregulated O6-methylguanine-DNA methyltransferase (MGMT) in some GBM can neutralize the cytotoxic effect of TMZ. We were employed pyrosequencing assay, quantitative RT-PCR and western blotting to check the methylation status and expression level of MGMT in various GBM cell lines. In addition, we knock down MGMT expression with siRNA in GBM cell lines to confirm if TMZ resistance in the cells can be reduced. Moreover, we established the GBM-initiating cells (GICs) from parental GBM cell lines, and check the difference of MGMT methylation status between parental GBM cells and GICs. Then the GICs were determined the effect of TMZ on cell viability. In summary, we found MGMT can influence TMZ efficacy in GBM, and the MGMT expression level might be a therapeutic prediction of response to TMZ.
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"In vitro studies on the mechanisms of hyperthermia- and TNF-α-induced apoptosis". 2002. http://library.cuhk.edu.hk/record=b5896015.

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by Yuen Wai Fan.
Thesis (M.Phil.)--Chinese University of Hong Kong, 2002.
Includes bibliographical references (leaves 211-232).
Abstracts in English and Chinese.
Acknowledgements --- p.i
List of Publications and Abstracts --- p.ii
Abbreviations --- p.iv
Abstract --- p.xi
Abstract in Chinese --- p.xiv
List of Figures --- p.xvii
List of Tables --- p.xxiii
Contents --- p.xxiv
Chapter Chapter 1. --- General Introduction --- p.1
Chapter 1.1 --- Hyperthermia --- p.2
Chapter 1.1.1 --- History of Hyperthermia --- p.2
Chapter 1.1.2 --- Biological Functions of Hyperthermia --- p.3
Chapter 1.1.3 --- Clinical Application of Hyperthermia --- p.4
Chapter 1.1.3.1 --- Whole-body Hyperthermia --- p.4
Chapter 1.1.3.2 --- Regional Hyperthermia --- p.4
Chapter 1.1.3.3 --- Local Hyperthermia --- p.5
Chapter 1.1.4 --- Combination Therapy --- p.5
Chapter 1.1.4.1 --- Combined treatment with Hyperthermia and Radiotherapy --- p.6
Chapter 1.1.4.2 --- Combined treatment with Hyperthermia and Chemotherapy --- p.6
Chapter 1.2 --- Tumour Necrosis Factor --- p.9
Chapter 1.2.1 --- History of Tumour Necrosis Factor --- p.9
Chapter 1.2.2 --- Sources of TNF-α and TNF-β --- p.9
Chapter 1.2.3 --- Biological Roles of TNF --- p.10
Chapter 1.2.3.1 --- Receptors of TNF-α --- p.11
Chapter 1.2.4 --- Signaling Pathway of TNF --- p.12
Chapter 1.2.4.1 --- Activation of Death Domain --- p.12
Chapter 1.2.4.2 --- Activation of Sphingomyelin Pathway --- p.13
Chapter 1.2.4.3 --- Activation of NF-kB pathway --- p.13
Chapter 1.3 --- Types of Cell Death: Necrosis and Apoptosis --- p.16
Chapter 1.3.1 --- Necrosis --- p.16
Chapter 1.3.2 --- Apoptosis --- p.16
Chapter 1.4 --- Signaling Pathway in Apoptosis --- p.19
Chapter 1.4.1 --- Factors Involved in Apoptotic Pathway --- p.19
Chapter 1.4.1.1 --- Caspases --- p.19
Chapter 1.4.1.2 --- Death Substrates --- p.20
Chapter 1.4.1.3 --- Bcl-2 Protein Family --- p.21
Chapter 1.4.1.4 --- Role of Mitochondria --- p.23
Chapter 1.5 --- Objectives of the Project --- p.26
Chapter Chapter 2. --- Materials and Methods --- p.28
Chapter 2.1 --- Materials --- p.29
Chapter 2.1.1 --- Culture of Cells --- p.34
Chapter 2.1.1.1 --- "TNF-α Sensitive Cell Line, L929" --- p.34
Chapter 2.1.1.2 --- "TNF-α Resistance Cell Line, L929-11E" --- p.34
Chapter 2.1.1.3 --- Preservation of Cells --- p.35
Chapter 2.1.2 --- Culture Media --- p.36
Chapter 2.1.2.1 --- RPMI 1640 (Phenol Red Medium) --- p.36
Chapter 2.1.2.2 --- RPMI 1640 (Phenol Red-Free Medium) --- p.36
