oblimersen and Carcinoma--Small-Cell

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

Small cell lung cancer continues to recur and claim the lives of most of its victims. Thus, management of the patient with recurrent disease remains an active area of research. This review provides an update of clinical research experience over the past decade with relatively new conventional cytotoxins in this setting, such as the topoisomerase I inhibitors and the taxanes. Additionally, novel molecular targeted approaches with specific relevance for small cell lung cancer are discussed.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Small Cell; Clinical Trials as Topic; Gefitinib; Humans; Immunotoxins; Lung Neoplasms; Neoplasm Recurrence, Local; Oligonucleotides, Antisense; Prognosis; Quinazolines; Thionucleotides

To assess the efficacy and toxicity of carboplatin, etoposide, and the bcl-2 antisense oligonucleotide oblimersen as initial therapy for extensive-stage small-cell lung cancer (ES-SCLC). bcl-2 has been implicated as a key factor in SCLC oncogenesis and chemotherapeutic resistance.. A 3:1 randomized phase II study was performed to evaluate carboplatin and etoposide with (arm A) or without oblimersen (arm B) in 56 assessable patients with chemotherapy-naïve ES-SCLC. Outcome measures including toxicity, objective response rate, complete response rate, failure-free survival, overall survival, and 1-year survival rate.. Oblimersen was associated with slightly more grade 3 to 4 hematologic toxicity (88% v 60%; P = .05). Response rates were 61% (95% CI, 45% to 76%) for arm A and 60% (95% CI, 32% to 84%) for arm B. The percentage of patients alive at 1 year was 24% (95% CI, 12% to 40%) with oblimersen, and 47% (95% CI, 21% to 73%) without oblimersen. Hazard ratios for failure-free survival (1.79; P = .07) and overall survival (2.13; P = .02) suggested worse outcome for patients receiving oblimersen. These results hold when adjusted for other prognostic factors, such as weight loss, in multivariate regression analysis.. Despite extensive data supporting a critical role for Bcl-2 in chemoresistance in SCLC, addition of oblimersen to a standard regimen for this disease did not improve any clinical outcome measure. Emerging data from several groups suggest that this lack of efficacy may be due to insufficient suppression of Bcl-2 in vivo. Additional evaluation of this agent in SCLC is not warranted.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Small Cell; Disease-Free Survival; Etoposide; Female; Humans; Lung Neoplasms; Male; Middle Aged; Multivariate Analysis; Neoplasm Staging; Odds Ratio; Thionucleotides; Treatment Outcome

Bcl-2 is expressed in the majority of cases of small cell lung cancer (SCLC) and may contribute to chemotherapeutic resistance. Bcl-2 suppression by G3139 (oblimersen sodium), a phosphorothioate oligonucleotide complementary to the bcl-2 mRNA, has the potential to enhance the antitumor efficacy of standard cytotoxic chemotherapy. A dose-finding study was performed evaluating the combination of G3139, carboplatin, and etoposide in patients with previously untreated extensive stage SCLC.. Sixteen patients were treated in three consecutive cohorts. Cohort 1 (n=5) received G3139 5 mg/kg/d on days 1 to 8 of a 21 day cycle, with carboplatin area under the curve (AUC)=6 on day 6, and etoposide 80 mg/m2/d on days 6 to 8. In cohort 2 (n=4), carboplatin dose was reduced to AUC=5. In cohort 3 (n=7), G3139 dose was escalated to 7 mg/kg/d. G3139 plasma concentrations and Bcl-2 protein levels in peripheral blood mononuclear cells were evaluated.. Two of three assessable patients in cohort 1 experienced cycle 1 dose-limiting toxicity (grade 4 neutropenia). No cycle 1 dose-limited toxicity was observed in cohorts 2 or 3. Of 14 patients assessable for response, partial response was documented in 12 patients (86%), and stable disease in two. Median time to progression was 5.9 months. Carboplatin and etoposide administration did not appear to alter G3139 pharmacokinetics. No evidence of Bcl-2 suppression in peripheral blood mononuclear cells was observed.. The combination of G3139, carboplatin, and etoposide is well tolerated and results in an encouraging response rate and time to progression in patients with extensive stage SCLC.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Small Cell; Disease-Free Survival; Dose-Response Relationship, Drug; Etoposide; Female; Humans; Lung Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Oligonucleotides, Antisense; Proto-Oncogene Proteins c-bcl-2; Survival Rate; Thionucleotides; United States

