Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:A9QXG9 (bcl-2)
 7,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Small cell lung cancer (SCLC) is characterised by neuroendocrine differentiation, early metastatic potential and initial responsiveness to cytotoxic therapy. Unfortunately, despite recent therapeutic advances, most patients relapse and the overall five-year survival rate is only 5%. Standard treatment of SCLC consists of platinum-based combination chemotherapy, with thoracic irradiation added for patients with limited-stage disease. Several newer chemotherapeutic drugs have recently been shown to have significant activity in patients with untreated or relapsed SCLC. These agents include: the topoisomerase I inhibitors, topotecan and irinotecan; the taxanes, paclitaxel and docetaxel; the pyrimidine analogue, gemcitabine; and the vinca alkaloid, vinorelbine. Recent advances in our understanding of the molecular events involved in the pathogenesis and progression of SCLC have led to the identification of a variety of potential targets for novel therapeutic interventions. Strategies aimed at inhibiting the myriad of growth factor pathways that control the proliferation of SCLC cells, include: broad spectrum neuropeptide antagonists (e.g., substance P analogues); growth factor/receptor-specific inhibitors (e.g., anti-GRP monoclonal antibodies, bradykinin antagonist dimers); and a variety of selective protein kinase inhibitors. The importance of cell death pathways in carcinogenesis and treatment-resistance has led to several novel strategies targeting apoptotic mediators, such as bcl-2, that are frequently dysregulated in SCLC (e.g., bcl-2 antisense). Our current challenges are to further refine these promising therapeutic strategies, efficiently evaluate their activity in the clinical setting and integrate them into more effective treatment regimens to improve the overall prognosis of patients with SCLC.
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PMID:Therapeutic advances in small cell lung cancer. 1106 Jun 96

G-3139 is an antisense phosphorothioate oligodeoxynucleotide (AS PS ON) which suppresses bcl-2 expression and is being developed by Genta Inc for the potential treatment of various cancers [308375]. G-3139 is in various stages of phase I/lIa trials. One study, initiated in May 1999, at the Lombardi Cancer Center at Georgetown University Medical Center, US, will examine G-3139 in conjunction with docetaxel. In a phase I/IIa dose-escalating trial to treat non-Hodgkin's lymphoma (NHL), at the Royal Marsden NHS Trust, UK, no serious, clearly drug-attributable or doselimiting adverse effects were noted and in some patients encouraging signs of potential drug activity were observed. The responses included one patient in whom cancer mass was reduced and one who developed a complete response for over 38 weeks in duration [239159,291608,325262]. A new phase II protocol using G-3139 combined with standard chemotherapies in relapsed NHL patients has also begun [325262]. Other phase I/lIa studies include: the safety and efficacy of G-3139 in the treatment of hormone-resistant, metastatic prostate cancer, when administered with mitoxantrone [305822]; the treatment of relapsed follicular NHL, when administered with cyclophosphamide [311217]; the treatment of Stage III and IV metastatic malignant melanoma in combination with dacarbazine [289755]; the treatment of hormone-resistant, metastatic prostate cancer when administered over a significantly longer duration than studied previously and in combination with an androgen-receptor blocking agent [291608]. The National Cancer Institute (NCI) funded and conducted preclinical studies of G-3139 in July 1996 and in June 1998, the NCI and Genta entered into a Cooperative Research and Development Agreement (CRADA) for the development of G-3139 [290153]. Clinical trials,focusing on colorectal cancer, small cell lung cancer and leukemia, were underway as of April 1999. The company licensed the rights for the use of bcl-2 as a target for antisense and gene therapy-based treatments from the University of Pennnsylvania. In June 1998, Genta received two patents relating to its antisense compounds [289685].
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PMID:Technology evaluation: G-3139. 1171 6