Chapter 2.1.3 --- Buffers and Reagents --- p.37
Chapter 2.1.3.1 --- Preparation of Buffers --- p.37
Chapter 2.1.3.2 --- Buffer for Common Use --- p.37
Chapter 2.1.3.3 --- Reagents for Annexin-V-FITC/PI assay --- p.37
Chapter 2.1.3.4 --- Reagents for Cytotoxicity Assay --- p.37
Chapter 2.1.3.5 --- Reagents for Molecular Biology Work --- p.38
Chapter 2.1.3.6 --- Reagents for Western Blotting Analysis --- p.38
Chapter 2.1.4 --- Chemicals --- p.40
Chapter 2.1.4.1 --- Recombinant Murine TNF-α --- p.40
Chapter 2.1.4.2 --- Dye for Cytotoxicity Assay --- p.41
Chapter 2.1.4.3 --- Fluorescence Dyes --- p.41
Chapter 2.1.4.4 --- Chemicals Related to Mitochondrial Studies --- p.41
Chapter 2.1.4.5 --- Inhibitors of Caspases --- p.42
Chapter 2.1.4.6 --- Antibodies for Western Blotting --- p.42
Chapter 2.1.4.7 --- Other Chemicals --- p.43
Chapter 2.2 --- Methods --- p.44
Chapter 2.2.1 --- Treatment with TNF-α --- p.44
Chapter 2.2.2 --- Treatment with Hyperthermia --- p.44
Chapter 2.2.3 --- In vitro Cell Cytotoxicity Assay --- p.45
Chapter 2.2.4 --- Flow Cytometry --- p.46
Chapter 2.2.4.1 --- Introduction --- p.46
Chapter 2.2.4.2 --- Analysis by FCM --- p.48
Chapter 2.2.4.3 --- Determination of Apoptotic and Late Apoptotic/Necrotic Cells with Annexin-V-FITC/PI Cytometric Analysis --- p.50
Chapter 2.2.4.4 --- Determination of Mitochondrial Membrane Potential (ΔΨm) --- p.51
Chapter 2.2.4.5 --- Determination of Hydrogen Peroxide (H202) Release --- p.52
Chapter 2.2.4.6 --- Determination of Intracellular Free Calcium ([Ca2+]i) Level --- p.52
Chapter 2.2.4.7 --- Determination of the Relationship of ΔΨm and [Ca2+]i Level --- p.53
Chapter 2.2.5 --- Western Blotting Analysis --- p.53
Chapter 2.2.5.1 --- Preparation of Proteins from Cells --- p.53
Chapter 2.2.5.2 --- SDS Polyacrylamide Gel Electophoresis (SDS- PAGE) --- p.56
Chapter 2.2.5.3 --- Electroblotting of Proteins --- p.57
Chapter 2.2.5.4 --- Probing Antibodies for Proteins --- p.57
Chapter 2.2.5.5 --- Enhanced Chemiluminescence (ECL) assay --- p.58
Chapter 2.2.6 --- Reverse Transcriptase Polymerase Chain Reaction --- p.58
Chapter 2.2.6.1 --- Extraction of RNA by Trizol Reagent --- p.59
Chapter 2.2.6.2 --- Determination of the Amount of RNA --- p.60
Chapter 2.2.6.3 --- Agarose Gel Electrophoresis --- p.60
Chapter 2.2.6.4 --- Reverse Transcription --- p.63
Chapter 2.2.6.5 --- Polymerase Chain Reaction (PCR) --- p.63
Chapter 2.2.6.6 --- Design of Primers for Different Genes --- p.64
Chapter 2.2.6.7 --- Determination of the Number of Cycles in PCR for Different Genes --- p.67
Chapter 2.2.7 --- Caspase Fluorescent Assay --- p.67
Chapter 2.2.7.1 --- Caspase-3 or ´ؤ8 Assay --- p.67
Chapter Chapter 3. --- Results --- p.59
Chapter 3.1 --- Studies of the Characteristics of L929 and L929-11E cells --- p.70
Chapter 3.1.1 --- Determination of the Growth Curve of L929 and L929-11E Cells --- p.70
Chapter 3.2 --- Studies on the Effect of TNF-α on L929 and L929-11E Cells --- p.73
Chapter 3.2.1 --- TNF-α Induced Cell Death in L929 Cells but not in L929- 11E Cells --- p.73
Chapter 3.2.2 --- TNF-α Induced Apoptosis in a Time-dependent Manner in L929Cells but not in L929-11E Cells --- p.80
Chapter 3.2.3 --- TNF-α Induced Mitochondrial Membrane Depolarization in a Time-dependent Manner in L929 Cells but notin L929-11E Cells --- p.87
Chapter 3.2.4 --- TNF-α Induced Cytochrome c Release in a Time- dependent Manner in L929 Cells but not in L929-11E Cells --- p.92
Chapter 3.3 --- Effect of Hyperthermia on L929 and L929-11E Cells --- p.96
