Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Temozolomide is an alkylating agent that mediates its cytotoxic effects via O(6)-methylguanine (O(6)-meG) adducts in DNA. O(6)-alkylguanine-DNA-alkyltransferase (MGMT) can repair such adducts and therefore constitutes a major resistance mechanism to the drug. MGMT activity can be attenuated in vitro and in vivo by the pseudosubstrate O(6)-(4-bromothenyl)guanine (PaTrin-2, Patrin, Lomeguatrib), which in clinical trials is in combination with temozolomide. Resistance to cytotoxic agents can also be mediated by the Bcl-2 protein, which inhibits apoptosis and is frequently up-regulated in tumor cells. Attenuation of Bcl-2 expression can be affected by treatment of cells with the antisense oligonucleotide, oblimersen sodium (Genasense), currently in phase III clinical trials in combination with the methylating agent dacarbazine. Using a human ovarian cancer cell line (A2780) that expresses both Bcl-2 and MGMT, we show that cells treated with active dose levels of either oblimersen (but not control reverse sequence or mismatch oligonucleotides) or PaTrin-2 are substantially sensitized to temozolomide. Furthermore, the exposure of oblimersen-pretreated cells to PaTrin-2 leads to an even greater sensitization of these cells to temozolomide. Thus, growth of cells treated only with temozolomide (5 microg/mL) was 91% of control growth, whereas additional exposure to PaTrin-2 alone (10 micromol/L) or oblimersen alone (33 nmol/L) reduced this to 81% and 66%, respectively, and the combination of PaTrin-2 (10 micromol/L) and oblimersen (33 nmol/L) reduced growth to 25% of control. These results suggest that targeting both Bcl-2 with oblimersen and MGMT with PaTrin-2 would markedly enhance the antitumor activity of temozolomide and merits testing in clinical trials.
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PMID:Sensitization of a human ovarian cancer cell line to temozolomide by simultaneous attenuation of the Bcl-2 antiapoptotic protein and DNA repair by O6-alkylguanine-DNA alkyltransferase. 1548 88

New strategies have evolved in the treatment of patients with non-Hodgkin's lymphoma (NHL). Anti-sense oligonucleotides (ASO) and monoclonal antibody (mAb) therapy, though proven to be safe and effective, have not demonstrated to be curative when used as single agents. We tested an innovative combination strategy involving various mAbs and ASO against Bcl-2 (G3139) in aggressive preclinical models. G3139, under optimal transfection conditions, decreased the proliferation rate of lymphoma cells by 60-75% when compared with controls. In addition, apoptosis was demonstrated in Raji (25%) and DHL-4 cells (30%) treated with Genasense following downregulation of Bcl-2 protein. Downregulation of Bcl-2 by G3139 was associated with a higher degree of rituximab-associated, complement-mediated cytotoxicity and antibody dependent cellular cytotoxicity when compared with rituximab alone-treated controls. In vivo studies in severe combined immunodeficiency (SCID) mice clearly demonstrated synergistic activity between G3139 and rituximab. Treatment of lymphoma-bearing SCID mice with G3139 for two consecutive days prior to each rituximab dose resulted in better disease control and survival than treatment with either agent alone or controls. Our findings suggest that Bcl-2 downregulation by G3139, followed by the administration of rituximab is an efficient anti-tumour strategy associated with improved survival in lymphoma-bearing SCID mice.
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PMID:Pro-apoptotic therapy with the oligonucleotide Genasense (oblimersen sodium) targeting Bcl-2 protein expression enhances the biological anti-tumour activity of rituximab. 1556 55

Overexpression of Bcl-2 protein in cancer cells can inhibit programmed cell death and engender chemoresistance. Reducing Bcl-2 protein levels by using antisense oligonucleotides targeting the gene message can increase the sensitivity of cancer cells to cytotoxic agents. The objective of this work was to investigate the antitumor efficacy of the Bcl-2 antisense oligonucleotide oblimersen (Genasense; G3139), alone and in combination with vinorelbine (VNB), in an ectopic and orthotopic xenograft model of NCI-H460 human non-small-cell lung cancer. In addition to assessing therapeutic effect, Bcl-2 protein expression in tumor tissue isolated from lung and heart was measured. In the ectopic xenograft model, oblimersen at 5 and 10 mg/kg significantly inhibited tumor growth compared with saline-treated control groups, and furthermore, the antitumor effect of oblimersen was associated with down-regulation of Bcl-2 protein in isolated tumor tissue. Moreover, the combination of oblimersen with VNB was more active in inhibiting tumor growth than either drug used alone. In the orthotopic model, oblimersen treatment (5 mg/kg) increased the median survival time of mice to 33 days in comparison with a median survival time of 21 days in the control animals. With this model, the anticancer effect was demonstrated by assessing tumor growth in lung and heart tissues by hematoxylin and eosin staining and Bcl-2 expression by immunohistochemistry. When VNB at 5 mg/kg was combined with oblimersen administered at 5 mg/kg, 33% of mice survived more than 90 days. These data suggest that the combination of oblimersen and VNB may provide enhanced antitumor activities against non-small-cell lung cancer.
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PMID:Antitumor efficacy of oblimersen Bcl-2 antisense oligonucleotide alone and in combination with vinorelbine in xenograft models of human non-small cell lung cancer. 1556 99

