oblimersen and Melanoma

oblimersen has been researched along with Melanoma* in 28 studies

Reviews

7 review(s) available for oblimersen and Melanoma

ArticleYear
Oblimersen in the treatment of metastatic melanoma.
    Future oncology (London, England), 2007, Volume: 3, Issue:3

    Oblimersen (Genasense is a Bcl-2 antisense compound that selectively targets Bcl-2 RNA for degradation by RNase H and thereby decreases Bcl-2 protein production. Bcl-2 protein plays a major role in preventing apoptosis and has been linked to chemotherapy resistance in melanoma. Preclinical studies with oblimersen in melanoma cell lines and xenograft models of melanoma have demonstrated downregulation of Bcl-2 protein, induction of apoptosis and enhanced tumor response when combined with chemotherapy. Results of a Phase I/II study have shown that reducing Bcl-2 with oblimersen coincident with the administration of dacarbazine may amplify apoptosis and improve therapeutic outcome. A subsequent Phase III trial showed that the addition of oblimersen to dacarbazine significantly improved multiple clinical outcomes relative to dacarbazine alone based on an intent-to-treat analysis of progression-free survival and response rate (overall, complete and durable), as well as overall survival in patients with normal lactate dehydrogenase. This article reviews the biochemistry, pharmacodynamics and pharmacokinetics, safety and efficacy data related to oblimersen in melanoma.

    Topics: Antineoplastic Agents, Alkylating; Humans; Melanoma; Oligonucleotides, Antisense; Proto-Oncogene Proteins c-bcl-2; Skin Neoplasms; Thionucleotides

2007
Individualized therapy of disseminated cancer using malignant melanoma as a model.
    Cancer metastasis reviews, 2006, Volume: 25, Issue:2

    Approximately 20 to 25% of patients with malignant melanoma will die of metastatic disease. The current standards of care for advanced metastatic melanoma (stage IV, AJCC classification) are poor. To date, randomized trials have failed to demonstrate that one regimen is better than another. It is therefore crucial that patients with disseminated malignant melanoma be recruited into clinical trials. In recent years, there have been impressive advances in our knowledge of the biology and nature of cancer development and the growth and progression to metastasis. The approach "from bench to bedside" is current reality in the treatment of several solid tumors and hematologic malignancies. The identification of new targets to facilitate individualized melanoma treatment is now an important issue. This article will give an overview of recent developments in clinical trials of targeted therapies in metastatic melanoma patients.

    Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Humans; Melanoma; Neoplasm Metastasis; Oligonucleotides, Antisense; Signal Transduction; Thionucleotides

2006
Bcl-2-targeted antisense therapy (Oblimersen sodium): towards clinical reality.
    Reviews on recent clinical trials, 2006, Volume: 1, Issue:3

    The identification of activated oncogenes, such as the bcl-2, in several types of cancer has made it possible to consider such genes as targets for antitumor therapy. Bcl-2 is an anti-apoptotic protein, whose overexpression is associated with chemotherapy resistant cancer, aggressive clinical course and poor survival. The development of novel targeted gene-silencing strategies, such as those based on the use of antisense oligonucleotides, represents a renewed hope in the treatment of cancer. Within this scope, this review covers the main pre-clinical aspects and the most recent clinical data obtained with Oblimersen sodium (Genta Inc.). Oblimersen is a 18-mer phosphorothioate antisense oligonucleotide designed to bind to the first six codons of the human bcl-2 mRNA. Phase I/II trials indicate that infusion of Oblimersen provides biologically relevant plasma levels that lead to downregulation of target Bcl-2 protein. Moreover, the use of Oblimersen in combination with chemotherapy in a variety of cancers has shown promising response rates with good tolerability. Randomized phase III trials are currently underway to evaluate whether the combined use of Oblimersen with standard treatment is superior to standard treatment alone in chronic lymphocytic leukaemia, malignant melanoma and multiple myeloma. Overall, the enhanced efficacy of anticancer treatments of this bcl-2-targeted antisense therapy represents a promising new apoptosis-modulating strategy.

    Topics: Breast Neoplasms; Carcinoma, Small Cell; Clinical Trials as Topic; Colorectal Neoplasms; Down-Regulation; Drug Therapy, Combination; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myeloid, Acute; Lymphoma, Non-Hodgkin; Male; Melanoma; Oligonucleotides, Antisense; Prostatic Neoplasms; Proto-Oncogene Proteins c-bcl-2; Thionucleotides

2006
Induction of apoptosis by G3139 in melanoma cells.
    Annals of the New York Academy of Sciences, 2005, Volume: 1058

    G3139 is an 18mer phosphorothioate oligonucleotide targeted to the initiation codon region of the Bcl-2 mRNA. Because of the ability of this antisense construct to downregulate the expression of Bcl-2 mRNA and protein, it has entered phase III clinical trials in a number of human cancers, including advanced melanoma. However, the actual mechanism of this agent is far from certain. In this work, we demonstrate that G3139 induces the relatively rapid release of cytochrome c into the cytoplasm of treated 518A2 melanoma cells. This release activates the intrinsic pathway of apoptosis, eventually leading to a mitochondrial permeability transition and cell death. By employing an siRNA strategy, we also show that this entire process appears to be Bcl-2 independent, as downregulation of Bcl-2 protein expression does not alter the induction of apoptosis by G3139. Furthermore, forced overexpression of Bcl-2 protein contributes relatively little to chemoresistance in this cell line. While these results may or may not be reflective of the in vivo situation, the value of Bcl-2 as a target in advanced melanoma must at least be questioned.