Chapter 3.3.1 --- Introduction --- p.95
Chapter 3.3.2 --- Hyperthermia Induced Apoptosis in L929 and L929-11E Cells --- p.96
Chapter 3.3.3 --- Effect of Hyperthermia on Mitochondrial Membrane Depolarization --- p.100
Chapter 3.3.4 --- Hyperthermia Induced Cyto c Release in a Time-dependent Manner in L929 and L929-11E Cells --- p.105
Chapter 3.4 --- Relationship of Hyperthermia and TNF-α with PTP in L929 Cells --- p.107
Chapter 3.5 --- Effect of TNF-α and Hyperthermia on the Level of Hydrogen Peroxide (H202) in L929 and L929-11E Cells --- p.114
Chapter 3.5.1 --- Introduction --- p.114
Chapter 3.5.2 --- TNF-α Enhanced the Level of H202 in L929 cells but not in L929-11E Cells --- p.115
Chapter 3.5.3 --- Hyperthermia Enhanced the Level of H202 in L929 and L929-11E cells --- p.117
Chapter 3.6 --- Effect of TNF-α and Hyperthermia on the Level of Intracellular Calcium in L929 and L929-11E Cells --- p.122
Chapter 3.6.1 --- Increase in the Intracellular Calcium Level Induced by TNF-α Was Related to the Mitochondrial Membrane Depolarization in L929 Cells but not in L929-11E Cells --- p.122
Chapter 3.6.2 --- Hyperthermia Increased the Level of [Ca2+]i in L929 and L929-11E Cells in a Time-dependent Manner --- p.124
Chapter 3.7 --- Effect of Combined Hyperthermia and TNF-α Treatment on the Induction of Apoptosis in L929 and L929-1 1E Cells --- p.129
Chapter 3.7.1 --- Combined Treatment with Hyperthermia and TNF- α Induced Apoptosis in Both L929 and L929-11E cells --- p.129
Chapter 3.7.2 --- Hyperthermia and Its Combined Treatment with TNF-α Induced Mitochondrial Membrane Depolarization in L929 and L929-11E Cells --- p.135
Chapter 3.8 --- Investigation of the Downstream Apoptotic Pathway in L929 and L929-11E Cells Upon Hyperthermia and TNF-a treatment --- p.142
Chapter 3.8.1 --- Introduction --- p.142
Chapter 3.8.2 --- Effect ofTNF-α and Hyperthermia on p53 Expression --- p.142
Chapter 3.8.3 --- Effect of Hyperthermia and TNF-α on PARP --- p.146
Chapter 3.8.4 --- Effect of Hyperthermia and TNF-α on Caspase-3 Activity --- p.149
Chapter 3.8.5 --- Effect of Hyperthermia and TNF-α on Bid protein --- p.158
Chapter 3.8.6 --- Effect of Hyperthermia and TNF-α on Caspase-8 Activity --- p.165
Chapter 3.8.7 --- Effect ofTNF-α on TNFR1 Expression --- p.169
Chapter Chapter 4. --- Discussion
Chapter 4.1 --- TNF-α Induced Apoptosis and Changed the Mitochondrial Activities in L929 Cells --- p.176
Chapter 4.2 --- L929-11E cells Possessed Resistance Towards TNF-α --- p.187
Chapter 4.3 --- Hyperthermia Triggered Apoptosis and Changed Mitochondrial Activities in L929 and L929-11E cells --- p.190
Chapter 4.4 --- Combined hyperthermia and TNF-α treatment induced cell death and changed mitochondria activities in L929 and L929-11E cells --- p.195
Chapter 4.5 --- Reversal of the TNF-α resistance and Enhancement of Sensitivity Towards Hyperthermia in L929-11E cells --- p.197
Chapter 4.6 --- Proposed Pathway in the TNF-α- and Hyperthermia-mediated Apoptosis --- p.200
Chapter 4.7 --- Application of TNF-α and Hyperthermia on Clinical Cancer Treatment --- p.203
Chapter Chapter 5. --- Future Perspective of the Project --- p.206
References --- p.210
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Teesdale-Spittle, P. H., Klaus Pors, R. Brown, Laurence H. Patterson i J. A. Plumb. "Development of nonsymmetrical 1,4-disubstituted anthraquinones that are potently active against cisplatin-resistant ovarian cancer cells". 2005. http://hdl.handle.net/10454/3191.

