Cytochrome P450-based cancer gene therapy: recent advances and future prospects

Cytochrome P450-based cancer gene therapy is a novel prodrug activation strategy for cancer treatment that has substantial potential for improving the safety and efficacy of cancer chemotherapeutics. The primary goal of this strategy is to selectively increase tumor cell exposure to cytotoxic drug metabolites generated locally by a prodrug-activating P450 enzyme. This strategy has been exemplified for the alkylating agents cyclophosphamide and ifosfamide, which are bioactivated by select P450 enzymes whose expression is generally high in liver and deficient in tumor cells. Transduction of tumors with a prodrug-activating P450 gene, followed by prodrug treatment, greatly increases intratumoral formation of activated drug metabolites. This leads to more efficient killing of the transduced tumor cells without a significant increase in host toxicity. P450 gene therapy is accompanied by substantial bystander cytotoxicity which greatly enhances the therapeutic effect by extending it to nearby tumor cells not transduced with the therapeutic P450 gene. Although endogenous P450 reductase is not expected to be a limiting factor in prodrug activation in tumor cells that express moderate levels of an exogenous P450 gene, P450 reductase transduction has recently been found to substantially enhance intratumoral prodrug activation and its associated therapeutic effects. Using this gene combination, an overall 50- to 100-fold increase in tumor cell kill in vivo over that provided by hepatic drug activation alone has been observed. Striking improvements in therapeutic effects can thus be achieved using an established anticancer drug in an intratumoral prodrug activation strategy based on the combination of a cytochrome P450 gene with the gene encoding NADPH-P450 reductase. This strategy is readily extendable to several other widely used P450-activated cancer chemotherapeutic prodrugs, as well as to prodrugs that undergo P450 reductase-dependent bioreductive activation and which may exhibit synergy when combined with P450-activated prodrugs in a P450/P450 reductase-based cancer gene therapeutic regimen.