    Topics: Animals; Apoptosis; Caspases; Cell Survival; Clinical Trials as Topic; Cytoplasm; Enzyme Inhibitors; Humans; Melanoma; Mitochondria; Oligonucleotides, Antisense; Proto-Oncogene Proteins c-bcl-2; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Thionucleotides

2005
Management of metastatic cutaneous melanoma.
    Oncology (Williston Park, N.Y.), 2004, Volume: 18, Issue:11

    The results of treatment for metastatic melanoma remain disappointing. Single-agent chemotherapy produces response rates ranging from 8% to 15%, and combination chemotherapy, from 10% to 30%. However, these responses are usually not durable. Immunotherapy, particularly high-dose interleukin (IL)-2 (Proleukin), has also shown a low response rate of approximately 15%, although it is often long-lasting. In fact, a small but finite cure rate of about 5% has been reported with high-dose IL-2. Phase II studies of the combination of cisplatin-based chemotherapy with IL-2 and interferon-alfa, referred to as biochemotherapy, have shown overall response rates ranging from 40% to 60%, with durable complete remissions in approximately 8% to 10% of patients. Although the results of the phase II single-institution studies were encouraging, phase III multicenter studies have reported conflicting results, which overall have been predominantly negative. Various factors probably explain these discrepancies including different biochemotherapy regimens, patient selection, and, most importantly, "physician selection." Novel strategies are clearly needed, and the most encouraging ones for the near future include high-dose IL-2 in combination with adoptive transfer of selected tumor-reactive T cells after nonmyeloablative regimens, BRAF inhibitors in combination with chemotherapy, and the combination of chemotherapeutic agents and biochemotherapy with oblimersen sodium (Genasense).

    Topics: Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Combined Modality Therapy; Dacarbazine; Humans; Immunotherapy; Interleukin-2; Melanoma; Multicenter Studies as Topic; Neoplasm Staging; Prognosis; Randomized Controlled Trials as Topic; Skin Neoplasms; Survival Analysis; Temozolomide; Thionucleotides; Treatment Outcome

2004
Apoptosis, Bcl-2 antisense, and cancer therapy.
    Oncology (Williston Park, N.Y.), 2004, Volume: 18, Issue:13 Suppl 1

    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.

    Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Dacarbazine; Genes, bcl-2; Humans; Melanoma; Neoplasms; Oligonucleotides, Antisense; Proto-Oncogene Mas; Proto-Oncogene Proteins c-bcl-2; Randomized Controlled Trials as Topic; Thionucleotides; Transplantation, Heterologous

2004
G 3139. Augmerosen, Bcl-2 antisense oligonucleotide--Genta, GC 3139, Genasense.
    Drugs in R&D, 2002, Volume: 3, Issue:1

    Topics: Animals; Antineoplastic Agents; Humans; Lymphoma, Non-Hodgkin; Male; Melanoma; Neoplasms; Oligonucleotides, Antisense; Prostatic Neoplasms; Thionucleotides

2002

Trials

4 trial(s) available for oblimersen and Melanoma

ArticleYear
Dacarbazine with or without oblimersen (a Bcl-2 antisense oligonucleotide) in chemotherapy-naive patients with advanced melanoma and low-normal serum lactate dehydrogenase: 'The AGENDA trial'.
    Melanoma research, 2014, Volume: 24, Issue:3

    In a previous large randomized, open-label study, retrospective subset analysis revealed that the addition of the Bcl-2 antisense oligonucleotide oblimersen to dacarbazine (Dac) significantly improved overall survival, progression-free survival, and the response rate in chemotherapy-naive patients with advanced melanoma and normal baseline serum lactate dehydrogenase (LDH) levels. To confirm and expand on this observation, we conducted a prospective double-blind, placebo-controlled study to determine whether oblimersen augmented the efficacy of Dac in advanced melanoma patients with low-normal baseline LDH levels. A total of 314 chemotherapy-naive patients were randomly assigned to receive Dac (1000 mg/m(2)) preceded by a 5-day continuous intravenous infusion of either oblimersen sodium (7 mg/kg/day) or placebo every 21 days for less than eight cycles. Co-primary efficacy endpoints were overall survival and progression-free survival. Response and progression of the disease were assessed by independent blinded review of computed tomography scan images. No difference in overall nor progression-free survival was observed between the Dac-oblimersen and Dac-placebo groups. Although the overall (17.2 vs. 12.1%) and durable (10.8 vs. 7.6%) response rates numerically favored Dac-oblimersen over Dac-placebo, they did not differ significantly (P=0.19 and 0.32, respectively). The incidence of hematologic adverse events, particularly thrombocytopenia and neutropenia, was higher in the Dac-oblimersen group than in the Dac-placebo group. Withdrawals from the study because of treatment-related adverse events were low (i.e. <2.5%) in both groups. The addition of oblimersen to Dac did not significantly improve overall survival nor progression-free survival in patients with advanced melanoma and low-normal levels of LDH at baseline.

