Promise and Problems of Bcl-2 Antisense Therapy

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Abstract
Ever since its implication in multidrug chemoresistance in tumors, the bcl-2 gene (also known as BCL2) has stood out among molecular targets in oncology ( 1 ). The protein encoded by bcl-2 is a potent suppressor of apoptosis and is found at inappropriately high levels in probably more than half of all cancers in humans [reviewed in ( 2 )]. Gene transfer-mediated overexpression of Bcl-2 in a wide variety of tumor cell lines has been shown to confer marked resistance to the cytotoxic actions of essentially every type of anticancer drug presently available, as well as γ irradiation [reviewed in ( 3 )]. High levels of Bcl-2 have also been associated with progression to hormone independence in prostate cancers ( 4 , 5 ), presumably reflecting the consequences of blocking the apoptotic cell death that would normally ensue upon androgen deprivation in prostatic epithelial cells. Moreover, the relationship between Bcl-2 and chemoresistance has been borne out by clinical correlative studies showing that elevated expression of Bcl-2 can be associated with shorter survival and other indicators of worse clinical outcome in patients with at least some types of cancer, including aggressive non-Hodgkin's lymphomas, acute myelogenous leukemias, and adenocarcinomas of the prostate ( 6 – 13 ).