oblimersen and Colorectal-Neoplasms

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

To assess the feasibility and antitumor activity of oblimersen sodium, an antisense oligonucleotide directed to the Bcl-2 mRNA, combined with irinotecan in patients with advanced colorectal carcinoma, characterize the pharmacokinetic behavior of both oblimersen sodium and irinotecan, and examine Bcl-2 protein inhibition in peripheral blood mononuclear cells (PBMC).. Patients were treated with escalating doses of oblimersen sodium administered by continuous intravenous infusion (CIVI) days 1-8, and irinotecan administered intravenously on day 6 once every 3 weeks.. Twenty patients received a total of 84 courses at doses ranging from 3 to 7 mg/kg/day for oblimersen sodium and from 280 to 350 mg/m2 for irinotecan. Febrile neutropenia and diarrhea limited escalation of oblimersen sodium and irinotecan to 5 mg/kg/day and 350 mg/m2, respectively. Other toxicities included nausea, vomiting, fever and fatigue. Steady-state plasma concentrations were achieved within 48 h of beginning oblimersen sodium treatment and the agent was undetectable 24 h after the discontinuation of the infusion. Reduction in levels of Bcl-2 protein in PBMC was documented following treatment with oblimersen sodium. One patient experienced a partial response and 10 additional patients had stable disease lasting 2.5-10 months.. The combination is well tolerated at the recommended phase II oblimersen sodium dose of 7 mg/kg/day CIVI days 1-8 with irinotecan 280 mg/m2 intravenously on day 6 every 3 weeks.

Topics: Adult; Aged; Antineoplastic Agents, Phytogenic; Camptothecin; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Combinations; Female; Humans; Irinotecan; Leukocytes, Mononuclear; Lymphopenia; Male; Middle Aged; Neoplasm Metastasis; Neutropenia; Oligonucleotides, Antisense; Thionucleotides

Overexpression of anti-apoptotic bcl-2 protein has been found in hematological and solid tumors and has been associated with increased resistance against cytotoxic therapy. While bcl-2 antisense (AS) treatment combined with chemotherapy has been successfully tested in clinical trials, trials evaluating the combination of bcl-2 AS with radiotherapy have not yet been performed. The aim of this study was to investigate in vivo anti-tumor effects of a combined modality treatment scheme consisting of radiation and the bcl-2 targeted AS oligonucleotide (ODN) G3139 (Oblimersen Sodium). Two human colon carcinoma cell lines, SW620, bcl-2 positive and HT-29, bcl-2 negative, were grown as xenografts and compared in their response to combined bcl-2 AS/radiation treatment. G3139 potentiated the radiation response of bcl-2 positive SW620 tumors, but had no significant effect on bcl-2 negative HT-29 tumors assayed by tumor growth delay. The profound enhancement of SW620 tumor growth delay by G3139 did not translate into effects on tumor cure, as no significant effect of G3139 was found on SW620 radiocurability (TCD50 assay). The control ODN G3622 had no effect on SW620 radiation response, indicating an ODN sequence specific effect.

Topics: Animals; Antineoplastic Agents; Carcinoma; Cell Line, Tumor; Colorectal Neoplasms; Combined Modality Therapy; Cyclin D1; Gamma Rays; Humans; Mice; Mice, Nude; Neoplasm Transplantation; Oligonucleotides, Antisense; Thionucleotides; Tumor Burden