    Topics: Aged; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Dacarbazine; Disease-Free Survival; Double-Blind Method; Drug Administration Schedule; Female; Gene Expression Regulation, Neoplastic; Humans; Infusions, Intravenous; Male; Melanoma; Middle Aged; Oligonucleotides, Antisense; Prospective Studies; Proto-Oncogene Proteins c-bcl-2; Skin Neoplasms; Thionucleotides; Time Factors; Tomography, X-Ray Computed; Treatment Outcome

2014
Oblimersen in combination with temozolomide and albumin-bound paclitaxel in patients with advanced melanoma: a phase I trial.
    Cancer chemotherapy and pharmacology, 2013, Volume: 71, Issue:1

    The combination of oblimersen, a bcl-2 antisense oligonucleotide, and dacarbazine lead to superior progression-free survival in advanced melanoma patients. Albumin-bound paclitaxel (nab-paclitaxel) has single-agent activity in melanoma.. In a phase I trial, chemotherapy-naïve patients with metastatic melanoma and normal LDH levels were enrolled on 3 cohorts. The treatment regimen consisted of 56-day cycles of oblimersen (7 mg/kg/day continuous IV infusion on day 1-7 and 22-28 in cohort 1 and 2; 900 mg fixed dose, twice weekly in weeks 1-2, 4-5 for cohort 3), temozolomide (75 mg/m(2), days 1-42), and nab-paclitaxel (175 mg/m(2) in cohort 1 and 3, 260 mg/m(2) in cohort 2 on day 7 and 28). Apoptosis markers were tested in pre- and post-treatment specimens of a subset of patients.. Six grade 3 events (neutropenia, renal insufficiency, hyponatremia, elevated creatinine, allergic reaction, and neuropathy) and 2 grade 4 events (neutropenia and thrombocytopenia) were seen in 32 patients. The objective response rate was 40.6% (2 complete responses and 11 partial responses) and 11 patients had stable disease, for a disease control rate of 75%.. The combination of oblimersen, temozolomide, and nab-paclitaxel was well tolerated and demonstrated encouraging activity in patients with advanced melanoma.

    Topics: Adult; Aged; Albumin-Bound Paclitaxel; Albumins; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Dacarbazine; Humans; Male; Melanoma; Middle Aged; Neoplasm Metastasis; Oligonucleotides, Antisense; Paclitaxel; Skin Neoplasms; Temozolomide; Thionucleotides; Treatment Outcome

2013
LDH correlation with survival in advanced melanoma from two large, randomised trials (Oblimersen GM301 and EORTC 18951).
    European journal of cancer (Oxford, England : 1990), 2009, Volume: 45, Issue:10

    In a randomised study (GM301; dacarbazine with/without oblimersen), patients with advanced melanoma were stratified based on performance status, metastatic site and lactate dehydrogenase (LDH). Progression-free survival and response and durable response rates showed a highly significant difference favouring dacarbazine-oblimersen and a nearly significant survival difference. All efficacy parameters significantly favoured dacarbazine-oblimersen in patients with normal baseline LDH [1.1xupper limit of normal (ULN)]. Each stratification factor was assessed for an interaction with treatment on survival and an interaction was detected only for LDH.. Baseline LDH values in Study GM301 treatment groups were combined and analysed using cutoffs above and below 1xULN. Baseline LDH in EORTC study 18951 (dacarbazine, cisplatin, interferon-alfa-2b with/without interleukin-2 in advanced melanoma) was independently analysed using the same approach. In Study GM301, the relation between treatment effect and LDH, treatment effect and tumour size, LDH and tumour size and LDH and disease site were determined.. In Study GM301 (N=760) and Study 18951 (N=325), LDH was within the upper range of normal for a large number of patients. This was not exhibited in the general population, suggesting such values may be elevated rather than normal in melanoma. A highly ordered and monotonic relationship was apparent between LDH and survival: survival worsened as LDH became more elevated, even when LDH remained within normal range. LDH and tumour size were poorly correlated; elevated LDH was not associated with any one disease site. LDH was highly predictive of oblimersen effect.. In designing studies, LDH should be considered, regardless of tumour size or disease site.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Dacarbazine; Follow-Up Studies; Humans; L-Lactate Dehydrogenase; Liver Neoplasms; Melanoma; Prognosis; Skin Neoplasms; Survival Analysis; Thionucleotides; Treatment Outcome

2009
Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: the Oblimersen Melanoma Study Group.
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2006, Oct-10, Volume: 24, Issue:29

    Chemotherapy resistance in melanoma has been linked to antiapoptotic effects mediated by Bcl-2 protein. We evaluated whether targeting Bcl-2 using an antisense oligonucleotide (oblimersen sodium) could improve the efficacy of systemic chemotherapy in patients with advanced melanoma.. We randomly assigned chemotherapy-naïve patients with advanced melanoma to treatment with dacarbazine (1,000 mg/m2) alone or preceded by a 5-day continuous intravenous infusion of oblimersen sodium (7 mg/kg/d) every 3 weeks for up to eight cycles. Patients were stratified by Eastern Cooperative Oncology Group performance status, liver metastases, disease site, and serum lactate dehydrogenase (LDH). The primary efficacy end point was overall survival.. Among 771 patients randomly assigned, the addition of oblimersen to dacarbazine yielded a trend toward improved survival at 24-month minimum follow-up (median, 9.0 v 7.8 months; P = .077) and significant increases in progression-free survival (median, 2.6 v 1.6 months; P < .001), overall response (13.5% v 7.5%; P = .007), complete response (2.8% v 0.8%), and durable response (7.3% v 3.6%; P = .03). A significant interaction between baseline serum LDH and treatment was observed; oblimersen significantly increased survival in patients whose baseline serum LDH was not elevated (median overall survival, 11.4 v 9.7 months; P = .02). Neutropenia and thrombocytopenia were increased in the oblimersen-dacarbazine group; however, there was no increase in serious infections or bleeding events.. The addition of oblimersen to dacarbazine significantly improved multiple clinical outcomes in patients with advanced melanoma and increased overall survival in patients without an elevated baseline serum LDH.

    Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Combined Modality Therapy; Dacarbazine; Disease Progression; Drug Resistance, Neoplasm; Female; Humans; L-Lactate Dehydrogenase; Male; Melanoma; Middle Aged; Oligonucleotides, Antisense; Proto-Oncogene Proteins c-bcl-2; Skin Neoplasms; Survival Analysis; Thionucleotides; Treatment Outcome

2006

Other Studies

17 other study(ies) available for oblimersen and Melanoma

ArticleYear
Electroporation increases antitumoral efficacy of the bcl-2 antisense G3139 and chemotherapy in a human melanoma xenograft.
    Journal of translational medicine, 2011, Jul-28, Volume: 9

    Nucleic acids designed to modulate the expression of target proteins remain a promising therapeutic strategy in several diseases, including cancer. However, clinical success is limited by the lack of efficient intracellular delivery. In this study we evaluated whether electroporation could increase the delivery of antisense oligodeoxynucleotides against bcl-2 (G3139) as well as the efficacy of combination chemotherapy in human melanoma xenografts.. Melanoma-bearing nude mice were treated i.v. with G3139 and/or cisplatin (DDP) followed by the application of trains of electric pulses to tumors. Western blot, immunohistochemistry and real-time PCR were performed to analyze protein and mRNA expression. The effect of electroporation on muscles was determined by histology, while tumor apoptosis and the proliferation index were analyzed by immunohistochemistry. Antisense oligodeoxynucleotides tumor accumulation was measured by FACS and confocal microscopy.. The G3139/Electroporation combined therapy produced a significant inhibition of tumor growth (TWI, more than 50%) accompanied by a marked tumor re-growth delay (TRD, about 20 days). The efficacy of this treatment was due to the higher G3139 uptake in tumor cells which led to a marked down-regulation of bcl-2 protein expression. Moreover, the G3139/EP combination treatment resulted in an enhanced apoptotic index and a decreased proliferation rate of tumors. Finally, an increased tumor response was observed after treatment with the triple combination G3139/DDP/EP, showing a TWI of about 75% and TRD of 30 days.. These results demonstrate that electroporation is an effective strategy to improve the delivery of antisense oligodeoxynucleotides within tumor cells in vivo and it may be instrumental in optimizing the response of melanoma to chemotherapy. The high response rate observed in this study suggest to apply this strategy for the treatment of melanoma patients.

    Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cisplatin; Combined Modality Therapy; Down-Regulation; Electrodes; Electroporation; Gene Expression Regulation, Neoplastic; Humans; Melanoma; Mice; Muscle, Skeletal; Neoplasm Proteins; Oligonucleotides, Antisense; Proto-Oncogene Proteins c-bcl-2; RNA, Messenger; Thionucleotides; Treatment Outcome; Xenograft Model Antitumor Assays

2011
Off-target effects related to the phosphorothioate modification of nucleic acids.
    ChemMedChem, 2010, Aug-02, Volume: 5, Issue:8

    Phosphorothioate antisense oligonucleotides have been widely used in clinical studies for rational sequence-specific gene silencing. However, several sequence-unspecific off-target effects have been recently described for this compound class. In contrast to siRNA-mediated knockdown of the same gene, the bcl-2-targeted oblimersen (Genasense, G3139) downregulates a number of proteins involved in apoptotic resistance and several glycolytic enzymes in 607B human melanoma cells. Regardless of their target, phosphorothioate-modified antisense and siRNA compounds, but not oligonucleotides with a phosphodiester backbone, resulted in a similar impact on the proteome. Unspecifically downregulated proteins include cancer markers involved in apoptotic resistance and endoplasmatic reticulum (ER) stress such as the 78 kDa glucose regulated protein (GRP 78), protein disulfide isomerase A3 (PDIA3, GRP 58), calumenin, and galectin-1, as well as the glycolytic enzymes triose phosphate isomerase, glyceraldehyde phosphodehydrogenase, and phosphoglycerate mutase. The depletion of the glycolytic enzymes is reflected by a decrease in L-lactate production, indicating a partial reversal of the Warburg effect. Compared with other phosphorothioate oligonucleotides, oblimersen generally led to a more pronounced effect both in terms of the number of influenced proteins and the extent of downregulation, suggesting a synergistic effect of Bcl-2 downregulation.

    Topics: Apoptosis; Biomarkers, Tumor; Cell Line, Tumor; Electrophoresis, Gel, Two-Dimensional; Humans; Intercellular Adhesion Molecule-1; Lactates; Melanoma; Oligonucleotides, Antisense; Phosphates; Proto-Oncogene Proteins c-bcl-2; RNA Interference; RNA, Small Interfering; Thionucleotides

2010
A proteomic study reveals unspecific apoptosis induction and reduction of glycolytic enzymes by the phosphorothioate antisense oligonucleotide oblimersen in human melanoma cells.
    Journal of proteomics, 2009, Aug-20, Volume: 72, Issue:6

