Harnessing apoptosis for improved anticancer gene therapy

Advances in our understanding of the mechanisms by which tumor cells detect drug-induced DNA damage leading to apoptotic death have aided in the design of novel, potentially more selective strategies for cancer treatment. Several of these strategies use proapoptotic factors and have shown promise in sensitizing tumor cells to the cytotoxic actions of traditional cancer chemotherapeutic drugs. Although antiapoptotic factors are generally regarded as poor prognostic factors for successful cancer chemotherapy, strategies that use antiapoptotic factors in combination with suicide or other gene therapies can also be considered. The introduction of antiapoptotic factors that act downstream of drug-induced mitochondrial transition delays, but does not block, the ultimate cytotoxic response to cancer chemotherapeutic drugs that activate a mitochondrial pathway of cell death. Recent studies using the cytochrome P-450 prodrug cyclophosphamide exemplify how the antiapoptotic, caspase-inhibitory baculovirus protein p35 can be combined with P-450 gene-directed enzyme prodrug therapy to prolong localized, intratumoral production of cytotoxic drug metabolites without inducing tumor cell drug resistance. This model may be adapted to other gene therapies, including those that target death receptor pathways, to maximize the production of soluble, bystander. cytotoxic factors and prodrug metabolites and thereby amplify the therapeutic response.