Chemotherapeutic drugs eliminate cancer cells by induction of apoptosis. Resistance to chemotherapy is partly due to a decreased apoptosis rate. Here we investigated resistance to anticancer drugs in 9 small cell lung cancer (SCLC) cell lines. Apoptosis was induced by cisplatin, doxorubicin and etoposide and was found to be independent of caspase-8 expression. Since caspase-8 is essential for signal transduction of death receptor-mediated apoptosis, all known death receptor systems are thus not required for drug-induced apoptosis in SCLC. Furthermore, we found that anticancer drugs could activate the mitochondrial pathway of apoptosis without involvement of upstream caspases. Finally, by culturing 3 sensitive cell lines in subtherapeutic concentrations of etoposide, resistant cells were generated that exhibit cross-resistance to cisplatin and doxorubicin. Drug resistance was paralleled by strong upregulation of Bcl-2, which diminished apoptosis by inhibiting the loss of the mitochondrial transmembrane potential and the release of cytochrome c. The role of bcl-2 in these processes was supported by bcl-2 transfection and antisense inhibition. These results indicate that Bcl-2 contributes to drug resistance in SCLC, a finding that has profound therapeutic implications.
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PMID:Upregulation of Bcl-2 is involved in the mediation of chemotherapy resistance in human small cell lung cancer cell lines. 1180 82

Several studies have shown that extracellular matrix reduces chemotherapeutic drugs-induced apoptosis in small cell lung cancer cells, myelomas and gliomas. We have investigated the protective effect of defined extracellular matrix components and of extracellular matrix from different cell types (fibroblasts, hepatocytes and intestinal epithelial cells) on the toxicity of three types of chemotherapeutic drugs on colon cancer cells. Human colon cancer cell lines LS174T and LiM6 were plated on plastic, on hepatocyte-derived ECM or on stromal ECM and in the presence of the antimetabolite 5-fluorouracil (5-FU). the topoisomerase I inhibitor camptothecin and the topoisomerase II inhibitor etoposide. We determined IC50 for the drugs for each of these culture conditions. We also determined the expression of the anti-apoptotic proteins bcl-2 and bcl-x (L) under these culture conditions. We found that stromal ECM protected LiM6 cells from the toxicity of etoposide and LS174T, but not LiM6 cells, from the toxicity of camptothecin. Collagen 1, fibronectin and fibroblast-derived ECM rendered LiM6 cells, but not LS174T, more sensitive to the harmful effect of 5-FU. Both colon cell lines had increased expression of anti-apoptotic proteins bcl-2 and bcl-x(L) when cultured on the various ECMs and with the drugs, but there was no correlation between a protective ECM effect and expression of the anti-apoptotic proteins. Stromal-derived ECM may protect colon cancer cells from etoposide and camptothecin-induced apotosis, through a mechanism that is not bcl-2 or bcl-x(L) dependant.
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PMID:Stromal extracellular matrix reduces chemotherapy-induced apoptosis in colon cancer cell lines. 1191 83

Telomerase activity was examined by the telomeric repeat amplification protocol (TRAP) assay in 38 neuroendocrine (NE) lung tumours. A significantly (p = 0.001) different frequency of telomerase positivity was observed among different histological tumour types. Specifically, a positive TRAP signal was observed in 14 of 15 (93%) small cell lung cancers (SCLCs), 7 of 8 (87%) large-cell NE carcinomas (LCNECs), and only 1 of 15 (7%) typical carcinoid tumours. When telomerase activity was correlated with the gene product-based immunophenotypic profile of individual tumours, it was found that the absence of telomerase activity was associated with a lack of bcl-2, p53, and c-kit expression, and characterized by a low proliferation index consistent with the absence of cdk-4 expression and the presence of the cdk inhibitor Rb. Such a phenotype was appreciable in most of the carcinoid tumours. Conversely, telomerase-positive tumours generally showed an immunophenotype consistent with gene product alterations (including high expression of bcl-2, p53, and c-kit, and loss of Rb) and were characterized by a high proliferation index. These telomerase data support the previously reported evidence for two genetically unrelated groups of NE lung tumours (SCLC, and to some extent LCNEC, versus carcinoid tumours) that have distinct phenotypic profiles.
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PMID:Differential expression of telomerase activity in neuroendocrine lung tumours: correlation with gene product immunophenotyping. 1295 25