Apoptosis, or programmed cell death, is a complex process of cell turnover involved in both normal and pathologic processes in the body. Impairments in the apoptotic pathways contribute to tumorigenesis and the development of tumor resistance to chemotherapy. The proto-oncogene bcl-2 appears to serve a critical antiapoptotic function. Its broad expression in tumors coupled with its role in resistance to chemotherapy-induced apoptosis make bcl-2 a rational target for anticancer therapy. The Bcl-2 antisense drug oblimersen sodium (Genasense) enhances apoptosis alone and in combination with cytotoxic chemotherapy in vitro and in numerous xenograft models of solid tumors and hematologic cancers. Results from xenograft models of melanoma were especially encouraging, prompting melanoma to be identified as an initial human trial candidate. In a phase II trial in patients with advanced malignant melanoma resistant to first-line chemotherapy (including dacarbazine [DTIC-Dome]), three objective responses and three minor responses to oblimersen plus dacarbazine were observed among 14 patients. In a large randomized phase III trial, oblimersen plus dacarbazine showed a near doubling of response rate vs dacarbazine alone and a significant prolongation of progression-free survival. For the primary endpoint of overall survival, a significant benefit for the combination was not seen. The ability of oblimersen to modulate apoptosis suggests a new paradigm of anticancer therapy that has clinical potential in a variety of solid tumors and hematologic malignancies. Further, oblimersen is the first antisense molecule studied in clinical trials for its anticancer properties, opening up an entirely new direction for therapy.
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PMID:Apoptosis, Bcl-2 antisense, and cancer therapy. 1565 Nov 71

Most malignant plasma cells overexpress Bcl-2, which contributes to resistance against apoptosis induced by dexamethasone and other anticancer agents. Oblimersen sodium (Genasense, previously known as G3139), an antisense oligonucleotide that specifically binds to bcl-2 messenger RNA, decreases production of Bcl-2 protein in both human myeloma cell lines, as well as in ex vivo purified myeloma cells, and enhances the cytotoxicity of dexamethasone and doxorubicin. Combining oblimersen with other anticancer agents represents a therapy-enhancing strategy to reverse the multidrug resistance seen in multiple myeloma (MM). Phase II trials are evaluating the potential role of oblimersen in reversing resistance to standard therapies. Preliminary results from these trials in patients with refractory or relapsed MM indicate that the combination of oblimersen with dexamethasone/thalidomide (Thalomid) or vincristine/doxorubicin/dexamethasone is active and well tolerated and that oblimersen may help overcome chemotherapy resistance and restore sensitivity to MM cells. A randomized phase III clinical trial comparing dexamethasone plus oblimersen with dexamethasone alone in patients with relapsed or refractory myeloma has completed enrollment, with results expected to be available in 2004. Future studies will focus on the role of oblimersen in combination with novel biologic agents such as bortezomib (Velcade).
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PMID:Bcl-2 antisense therapy in multiple myeloma. 1565 Nov 73

Bcl-2 functions as a key survival factor for lymphocytes and is highly expressed in a majority of non-Hodgkin's lymphomas. The ability of oblimersen sodium (Genasense, previously known as G3139) to target bcl-2 messenger RNA and decrease Bcl-2 protein levels has the potential to enhance the activity of cytotoxic chemotherapy. Pretreatment with oblimersen followed by cyclophosphamide (Cytoxan, Neosar) markedly improved survival relative to single-agent cyclophosphamide in a murine xenograft model. Oblimersen has also enhanced the cytotoxicity of a variety of other agents against non-Hodgkin's lymphoma, including etoposide, rituximab (Rituxan), and alemtuzumab (Campath). An initial phase I study of oblimersen in non-Hodgkin's lymphoma demonstrated modest single-agent activity. Recent reports suggest that oblimersen may add to the activity of R-CHOP (rituximab-cyclophosphamide/doxorubicin/vincristine/prednisone) in previously untreated mantle cell lymphoma and to rituximab alone in a variety of subtypes of relapsed non-Hodgkin's lymphoma. Additional studies in both treatment-naive and relapsed patients will define the role of oblimersen in the treatment of non-Hodgkin's lymphoma.
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PMID:Targeting the proapoptotic factor Bcl-2 in non-Hodgkin's lymphoma. 1565 Nov 74

