Therapeutic potential of antisense Bcl‐2 as a chemosensitizer for cancer therapy

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Abstract
Bcl‐2 protein plays a critical role in inhibiting anticancer drug‐induced apoptosis, which is mediated by a mitochondria‐dependent pathway that controls the release of cytochrome c from mitochondria through anion channels. Constitutive overexpression of Bcl‐2 or unchanged expression after treatment with anticancer drugs confers drug resistance not only to hematologic malignancies but also to solid tumors. The down‐regulation of Bcl‐2 protein by the antisense (AS) Bcl‐2 (oblimesen sodium) may be a useful method for targeting the antiapoptotic protein and thereby increasing the chemotherapeutic effect of anticancer drugs. Several randomized, controlled, Phase III trials have compared standard chemotherapy with a combination of AS Bcl‐2 and standard chemotherapy for the treatment of patients with chronic lymphocytic leukemia, multiple myeloma, malignant melanoma, and nonsmall cell lung carcinoma. Nonrandomized clinical trials and preclinical evaluations of AS Bcl‐2 also are underway for patients with other malignancies. Here, the authors review the current clinical and preclinical evaluations of AS Bcl‐2 and discuss its potential to act as a chemosensitizer and to enhance the therapeutic effect of cancer chemotherapy. Cancer 2004. © 2004 American Cancer Society.