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No
A novel series of 1,4-disubstituted aminoanthraquinones were prepared by ipso-displacement of 1,4-difluoro-5,8-dihydroxyanthraquinones by hydroxylated piperidinyl- or pyrrolidinylalkyl-amino side chains. One aminoanthraquinone (13) was further derivatized to a chloropropyl-amino analogue by treatment with triphenylphosphine-carbon tetrachloride. The compounds were evaluated in the A2780 ovarian cancer cell line and its cisplatin-resistant variants (A2780/ cp70 and A2780/MCP1). The novel anthraquinones were shown to possess up to 5-fold increased potency against the cisplatin-resistant cells compared to the wild-type cells. Growth curve analysis of the hydroxyethylaminoanthraquinone 8 in the osteosarcoma cell line U-2 OS showed that the cell cycle is not frozen, rather there is a late cell cycle arrest consistent with the action of a DNA-damaging topoisomerase II inhibitor. Accumulative apoptotic events, using time lapse photography, indicate that 8 is capable of fully engaging cell cycle arrest pathways in G2 in the absence of early apoptotic commitment. 8 and its chloropropyl analogue 13 retained significant activity against human A2780/cp70 xenografted tumors in mice.
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Części książek na temat "Malignancy - Cytotoxicity"

1

Luciani, M. F., i P. Golstein. "Fas-based d10S-mediated cytotoxicity requires macromolecular synthesis for effector cell activation but not for target cell death". W The Role of Apoptosis in Development, Tissue Homeostasis and Malignancy, 67–73. Dordrecht: Springer Netherlands, 1995. http://dx.doi.org/10.1007/978-94-011-0553-8_12.

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Ohnishi, Takanori, Hiromitsu Iwasaki, Norio Arita, Shoju Hiraga i Toru Hayakawa. "Potentiation of VP-16 Cytotoxicity by Dipyridamole in Malignant Glioma Cells". W Biological Aspects of Brain Tumors, 252–59. Tokyo: Springer Japan, 1991. http://dx.doi.org/10.1007/978-4-431-68150-2_32.

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Schackert, G., M. Kirsch, H. Fischer, H. K. Schackert i S. Kunze. "Comparative Study of Monocyte-Mediated Cytotoxicity and Biological Response Modifier-Mediated Cytotoxicity Against Malignant Human Brain Tumor Cells In Vitro". W Advances in Neurosurgery, 312–20. Berlin, Heidelberg: Springer Berlin Heidelberg, 1993. http://dx.doi.org/10.1007/978-3-642-77997-8_58.

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4

Miyagi, Koichi, Jiro Mukawa, Hisashi Koga, Yasushi Higa, Susumu Nakasone, Susumu Mekaru i Marylou Ingram. "Interferon Effect on Cytotoxicity of Autologous Stimulated Lymphocytes from Patients with Malignant Glioma". W Biological Aspects of Brain Tumors, 207–14. Tokyo: Springer Japan, 1991. http://dx.doi.org/10.1007/978-4-431-68150-2_26.

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Phillips, David H. "Chemical carcinogens". W Oxford Textbook of Cancer Biology, redaktorzy Francesco Pezzella, Mahvash Tavassoli i David J. Kerr, 79–90. Oxford University Press, 2019. http://dx.doi.org/10.1093/med/9780198779452.003.0007.