    The question of specificity and the elucidation of the exact molecular mechanism of action of post-transcriptional gene silencing agents are two major challenges for their establishment as therapeutics. A proteomic off-target effect study (2-DE with MS) in combination with DIGE comparing the phosphorothioate antisense oligonucleotide oblimersen (Genasense, G3139) to a Bcl-2-targeting siRNA-sequence on human melanoma cells showed that additional off-target effects contribute to the apoptotic effect of oblimersen. When both oligonucleotides were transfected with lipofectamine 2000, only oblimersen increased apoptosis as determined by annexin staining and caspase activity measurement. In contrast to the highly specific siRNA, the expression level of a number of proteins was found to be altered after oblimersen treatment. Several proteins linked to apoptosis and stress response, among those galectin-1, cofilin-1, GRP78, HSP60, nucleophosmin, and peroxiredoxins, were identified and found to be down-regulated after oblimersen treatment. A down-regulation of enolase-1 and three other glycolytic enzymes indicates a reversion of the cancer-related Warburg effect. The observed effects may be caused by a phosphorothioate mediated blockage of the mitochondrial voltage dependent anion channel (VDAC).

    Topics: Anions; Annexins; Apoptosis; Cell Line, Tumor; Electrophoresis, Gel, Two-Dimensional; Endoplasmic Reticulum Chaperone BiP; Glycolysis; Humans; Mass Spectrometry; Melanoma; Oligonucleotides, Antisense; Proteomics; Proto-Oncogene Proteins c-bcl-2; RNA, Small Interfering; Thionucleotides

2009
Targeting Bcl-2 protein in treatment of melanoma still requires further clarifications.
    Annals of oncology : official journal of the European Society for Medical Oncology, 2008, Volume: 19, Issue:12

    Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Humans; Melanoma; Proto-Oncogene Proteins c-bcl-2; Thionucleotides

2008
Targeting metastatic melanoma.
    American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists, 2008, Dec-15, Volume: 65, Issue:24 Suppl 9

    New medications and combination treatment strategies for patients with metastatic melanoma are discussed.. Bcl-2 is an inhibitor of apoptosis that is overexpressed in approximately 80% of melanoma cell lines and is believed to contribute to the development of resistance to cytotoxic chemotherapy in patients with melanoma. Oblimersen, an antisense oligonucleotide that stops the translation of Bcl-2 mRNA to protein, significantly improved progression-free survival when administered in combination with dacarbazine. Overall survival was significantly improved in patients with low levels of serum lactate dehydrogenase (LDH), but not in patients with elevated LDH. RAF proteins are a family of serine/threonine kinases that regulate many aspects of cellular function. RAF mutations occur in 70% of melanoma cell lines. Although RAF kinases are thought to be important in the pathogenesis of melanoma, RAF inhibition with sorafenib has not significantly improved survival in patients with advanced disease. Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a naturally occurring inhibitor of T-cell function that prevents the complete activation of T cells upon exposure to antigens by antigen-presenting cells. Two monoclonal antibodies to CTLA-4 (tremelimumab and ipilimumab) have been developed to promote T-cell activation in melanoma and other types of cancer. Phase I and phase II clinical trials of these agents in patients with metastatic melanoma have demonstrated promising effects on tumor progression, with objective response rates of approximately 20% and sustained responses in some patients. Several vaccines have been developed to stimulate immune system responses against melanoma. Despite promising early findings with polyvalent melanoma vaccine and with vaccine containing heat shock proteins, results with these agents in larger clinical trials have been disappointing.. Ongoing clinical trials continue to evaluate these and other novel approaches to the treatment of metastatic melanoma.

    Topics: Antibodies, Monoclonal; Antigens, CD; Antineoplastic Agents; Benzenesulfonates; Cancer Vaccines; Clinical Trials as Topic; CTLA-4 Antigen; Humans; Melanoma; Niacinamide; Phenylurea Compounds; Pyridines; raf Kinases; Skin Neoplasms; Sorafenib; Thionucleotides

2008
Molecular classification of patients with malignant melanoma for new therapeutic strategies.
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2007, Jun-01, Volume: 25, Issue:16

    Topics: Combined Modality Therapy; Dacarbazine; Extracellular Signal-Regulated MAP Kinases; Humans; Melanoma; Oligonucleotides, Antisense; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Skin Neoplasms; Thionucleotides

2007
Genasense: it ain't over till the fat lady sings.
    Oligonucleotides, 2007,Winter, Volume: 17, Issue:4

    Topics: Antineoplastic Combined Chemotherapy Protocols; Dacarbazine; Drug Approval; Humans; Melanoma; Oligonucleotides, Antisense; Randomized Controlled Trials as Topic; Skin Neoplasms; Thionucleotides; United States; United States Food and Drug Administration

2007
A pharmacologic target of G3139 in melanoma cells may be the mitochondrial VDAC.
    Proceedings of the National Academy of Sciences of the United States of America, 2006, May-09, Volume: 103, Issue:19

