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

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.