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Large geographical and temporal differences in cancer incidence indicate that the causes of the majority of cases are a consequence of environmental and lifestyle factors. While many of these remain unknown, around half have known causes, and these include chemicals in air, water, and food, as well as products of industrial processes and of combustion. The major classes of chemical carcinogens and how they were discovered are described. A property shared by many of them is that they, or one or more of their metabolites, are electrophiles that can damage DNA in mammalian cells, leading to cellular responses including DNA repair, cytotoxicity, apoptosis, mutagenesis, and malignant transformation. Methods for predicting the carcinogenicity of new chemicals are part of the regulatory processes for safety assessment, and sensitive methods for monitoring human exposure to carcinogens provide insight into the aetiology of cancer. The mutational signatures that genotoxic carcinogens leave in the tumours they induce provide evidence of the chemicals that have caused them, and the approach has promise for shedding light on the many as-yet-unidentified cases of cancer worldwide.
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6

Sankar Satpathy, Bhabani, Binapani Barik, Ladi Alik Kumar i Sangram Biswal. "Potential of Lipid Based Nanodrug Carriers for Targeted Treatment of Glioblastoma: Recent Progress and Challenges Ahead". W Glioblastoma - Current Evidences [Working Title]. IntechOpen, 2022. http://dx.doi.org/10.5772/intechopen.108419.

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Malignant brain tumor at its fourth stage (glioblastoma) is the most dangerous and an unsolved medical challenge till today. Present therapeutic strategies including chemo treatment, radiation along with surgery all together have not succeeded to control the progression of glioblastoma. Challenges in the early detection, unavailability of specific therapeutic strategy and severe cytotoxicity of available chemotherapeutics are the some of the prime causes of treatment failure. Especially presence of blood-brain barrier (BBB) highly limits pharmacological effect of conventional chemotherapy. In lieu of this, lipid based nanodrug carriers (LNCs) have now been evolved with great potential in improving the drug efficacy for the treatment of glioma. Further, LNCs engineered with specific targeting ligand might significantly reduce the dosage regimen, increase specificity, improve bioavailability and reduce off-target distribution. Such modified LNCs possess sufficient ability to cross BBB to deliver the loaded cargo(s) at target location inside the brain; thereby ensuring improved treatment outcome with less side effects than conventional treatment. This review primarily focuses on recent advancements in various engineered LNCs for the treatment of brain cancer. Also, the existing impediments for nanomedicines associated with their effective large scale synthesis or sufficient clinical application have also been highlighted.
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7

Taber, Douglass. "The Roush Synthesis of ( + )-Superstolide A". W Organic Synthesis. Oxford University Press, 2011. http://dx.doi.org/10.1093/oso/9780199764549.003.0093.

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( + )-Superstolide A 3, isolated from the New Caledonian sponge Neosiphonia superstes, shows interesting cytotoxicity against malignant cell lines at ~ 4 ng/mL concentration. The key transformation in the synthesis of 3 described (J. Am. Chem. Soc. 2008, 130, 2722) by William R. Roush of Scripps Florida was the transannular Diels-Alder cyclization of 2, which established, in one step with high diastereocontrol, both the cis decalin and the macrolactone of 3. The octaene 1 was assembled from four stereodefined fragments. The first, the linchpin 6, was prepared from the stannyl aldehyde 4. Homologation gave the enyne 5, which on hydroboration and oxidation gave 6. Earlier, Professor Roush had optimized the crotylation of the protected alaninal 7. In this case, the Brown reagent 8 delivered the desired Felkin product 9. Protection followed by ozonolysis gave the aldehyde 10. Crotylation with the Roush-developed tartrate 11 then gave the alkene 12, setting the stage for conversion to the iodide 13. Coupling of 13 with 6 completed the preparation of 14. The third component of (+)-superstolide A 3, the phosphonium salt 21, was assembled by Brown allylation of the aldehyde 15, to give 17. Protecting group interchange followed by ozonolysis delivered 18, which via Still-Gennari homologation was carried on to 21. Condensation with the fourth component, the aldehyde 22 , and esterification with 14 then gave 1. Under high dilution Suzuki conditions 1 was converted to 2. Storage in CDCl3 for five days, or brief warming, cyclized 2 to a single diastereomer of the transannular Diels-Alder product, that was carried on to (+)-superstolide A 3. While acyclic trienes comparable to 2 could be induced to cyclize, the transannular Diels-Alder reaction proceeded with much higher diastereocontrol.
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8

Fenchel, K., L. Bergmann, B. Jahn i P. S. Mitrou. "Up-Regulation of Adhesion Molecules by Immunotherapy as a Mechanism of Cytotoxicity in Renal Cell Cancer, Malignant Melanoma, and Acute Myelocytic Leukemia". W Contributions to Oncology, 336–46. S. Karger AG, 1994. http://dx.doi.org/10.1159/000422840.

