Tumour cytochrome P450 and drug activation

Abstract

The expression of drug metabolising cytochrome P450s (CYPs) notably 1A, 1B, 2C, 3A, 2D subfamily members have been identified in a wide range of human cancers. Individual tumour types have distinct P450 profiles as studied by detection of P450 activity, identification of immunoreactive CYP protein and detection of CYP mRNA. Selected P450s, especially CYP1B1, are overexpressed in tumours including cancers of the lung, breast, liver, gastrointestinal tract, prostate, bladder. Several prodrug anti-tumour agents have retrospectively been identified as P450 substrates for which tumour CYP activation may hitherto have been underestimated. Those in clinical use include prodrug alkylating agents (cyclophosphamide, ifosphamide, dacarbazine, procarbazine), Tegafur, a prodrug fluoropyrimidine, methoxymorphylinodoxorubicin, a metabolically activated anthracycline, as well as flutamide and tamoxifen, two non-steroidal hormone receptor antagonists that are significantly more active following CYP-hydroxylation. More exciting is the prospect of developing new agents designed to be selectively dependent on tumour CYP activation. This can be illustrated with P450 activation of the 2-(4-aminophenyl)benzothiazoles exclusively in CYP1A1 inducible tumours. Also of interest is the bioreductive antitumour prodrug AQ4N, a CYP3A substrate that is activated to a cytotoxic metabolite specifically in hypoxic tumour regions.