    G3139, an 18-mer phosphorothioate antisense oligonucleotide targeted to the initiation codon region of the Bcl-2 mRNA, can induce caspase-dependent apoptosis via the intrinsic mitochondrial pathway in 518A2 and other melanoma cells. G3139-mediated apoptosis appears to be independent of its ability to down-regulate the expression of Bcl-2 protein, because the release of mitochondrial cytochrome c precedes in time the down-regulation of Bcl-2 protein expression. In this study, we demonstrate the ability of G3139 and other phosphorothioate oligonucleotides to bind directly to mitochondria isolated from 518A2 cells. Furthermore, we show that this interaction leads to the release of cytochrome c in the absence of a mitochondrial membrane permeability transition. Our data further demonstrate that there is an interaction between G3139 and VDAC, a protein that can facilitate the physiologic exchange of ATP and ADP across the outer mitochondrial membrane. Evidence from the electrophysiologic evaluation of VDAC channels reconstituted into phospholipid membranes demonstrates that G3139 is capable of producing greatly diminished channel conductance, indicating a closed state of the VDAC. This effect is oligomer length-dependent, and the ability of phosphorothioate homopolymers of thymidine of variable lengths to cause the release of cytochrome c from isolated mitochondria of 518A2 melanoma cells can be correlated with their ability to interact with VDAC. Because it has been suggested that the closure of VDAC leads to the opening of another outer mitochondrial membrane channel through which cytochrome c can transit, thus initiating apoptosis, it appears that VDAC may be an important pharmacologic target of G3139.

    Topics: Base Sequence; Cell Line, Tumor; Cytochromes c; Humans; Ion Channel Gating; Melanoma; Mitochondria; Mitochondrial Membranes; Oligonucleotides; Phosphates; Thionucleotides; Voltage-Dependent Anion Channels

2006
G3139 induces cell death by caspase-dependent and -independent apoptosis on human melanoma cell lines.
    Oncology reports, 2006, Volume: 15, Issue:6

    G3139 is an 18-mer phosphorothioate oligodeoxynucleotide (ODN) which has been targeted on the initiation codon region of the bcl-2 gene. Currently, clinical trials on G3139 for diverse tumors are underway in phase II and phase III. However, basic investigations of bcl-2 antisense ODN (G3139) and reverse ODN (G3622) have not been fully examined. In this report, we investigate cell death caused by G3139 and G3622 and the impact of antisense ODN in melanoma cell lines. We confirmed that G3139 reduced the level of bcl-2 protein and both G3139 and G3622 inhibited cell proliferation and induced apoptosis. G3139 was noted to produce a more intense effect than G3622. Although the general caspase inhibitor, Z-VAD-fmk, prevented apoptosis incompletely, the inhibition ratio of both ODNs was approximately equivalent. Our results suggested that inhibition of cell proliferation by ODNs is produced by apoptosis, but that the apoptotic pathway is not fully induced by the caspase-dependent pathway. Upon examination of the intracellular apoptotic protein dynamics, AIF localized within the mitochondria was translocated to the cytosol within 24 h, and subsequently to the nuclei after 48 h of treatment with G3139. Our results imply the following: the transfection of ODNs can induce apoptosis, the anti-tumor effect of G3139 is better than G3622, and the difference in the anti-tumor effect is specifically based upon the reduction of expression of the target DNA in malignant tumors. We consider that antisense ODNs may be an important tool for anti-tumor chemotherapy and the targeting of specific DNA is important in enhancing the anti-proliferative effect against tumors.

    Topics: Amino Acid Chloromethyl Ketones; Apoptosis; Apoptosis Inducing Factor; bcl-2-Associated X Protein; Caspase Inhibitors; Caspases; Cell Line, Tumor; Down-Regulation; Enzyme-Linked Immunosorbent Assay; Humans; Melanoma; Oligonucleotides, Antisense; Proto-Oncogene Proteins c-bcl-2; Thionucleotides; Transfection

2006
[Effects of bcl-2 antisense oligodeoxynucleotide on proliferation and apoptosis of human melanoma A375 cell line].
    Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology, 2006, Volume: 22, Issue:4

    To investigate effects of bcl-2 fully phosporothioated antisense oligodeoxynucleotide(bcl-2 ASODN) on proliferation and apoptosis of human melanoma A375 cell, and its possible mechanism.. Proliferation and apoptosis of A375 cell with bcl-2 ASODN treatment were evaluated by MTT colorimetric assay, laser scanning confocal microscope (LSCM), TUNEL and Annexin V/propidium iodide(PI), and the level of bcl-2 mRNA expression in A375 cell was detected by RT-PCR before and after being treated by bcl-2 ASODN.. MTT assay demonstrated that bcl-2 ASODN could inhibit the proliferation of the cells in both time and concentration dependent manner. Characteristic morphologic apoptosis changes were observed by LSCM after incubated with bcl-2 ASODN for 48 h. Most nucleus were labeled in brown by TUNEL in ASODN group, but not markedly labeled both in SODN and control group. The apoptosis rate of A375 cells in 30 micromol/L bcl-2 ASODN group was significantly higher than that in bcl-2 SODN and in control group. The bcl-2 ASODN-induced apoptosis of A375 cells, which was accompanied by declined expression of bcl-2 mRNA was distinctly lower than that in SODN and control groups.. These results suggest that bcl-1 ASODN can not only inhibit proliferation but also induce apoptosis of human melanoma A375 cells in vitro, and the apoptosis-induced mechanism is down-regulating expression of bcl-2 mRNA.

    Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Down-Regulation; Gene Expression Regulation, Neoplastic; Genes, bcl-2; Humans; Melanoma; Microscopy, Confocal; RNA, Messenger; Thionucleotides

2006
Bcl-2 protein in 518A2 melanoma cells in vivo and in vitro.
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2006, Aug-15, Volume: 12, Issue:16

    Bcl-2 is an apoptotic protein that is highly expressed in advanced melanoma. Several strategies have been employed to target the expression of this protein, including G3139, an 18-mer phosphorothioate oligodeoxyribonucleotide targeted to the initiation region of the Bcl-2 mRNA. This compound has recently completed phase III global clinical evaluation, but the function of Bcl-2 as a target in melanoma has not been completely clarified. To help resolve this question, we have permanently and stably down-regulated Bcl-2 protein and mRNA expression in 518A2 cells by two different technologies and evaluated the resulting clones both in vitro and in vivo.. 518A2 melanoma cells were transfected with plasmids engineered to produce either a single-stranded antisense oligonucleotide targeted to the initiation codon region of the Bcl-2 mRNA or a short hairpin RNA also targeted to the Bcl-2 mRNA. In vitro growth, the apoptotic response to G3139, and the G3139-induced release of cytochrome c from isolated mitochondria were evaluated. Cells were then xenografted into severe combined immunodeficient mice and tumor growth was measured.. In vitro, down-regulation of Bcl-2 expression by either method produced no change either in the rate of growth or in sensitivity to standard cytotoxic chemotherapeutic agents. Likewise, the induction of apoptosis by G3139 was entirely Bcl-2 independent. In addition, the G3139-induced release from isolated mitochondria was also relatively independent of Bcl-2 expression. However, when xenografted into severe combined immunodeficient mice, cells with silenced Bcl-2, using either technology, either failed to grow at all or grew to tumors of low volume and then completely regressed. In contrast, control cells with "normal" levels of Bcl-2 protein expression expanded to be large, necrotic tumors.. The presence of Bcl-2 protein profoundly affects the ability of 518A2 melanoma cells to grow as human tumor xenografts in severe combined immunodeficient mice. The in vivo role of Bcl-2 in melanoma cells thus differs significantly from its in vitro role, and these experiments further suggest that Bcl-2 may be an important therapeutic target even in tumors that do not contain the t14:18 translocation.

    Topics: Animals; Apoptosis; Base Sequence; Cytochromes c; DNA, Antisense; Down-Regulation; Gene Silencing; Humans; Melanoma; Mice; Mice, Inbred ICR; Mice, SCID; Mitochondria; Molecular Sequence Data; Proto-Oncogene Proteins c-bcl-2; RNA, Messenger; RNA, Small Interfering; Thionucleotides; Xenograft Model Antitumor Assays

2006
Reaching first base in the treatment of metastatic melanoma.
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2006, Oct-10, Volume: 24, Issue:29

    Topics: Cancer Vaccines; Humans; Melanoma; Neoplasm Metastasis; Oligonucleotides, Antisense; Prognosis; Skin Neoplasms; Survival; Thionucleotides

2006
Phosphorothioate oligodeoxynucleotides and G3139 induce apoptosis in 518A2 melanoma cells.
    Molecular cancer therapeutics, 2005, Volume: 4, Issue:2

    In a previous study, we showed that G3139, an antisense phosphorothioate oligonucleotide that down-regulates the expression of Bcl-2 protein, did not cause chemosensitization of 518A2 melanoma cells. In this work, we show that G3139, and the 2-base mismatch, G4126, can initiate apoptosis in this and other melanoma cell lines as shown by increased cell surface Annexin V expression, typical nuclear phenotypic changes as assessed by 4',6-diamidino-2-phenylindole staining, activation of caspase-3 (but not caspase-8) and Bid, appearance of DEVDase (but not IETDase) activity, and cleavage of poly(ADP-ribose)-polymerase 1. Depolarization of the mitochondrial membrane occurs as a relatively late event. All of these processes seem to be substantially, but perhaps not totally, Bcl-2 independent as shown by experiments employing an anti-Bcl-2 small interfering RNA, which as shown previously down-regulated Bcl-2 protein expression but did not produce apoptosis or chemosensitization in melanoma cells. In fact, these G3139-induced molecular events were not dramatically altered in cells that forcibly overexpressed high levels of Bcl-2 protein. Addition of irreversible caspase inhibitors (e.g., the pan-caspase inhibitor zVAD-fmk) to G3139-treated cells almost completely blocked cytotoxicity. Examination of the time course of the appearance of caspase-3 and cleaved poly(ADP-ribose)-polymerase 1 showed that this could be correlated with the release of cytochrome c from the mitochondria, an event that begins only approximately 4 hours after the end of the oligonucleotide/LipofectAMINE 2000 5-hour transfection period. Thus, both G3139 and cytotoxic chemotherapy activate the intrinsic pathway of apoptosis in these cells, although Bcl-2 expression does not seem to contribute strongly to chemoresistance. These findings suggest that the attainment of G3139-induced chemosensitization in these cells will be difficult.

    Topics: Antineoplastic Agents; Apoptosis; BH3 Interacting Domain Death Agonist Protein; Carrier Proteins; Caspase 3; Caspase Inhibitors; Caspases; Cell Line, Tumor; Cytochromes c; Cytoplasm; Drug Resistance, Neoplasm; Enzyme Activation; Humans; Lipids; Melanoma; Membrane Potentials; Mitochondria; Oligodeoxyribonucleotides, Antisense; Proto-Oncogene Proteins c-bcl-2; Thionucleotides; Transfection

2005
Enhanced antitumour efficacy of gimatecan in combination with Bcl-2 antisense oligonucleotide in human melanoma xenografts.
    European journal of cancer (Oxford, England : 1990), 2005, Volume: 41, Issue:8

