Cytochrome P450s (CYPs) represent a large class of
heme-containing
enzymes that catalyze the metabolism of multitudes of substrates both endogenous and exogenous. Until recently, however, CYPs have been largely overlooked in
cancer drug development, acknowledged only for their role in phase I metabolism of chemotherapeutics. The first successful strategy targeting CYP
enzymes in
cancer therapy was the development of potent inhibitors of
CYP19 (
aromatase) for the treatment of
breast cancer.
Aromatase inhibitors ushered in a new era in
hormone ablation
therapy for
estrogen dependent
cancers, and have paved the way for similar strategies (i.e., inhibition of
CYP17) that combat
androgen dependent
prostate cancer. Identification of CYPs involved in the inactivation of anti-
cancer metabolites of
vitamin D(3) and
vitamin A has triggered development of agents that target these
enzymes as well. The discovery of the over-expression of exogenous metabolizing CYPs, such as CYP1B1, in
cancer cells has roused interest in the development of inhibitors for
chemoprevention and of
prodrugs designed to be activated by CYPs only in
cancer cells. Finally, the expression of CYPs within
tumors has been utilized in the development of bioreductive molecules that are activated by CYPs only under hypoxic conditions. This review offers the first comprehensive analysis of strategies in drug development that either inhibit or exploit CYP
enzymes for the treatment of
cancer.