Chemorefractory small-cell lung cancer (SCLC) is defined as disease that progresses during primary therapy or within 3 months of completion of primary therapy. Patients with chemorefractory SCLC have a very poor prognosis, and no treatment has been shown to be of significant clinical benefit. Elevated expression of Bcl-2 is found in the majority of SCLCs and has been associated with therapeutic resistance. Suppression of Bcl-2 levels through the use of G3139, an antisense oligonucleotide complementary to the mRNA encoding Bcl-2, might increase the antitumor efficacy of cytotoxic therapy.. Twelve patients with chemorefractory SCLC participated in this pilot trial of paclitaxel combined with G3139. G3139 was given by continuous i.v. infusion over 7 days at a fixed dose of 3 mg/kg/day. Paclitaxel dose was initially 175 mg/m2 on day 6, but was decreased to 150 mg/m2 due to myelosuppression observed in two of the three patients treated in the first dose cohort.. The combination of paclitaxel at 150 mg/m2 and G3139 at 3 mg/kg/day was found to be feasible and well tolerated. No objective responses were observed, but two patients had stable disease, one remaining stable on therapy for >30 weeks. Plasma G3139 levels were determined, and were found to be highest in the patient with prolonged stable disease, suggesting that individual variation in metabolism and clearance of the antisense oligonucleotide may influence activity.. This study demonstrates that G3139 can be combined with paclitaxel in a cytotoxic dose range, and suggests that a similar combination be tested for activity in the context of chemoresponsive disease.

Topics: Adult; Aged; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Small Cell; Disease Progression; Drug Resistance, Neoplasm; Female; Genes, bcl-2; Humans; Infusions, Intravenous; Lung Neoplasms; Male; Middle Aged; Oligonucleotides, Antisense; Paclitaxel; Thionucleotides; Treatment Outcome

Oblimersen, an ODN targeting BCL-2 RNA, has been shown to be effective in reducing BCL-2 expression in vitro and in in vivo models engineered to overexpress BCL-2. The present study evaluated the efficacy of combining BCL-2 ODN and radiation in small-cell lung cancers (SCLC) cell lines.. The in vitro effect was determined using short term (cell viability) and long term (clonogenic) assays. Apoptosis, BCL-2 expression and intratumoural uptake of the FAM-ODN with or without prior radiation treatment were also evaluated. Combination of ODN and RT was also assessed in vivo.. Radiation was shown to increase intracellular and intratumoural penetration of oblimersen, confirming previous results obtained in prostate cancer xenograft models. Oblimersen decreased BCL-2 protein expression in vitro and in vivo. BCL-2 ODN sensitised H69 cells to radiation in vitro and in vivo. Oblimersen increased radiation-induced apoptosis and decreased in vivo tumoural vascularisation.. Oblimersen was shown to increase in vitro and in vivo effect of RT on SCLC cell lines. Radiation increases intracellular and intratumoural penetration of ODN. This pre-clinical study argues in favour of clinical development in localised SCLC.

Topics: Animals; Apoptosis; Carcinoma, Small Cell; Cell Line, Tumor; Cell Survival; Combined Modality Therapy; Female; Humans; Lung Neoplasms; Mice; Mice, Nude; Oligonucleotides, Antisense; Proto-Oncogene Proteins c-bcl-2; Thionucleotides; Xenograft Model Antitumor Assays

Topics: Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Small Cell; Disease Progression; Drug Resistance, Neoplasm; Genes, bcl-2; Humans; Lung Neoplasms; Oligonucleotides, Antisense; Paclitaxel; Thionucleotides; Treatment Outcome

Topics: Acute Disease; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Small Cell; Clinical Trials, Phase I as Topic; Humans; Leukemia, Myeloid; Lung Neoplasms; Middle Aged; Multicenter Studies as Topic; Oligonucleotides, Antisense; Thionucleotides

Topics: Carcinoma, Small Cell; Clinical Trials as Topic; Disease Progression; Genes, bcl-2; Humans; Lung Neoplasms; Oligonucleotides, Antisense; Proto-Oncogene Proteins c-bcl-2; Thionucleotides; Treatment Outcome