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.