    The anti-apoptotic protein Bcl-2 has been implicated in the intrinsic resistance of melanoma to chemotherapy. The aim of this study was to investigate the effects of anti-Bcl-2 oligonucleotide oblimersen on the antitumour activity of gimatecan, a novel lipophilic camptothecin currently undergoing clinical phase II studies. Results showed a reduced sensitivity of melanoma cells to gimatecan following Bcl-2 transfection and inversely, increased cell sensitivity to gimatecan in combination with oblimersen. In in vivo studies performed in two melanoma xenografts expressing different Bcl-2 levels, the antitumour activity of oblimersen itself was modest, but the combination with gimatecan produced a significant therapeutic advantage. The combination therapy inhibited tumour growth and delayed regrowth of the two tumours tested. The enhancement of antitumour activity was observed at doses that were tolerated well. The effects of oblimersen on antitumour activity and toxicity of gimatecan were dose-dependent. The capability of oblimersen to improve the efficacy of gimatecan supports the therapeutic potential of the drug combination in the treatment of human melanoma.

    Topics: Administration, Oral; Animals; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cell Division; Cell Line, Tumor; Cell Survival; Drug Resistance, Neoplasm; Female; Humans; Melanoma; Mice; Mice, Nude; Neoplasm Transplantation; Proto-Oncogene Proteins c-bcl-2; Thionucleotides; Transplantation, Heterologous

2005
518A2 melanoma cells are protected by G3139 and other antineoplastic agents against the cytotoxic effects of DTIC.
    Oligonucleotides, 2005,Fall, Volume: 15, Issue:3

    G3139 is an antisense Bcl-2 phosphorothioate oligonucleotide that has been combined with DTIC in a phase III clinical trial in melanoma. However, its actual mechanism of action in melanoma is controversial. Treatment of 518A2 melanoma cells with either G3139 or G4126 (a two-base mismatch) and then with light-activated DTIC caused these cells (but not SK-Mel-30 or 346.1 cells) to be protected against the cytotoxic effects of DTIC. This cytoprotection was not recapitulated with a phosphodiester congener of G3139 nor with a small interfering RNA (siRNA) also targeted to the Bcl-2 mRNA. Administering the drugs in reverse order also did not produce cytoprotection, and an 18- mer phosphorothioate homopolymer of thymidine was also inactive. Subsequently, it was discovered that gemcitibine and cis-platinum also induced cytoprotection to DTIC in this cell line, suggesting that the cytoprotection is a stress response to chemical proapoptotic stress. Cytoprotection was completely inhibited by O(6)-benzylguanine, an inhibitor of O(6)-guanosine alkyltransferase (OGAT) activity. However, a direct assay of OGAT activity demonstrated that 518A2 melanoma cells are essentially completely devoid of it, either basally or induced. The cytoprotection may thus be caused by a chemical stress-induced increase in mismatch repair activity.

    Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cisplatin; Dacarbazine; Deoxycytidine; Drug Resistance, Neoplasm; Gemcitabine; Guanine; Humans; Melanoma; Oligonucleotides, Antisense; Thionucleotides

2005
Lessons learnt from Genasense's failure.
    Nature reviews. Drug discovery, 2004, Volume: 3, Issue:7

    Topics: Drug Approval; Endpoint Determination; Humans; Melanoma; Survival Analysis; Thionucleotides; United States; United States Food and Drug Administration

2004
Relative Bcl-2 independence of drug-induced cytotoxicity and resistance in 518A2 melanoma cells.
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2004, Dec-15, Volume: 10, Issue:24

    Inhibition of the function of Bcl-2 protein has been postulated to sensitize cells to cytotoxic chemotherapy. G3139 (Genasense) is a phosphorothioate anti-Bcl-2 antisense oligonucleotide, but its mechanism of action is uncertain. The aim of the present work is to investigate inhibition of Bcl-2 expression in 518A2 melanoma cells, the cell line on which recent phase II and phase III clinical trials employing this agent were based.. We down-regulated the expression of Bcl-2 protein by two different strategies in these cells: one employing G3139 and controls, and the other using a small interfering RNA approach. Cell viability after treatment with oligonucleotides or small interfering RNA and cytotoxic agents including gemcitibine, DDP, docetaxel, and thapsigargin was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. A 518A2 melanoma cell line stably overexpressing Bcl-2 protein was constructed and treated with either these cytotoxic agents or G3139.. The cytotoxic effects of either G3139 or small interfering RNA treatment of 518A2 melanoma cells are Bcl-2 independent. In addition, in the Bcl-2-overexpressing cells, only a modest increment in chemoresistance was observed, and treatment with G3139 not only did not down-regulate Bcl-2 expression but produced essentially identical toxicity as was observed in the wild-type or mock-transfected cells.. Our results suggest that the mechanism whereby G3139 produces drug-induced cytotoxicity in the 518A2 melanoma line is not dependent on levels of Bcl-2. These findings emphasize the nonsequence specific effects of this phosphorothioate oligonucleotide and call into question the validity of Bcl-2 as a target in this cell line.

    Topics: Antineoplastic Agents; Apoptosis; Cisplatin; Deoxycytidine; Docetaxel; Down-Regulation; Drug Resistance, Neoplasm; Enzyme Inhibitors; Gemcitabine; Humans; Melanoma; Oligonucleotides, Antisense; Proto-Oncogene Proteins c-bcl-2; RNA, Messenger; RNA, Small Interfering; Skin Neoplasms; Taxoids; Thapsigargin; Thionucleotides; Tumor Cells, Cultured

2004