Bcl-2 protein inhibits apoptosis and confers resistance to treatment with traditional cytotoxic chemotherapy, radiotherapy, and monoclonal antibodies. Oblimersen sodium is an antisense oligonucleotide compound designed to specifically bind to human bcl-2 mRNA, resulting in catalytic degradation of bcl-2 mRNA and subsequent decrease in bcl-2 protein translation. Both small cell and non-small cell lung cancer show baseline and inducible expression of bcl-2, which may contribute to resistance to therapy. Preclinical studies have shown that combining bcl-2 antisense with chemotherapy improves antitumor response, increases apoptosis of tumor cells, and increases survival. Preliminary data from a large international randomized trial in melanoma show a trend toward increased survival and significantly improved response rates and response duration when oblimersen is added to dacarbazine. Phase I studies in small cell lung cancer patients demonstrate that oblimersen can be combined with paclitaxel or carboplatin and etoposide. The combination of docetaxel and oblimersen has been shown to be feasible in Phase I studies and is currently undergoing evaluation in comparison with docetaxel alone as first-line salvage therapy in patients refractory or relapsed after one prior chemotherapy regimen. Enhancement of the efficacy of anticancer treatments with oblimersen bcl-2 antisense therapy represents a promising new apoptosis-modulating strategy.
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PMID:Oblimersen sodium (Genasense bcl-2 antisense oligonucleotide): a rational therapeutic to enhance apoptosis in therapy of lung cancer. 1521 67

Histone deacetylase inhibitors modulate the transcription of target genes and represent a new class of anticancer agents. The histone deacetylase inhibitor FR901228 has been reported to show antiproliferative and apoptotic effects in various malignancies including small cell lung cancer (SCLC) in vitro; however, the underlying mechanism is not fully understood. BCL-2 and BCL-XL are antiapoptotic proteins, of which overexpression has been reported to confer resistance to anticancer agents. High levels of BCL-2 and BCL-XL are frequently expressed in SCLC tumors. The present study was designed to clarify the apoptotic pathway of FR901228 in SCLC cells in vitro. FR901228 induced apoptosis in three SCLC cell lines after 24 hours of treatment. FR901228 activated caspase-9 and caspase-3 but not caspase-8, and the caspase-3 inhibitor Z-DEVD-fmk blocked the cytotoxicity of FR901228. FR901228 down-regulated the expression of bcl-2 and bcl-xL mRNA through de novo protein synthesis and suppressed the expression of BCL-2 and BCL-XL proteins. In addition, the combination of bcl-2 antisense oligonucleotides with FR901228 enhanced FR901228-induced caspase-3 activity and cytotoxicity. These findings suggest that FR901228 induces caspase-dependent apoptosis via the mitochondrial pathway rather than the death receptor pathway. Considering the possible contributions of BCL-2 and BCL-XL to multidrug resistance, FR901228 is a promising agent in the treatment of refractory as well as primary SCLC tumors.
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PMID:The histone deacetylase inhibitor FR901228 induces caspase-dependent apoptosis via the mitochondrial pathway in small cell lung cancer cells. 1554 78

Small cell lung cancer (SCLC) is one of the most fatal cancers in humans and many factors are known to be related to its poor prognosis. Immunohistochemical (IHC) stainings were done on SCLC specimens in order to investigate the prognostic value of the apoptosis-related gene expression and the tumor proliferative maker, and the relationships among these IHC results and patients clinical characteristics, chemoresponsiveness, and survival were analyzed. The medical records of 107 patients were reviewed retrospectively. IHC stainings for p53, bcl-2 and Ki-67 expressions were performed in the 66 paraffin-embedded biopsy samples. Sixty-six out of the 107 patients were evaluable for response rate and survival. The overall response rate was 75% (95% Confidence Interval=74-76%) and the median survival time was 14 months. The median survival time of limited stage was 16 months and that of extensive stage was 10 months. The prevalence of p53, bcl-2 and Ki-67 expression was 62%, 70%, and 49%, respectively. There were no correlations among the immunoreactivities of p53, bcl-2 and Ki-67 with clinical stage, chemoresponsiveness or overall survival. The clinical stage was the only prognostic factor influencing survival. The expression rates of p53, bcl-2, and Ki-67 were relatively high in SCLC without any prognostic significance. The exact clinical role of these markers should be defined through further investigations.
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PMID:Prognostic value of immunohistochemical staining of p53, bcl-2, and Ki-67 in small cell lung cancer. 1647 62