Bcl-2 protein is upregulated in a wide variety of lymphoid malignancies, including chronic lymphocytic leukemia (CLL). The protein is thought to be responsible for maintaining the viability of malignant lymphoid cells and may contribute to chemotherapy and radiotherapy resistance. Previous studies have shown that reduction of bcl-2 expression by antisense therapy sensitizes cells to chemotherapy-induced apoptosis. In vitro, the Bcl-2 antisense drug oblimersen sodium (Genasense, previously known as G3139) enhances the apoptotic response in CLL cells to fludarabine (Fludara), corticosteroids, alemtuzumab (Campath), and rituximab (Rituxan). A phase I trial in patients with refractory/relapsed CLL showed that patients with CLL were more sensitive to oblimersen than patients with solid tumors. The maximum tolerated oblimersen dose was 3 mg/kg/d, and the most common dose-limiting reaction was hypotension, frequently in association with high spiking fever. In this study, oblimersen displayed limited single-agent activity, including tumor lysis syndrome, transient decreases in circulating CLL cells, and reduction of splenomegaly and size of lymph nodes. Major responses were observed in 9% of patients. Subsequently, a phase III trial evaluating fludarabine and cyclophosphamide with or without oblimersen (3 mg/kg/d for 7 days) was initiated in patients with relapsed or refractory CLL. This trial recently completed accrual of 241 patients.
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PMID:Potential therapeutic applications of oblimersen in CLL. 1565 Nov 75

Oblimersen sodium is an antisense oligonucleotide to the first 6 codons of the B-cell leukemia gene 2 (bcl-2) open reading frame. It prevents the expression of the bcl-2 gene product and leads to apoptosis in cells that express Bcl-2. bcl-2 is one of the major apoptosis regulatory gene families and is found in a variety of low-grade B-cell non-Hodgkin's lymphomas. The in vitro use of oblimersen in Waldenstrom's macroglobulinemia (WM) cell line results in enhanced toxicity when exposed to fludarabine, dexamethasone, or rituximab. Oblimersen should also enhance the cytotoxic effect of chemotherapy in WM. Presented herein are early data on the phase I portion of a phase I/II study of oblimersen in WM to identify the maximum tolerated dose and to evaluate response in patients with symptomatic WM.
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PMID:Early results of a phase I trial of oblimersen sodium for relapsed or refractory Waldenstrom's macroglobulinemia. 1579 66

Nasopharyngeal carcinoma (NPC) is causally linked to Epstein-Barr virus (EBV), and the EBV oncoprotein, latent membrane protein 1 (LMP-1), is expressed in the majority of NPCs. LMP-1 upregulates antiapoptotic genes, including bcl-2, and Bcl-2 protein is overexpressed in NPC. Given the antiapoptotic and chemoprotective effects of Bcl-2, it represents a rational therapeutic target in NPC. We have investigated the antitumor and chemosensitizing effects of the Bcl-2 antisense oligodeoxynucleotide G3139 (oblimersen, Genasense) in NPC. For these studies, we used the C666-1 line, a stably infected NPC-derived line that co-expresses LMP-1 and Bcl-2. We have shown that G3139 treatment of C666-1 in vitro caused sequence-dependent suppression of Bcl-2 protein, inhibition of cell growth and enhanced sensitivity to cisplatin (CDDP), as measured by increased antiproliferative and apoptotic effects. In vivo, G3139 treatment (25 mg/kg every 3 days x 5 doses) delayed engraftment and significantly inhibited growth of established C666-1 xenografts in SCID mice compared to control oligo-treated animals. However, G3139 alone did not prevent engraftment or cure established tumors in any animals. In contrast, G3139 treatment (25 mg/kg every 3 days x 5 starting on day 7) in combination with CDDP (8 mg/kg on day 14) completely abrogated tumor engraftment in 80% of animals compared to CDDP (0%) or CDDP + control oligo (0%). When treatment was delayed until tumor was established, G3139 in combination with CDDP significantly inhibited tumor growth compared to CDDP or CDDP + control oligo, and cured 69% animals with established tumors. No animals treated with G3139, CDDP or CDDP + control oligo were cured. Tumor burden and response to treatment correlated with EBV DNA load in serum, measured by real-time PCR. Western blots of tumor extracts obtained during oligo treatment showed that Bcl-2 levels were significantly decreased in G3139-treated animals. Our studies have demonstrated that the Bcl-2 antisense oligodeoxynucleotide, G3139, has proapoptotic effects in C666-1, and in combination with CDDP, is curative in C666-1 NPC xenograft tumors in vivo. The sequence-dependency of these effects is consistent with an antisense mechanism. These studies suggest that Bcl-2 may represent a biologically relevant target for the development of novel combinatorial therapies for NPC.
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PMID:Systemic Bcl-2 antisense oligodeoxynucleotide in combination with cisplatin cures EBV+ nasopharyngeal carcinoma xenografts in SCID mice. 1647 27


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