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Streszczenia konferencji na temat "Malignancy - Cytotoxicity"

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Hussein, Ola, Feras Alali, Ala‐Eddin Al Mustafa i Ashraf Khalil. "Development of Novel Chalcone Analogs as Potential Multi-Targeted Therapies for Castration-Resistant Prostate Cancer". W Qatar University Annual Research Forum & Exhibition. Qatar University Press, 2021. http://dx.doi.org/10.29117/quarfe.2021.0114.

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Prostate cancer (PCa) is the second most frequently diagnosed malignancy, as well as a leading cause of cancer-related mortality in men globally. Despite the initial response to hormonal targeted therapy, the majority of patients ultimately progress to a lethal form of the disease, castration-resistant prostate cancer (CRPC). Therefore, the objective of this study was to discover and develop novel treatment modalities for CRPC. Chalcones are among the highly attractive scaffolds being investigated for their antitumor activities. A library of 26 chalcone analogs were designed, synthesized and evaluated as potential therapies for CRPC. The design was guided by in-silico ADMET prediction in which analogs with favorable drug-likeness properties were prioritized. The new compounds were synthesized, purified and characterized by extensive structural elucidation studies. The compounds in vitro cytotoxicity was evaluated against two androgen receptor (AR)-negative prostate cancer cell lines (PC3 and DU145). Among the tested compounds, pyridine containing analogs (13, 15 and 16) showed potent antiproliferative activities with IC50 values ranging between 4.32-6.47 µM against PC3 and DU145 cell lines. Detailed biological studies of the lead molecule 16 revealed that it can significantly induce apoptosis through upregulation of Bax and downregulation of Bcl-2. In addition, compound 16 potently inhibited colony formation and reduced cell migration of AR-negative PCa cell lines (PC3 and DU145). The molecular pathway analysis showed that the anticancer activity of compound 16 is associated with blocking of ERK1/2 and Akt activities. Furthermore, compound 16 inhibited angiogenesis in the chick chorioallantoic membrane (CAM) model as compared to control. Structure-activity relationship study revealed that the cytotoxicity could dramatically improve via changing the methoxylation pattern by more than 2-folds (IC50 << 2.5 μM). These results indicate that pyridine-based chalcones could serve as promising lead molecules for the treatment of CRPC; thus, further in vitro and in vivo studies are warranted.
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2

Hussein, Ola, Feras Alali, Ala-Eddin Al Moustafa i Ashraf Khalil. "Design, Synthesis and Biological Evaluation of Novel Chalcone Analogs as Potential Therapeutic Agents for Castration-Resistant Prostate Cancer". W Qatar University Annual Research Forum & Exhibition. Qatar University Press, 2020. http://dx.doi.org/10.29117/quarfe.2020.0179.

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Prostate cancer (PCa) is the second most frequently diagnosed malignancy, as well as a leading cause of cancer-related mortality in men globally. Despite the initial response to hormonal targeted therapy, the majority of patients ultimately progress to a lethal form of the disease, termed as castration-resistant prostate cancer (CRPC), which currently lacks curative therapeutic options and is associated with poor prognosis. Therefore, the development of novel treatment modalities for PCa is urgently needed. Chalcones, also known as 1,3-diphenyl-2-propen-1-ones, are among the highly attractive scaffolds being investigated for their antitumor activities. Three series of 18 cyclic (tetralone-based) and two acyclic chalcone analogs, in which ring B was either substituted with nitrogen mustard or replaced by pyrrole or pyridine heterocyclic rings, were designed, synthesized and evaluated as potential therapies for CRPC. Compounds were synthesized by Claisen-Schmidt condensation reaction, purified using columnchromatography or recrystallization and characterized by 1H-NMR, 13C-NMR and LC-MS. The compounds' in-vitro cytotoxicity was evaluated against three prostate cancer cell lines (PC3, DU145, and LNCaP). Among the tested compounds, OH14, OH19 and OH22 showed potent antiproliferative activities at low micromolar levels with IC50 values ranging between 4.4 and 10 µM against PC3 and DU145 cell lines. Detailed biological studies of the lead molecule OH19 revealed that it significantly induces apoptosis through upregulation of Bax and downregulation of BCL-2. In addition, OH19 potently inhibits colony formation and reduces cell migration of androgen-independent PCa cell lines (PC3 and DU145). The molecular pathway analysis show that the anticancer activity of OH19 is associated with attenuation in the phosphorylation of Akt and ERK. Furthermore, OH19 inhibits blood vessel formation in the chick chorioallantoic membrane (CAM) model as compared to control. These results indicate that OH19 could serve as a potential promising lead molecule for the treatment of CRPC and thus, further in-vitro and invivo studies are warranted.
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3