Osteopontin (OPN) is a multi-functional cytokine involved in cell survival, migration and adhesion which is associated with tumorigenesis, progression and metastasis. However, the role of OPN in chemo-sensitivity of human lung cancer has not yet been elucidated. The purpose of this study is to investigate the role of OPN in chemo-sensitivity of lung cancer cells. We developed a stable OPN transfectant (SBC-3/OPN) and a control transfectant (SBC-3/NEO) from human small cell lung cancer cell line, SBC-3. SBC-3/OPN cells were more resistant to cisplatin than SBC-3/NEO cells. Multi-drug resistance-associated protein (MRP) does not appear to be involved in the development of acquired chemo-resistance, since MRP inhibitor did not alter chemo-sensitivity. After exposure to cisplatin, the apoptotic SBC-3/OPN cells were reduced in number compared to SBC-3/NEO cells. Treatment with cisplatin revealed that the expression of anti-apoptotic protein, bcl-2, was down-regulated in SBC-3/NEO cells, while that of SBC-3/OPN cells was not altered. In contrast, pro-apoptotic protein, bax, was not altered in both SBC-3/OPN and SBC-3/NEO cells, thus bcl-2/bax ratio was decreased in SBC-3/NEO but not altered in SBC-3/OPN cells. Activation of caspase-3 and caspase-9 was increased in SBC-3/NEO cells, but not in SBC-3/OPN cells. Our results suggest that OPN enhances chemo-resistance of cisplatin in SBC-3 cells by suppressing bcl-2 protein down-regulation, thereby blocking the caspase-9- and caspase-3-dependent cell apoptosis.
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PMID:Osteopontin is involved in the development of acquired chemo-resistance of cisplatin in small cell lung cancer. 1928 49

Epithelial and endothelial tyrosine kinase (Etk), also known as Bmx (bone marrow X kinase), plays an important role in the apoptosis of epithelial cells. The aim of this study was to investigate whether Etk is involved in the chemoresistance of small cell lung cancer (SCLC) and to correlate the drug resistance associated proteins such as bcl-2, bcl-X(L) and p53. Drug-resistant small lung cancer cells (H69AR) which were originally developed by ADM and which demonstrated multi-drug resistance to chemotherapeutic agents were used in the study. Western blot analysis revealed that H69AR cells over-expressed the proteins Etk and bcl-X(L), but not bcl-2 and p53 when compared to parent H69 cells. Knockdown of Etk expression by Etk-specific small interfering RNA sensitised H69AR cells to chemotherapeutic drugs and inhibited bcl-X(L) expression but not bcl-2 and p53. Co-immunoprecipitation was performed to further evaluate the relationship between Etk and bcl-X(L) with anti-Etk and anti-phospho-Etk antibodies. The bcl-X(L) was accompanied with a robust increase of Etk and tyrosine phosphorylated Etk at Tyr-40 in H69AR cells. In conclusion, our results suggest that non-receptor tyrosine kinase Etk is involved in drug resistance to SCLC by mediating bcl-X(L) via Tyr(P)-40. The potential approach for downregulation of Etk activity on expression would be a novel, potentially clinically practical strategy for interfering with chemoresistance in SCLC.
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PMID:Non-receptor tyrosine kinase Etk regulation of drug resistance in small-cell lung cancer. 2000 64


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