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Oblimersen Bcl-2 antisense: facilitating apoptosis in anticancer treatment
Richard J Klasa1, Amanda M Gillum, Robert E Klem
1Department of Advanced Therapeutics, British Columbia Cancer Agency, Vancouver, Canada.
Abstract:
The components of the apoptotic program are targets for anticancer therapy. Bcl-2 protein inhibits apoptosis and confers resistance to treatment with traditional cytotoxic chemotherapy, radiotherapy, and monoclonal antibodies (mAb). Oblimersen sodium (G3139, Genasense, Genta Inc., Berkeley Heights, NJ) is an antisense oligonucleotide (AS-ON) compound designed to specifically bind to the first 6 codons of the human bcl-2 mRNA sequence, resulting in degradation of bcl-2 mRNA and subsequent decrease in Bcl-2 protein translation. Oblimersen is the first oligonucleotide to demonstrate proof of principle of an antisense effect in human tumors by the documented downregulation of the target Bcl-2 protein. A growing body of preclinical and clinical evidence suggests that oblimersen synergizes with many cytotoxic and biologic/immunotherapeutic agents against a variety of hematologic malignancies and solid tumors. Randomized clinical trials are currently underway to evaluate the efficacy and tolerability of oblimersen in combination with cytotoxic chemotherapy in chronic lymphocytic leukemia, multiple myeloma, malignant melanoma, and non-small cell lung cancer. In addition, nonrandomized trials are under way to evaluate oblimersen in non-Hodgkin's lymphoma, acute myeloid leukemia, and hormone-refractory prostate cancer. Preclinical data also support the clinical evaluation of oblimersen in additional tumor types, including chronic myelogenous leukemia and breast, small cell lung, gastric, colon, bladder, and Merkel cell cancers. Enhancement of the efficacy of anticancer treatments with oblimersen Bcl-2 antisense therapy represents a promising new apoptosis-modulating strategy, and ongoing clinical trials will test this therapeutic approach.
Insights
Oblimersen sodium, an antisense oligonucleotide, effectively reduces Bcl-2 protein, enhancing cancer therapy. Clinical trials are evaluating its synergistic effects with various treatments across multiple cancer types.
Area of Science:
- Oncology
- Molecular Biology
- Anticancer Therapeutics
Background:
- Bcl-2 protein inhibits apoptosis, leading to chemoresistance.
- Anticancer therapies target apoptotic pathways.
- Oblimersen sodium is an antisense oligonucleotide targeting Bcl-2.
Purpose of the Study:
- To evaluate Oblimersen sodium's efficacy as an anticancer therapeutic.
- To demonstrate the antisense effect of Oblimersen sodium in human tumors.
- To assess the synergistic potential of Oblimersen sodium with other anticancer agents.
Main Methods:
- Oblimersen sodium designed to bind bcl-2 mRNA, causing degradation.
- Demonstration of Bcl-2 protein downregulation in human tumors.
- Preclinical and clinical studies in various hematologic malignancies and solid tumors.
Main Results:
- Oblimersen sodium is the first oligonucleotide to show an antisense effect in human tumors.
- Documented downregulation of Bcl-2 protein.
- Evidence suggests Oblimersen sodium synergizes with cytotoxic and biologic agents.
Conclusions:
- Oblimersen sodium represents a promising apoptosis-modulating strategy.
- Ongoing clinical trials are evaluating Oblimersen sodium in combination therapies.
- Potential for enhancing efficacy of anticancer treatments across diverse cancers.