Song, Michael M., Monish R. Makena, Ashly Hindle, Balakrishna Koneru, Thinh H. Nguyen, Hwangeui Cho, Barry J. Maurer, Min H. Kang i C. Patrick Reynolds. "Abstract 2616: Comparison of the cytotoxicity and increase of reactive oxygen species and dihydroceramides of fenretinide to its major metabolites (4-oxo- and 4-methoxyphenyl fenretinide) in T-cell lymphoid malignancy, neuroblastoma, and ovarian cancer cell lines". W Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-7445.am2015-2616.

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Lee, David J., Yeo-Hyun Hwang i In Ah Kim. "Abstract A37: MicroRNA-26b potentiates cytotoxicity of malignant glioma cells by radiation". W Abstracts: Third AACR International Conference on Frontiers in Basic Cancer Research - September 18-22, 2013; National Harbor, MD. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1538-7445.fbcr13-a37.

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Kaza, Niroop, i Kevin A. Roth. "Abstract A34: Analysis of gossypol-induced cytotoxicity in malignant peripheral nerve sheath tumor cells." W Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics--Nov 12-16, 2011; San Francisco, CA. American Association for Cancer Research, 2011. http://dx.doi.org/10.1158/1535-7163.targ-11-a34.

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Truxova, Iva, Lenka Kasikova, Cyril Salek, Michal Hensler, Daniel Lysak, Peter Holicek, Pavla Bilkova i in. "Abstract B96: Calreticulin exposure on malignant blasts correlates with improved NK cell-mediated cytotoxicity in AML patients". W Abstracts: AACR Special Conference on Tumor Immunology and Immunotherapy; November 17-20, 2019; Boston, MA. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/2326-6074.tumimm19-b96.

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Jane, Esther P., Daniel R. Premkumar, Naomi R. Agostino, Joseph L. Scialabba i Ian F. Pollack. "Abstract 5209: Abrogation of STAT3 activation by JSI-124 enhances dasatinib-induced cytotoxicity in malignant human glioma cell lines". W Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC. American Association for Cancer Research, 2010. http://dx.doi.org/10.1158/1538-7445.am10-5209.

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Cooper, Jason P., Charles P. Reynolds, Robert W. Curley i Min H. Kang. "Abstract 1676: Cytotoxicity of fenretinide and its metabolite 4-oxo-4-HPR in malignant lymphoid cells can be dependent and independent of reactive oxygen species (ROS)". W Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC. American Association for Cancer Research, 2010. http://dx.doi.org/10.1158/1538-7445.am10-1676.

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Santos, Javier V., Alex Vara, Craig Thomas, Medhi Wangpaichitr, Min You, Niramol Savaraj i Dao M. Nguyen. "Abstract 3489: Profound cytotoxicity of the histone deacetylase inhibitor SAHA (Suberoylanilide Hydroxamic Acid) and TRAIL (Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand) combination in malignant pleural mesothelioma". W Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC. American Association for Cancer Research, 2010. http://dx.doi.org/10.1158/1538-7445.am10-3489.

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Santos, Javier V., Min You, Medhi Wangpaichitr, Niramol Savaraj i Dao M. Nguyen. "Abstract LB-222: Identifying cFLIP as a marker and also a potentially “druggable” target of SAHA+TRAIL (TNF-Related Apoptosis Inducing Ligand), cytotoxicity in malignant pleural mesothelioma (MPM)". W Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL. American Association for Cancer Research, 2011. http://dx.doi.org/10.1158/1538-7445.am2011-lb-222.

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