Induction of Tumor Cell Apoptosis and Chemosensitization by Antisense Strategies

Radiation and traditional chemotherapy kill both normal and tumor cells owing to lack of target selectivity. In this chapter, we review methods for the use of antisense oligodeoxynucleotides (AS-DONs) directed against gene products overexpressed in tumor cells in synergy with other anticancer agents. In contrast to the low basal levels of the mitogen-dependent cyclin D1 and of the DNA-damage-inducible p53 tumor suppressor protein, tumors with greater genetic instability and poor therapeutic response show a mutant-stabilized p53 protein, a mitogen-independent constitutive cyclin D1, and overexpression of antiapoptotic genes such as bcl-2 and bcl-xL . Since overexpression of any one of these gene products decreases apoptosis in malignant cells, we propose the use of subtoxic antisense technology specifically directed against some of these tumor-associated targets prior to treatment with sublethal chemotherapy as a strategy to diminish damage to normal cells and the emergence of cancer cells resistant to conventional therapy. AS-ODN technology capable of antagonizing gene sequences preferentially expressed in tumors combined with standard anticancer therapy offers an alternative approach to improve target selectivity, diminish anticancer toxicity, and lower drug resistance.