Modulation of cytochrome P450 activity: implications for cancer therapy

Summary

Although metabolism mediated by cytochrome P450 isoenzymes is known to play a major part in the biotransformation of anticancer agents in vivo, few clinical studies have investigated activity of cytochrome P450s and therapeutic outcome in people with cancer. Variability between individuals in the pharmacokinetics of cancer chemotherapy has important consequences in terms of therapeutic efficacy and safety. We discuss here the effect of drug metabolism mediated by cytochrome P450 on therapeutic outcome. As examples, the biotransformation pathways of cyclophosphamide, ifosfamide, tamoxifen, docetaxel, paclitaxel, and irinotecan are discussed. Since most anticancer agents are transformed by enzymes, better knowledge of their metabolic pathways could help improve treatment outcome and safety. Furthermore, a more complete understanding of the metabolism of anticancer agents through phenotyping and genotyping approaches will facilitate the prediction of interactions between drugs. More clinical evidence is needed on the metabolic transformation and drug interactions with these agents to improve cancer therapeutics.

Introduction

Anticancer agents have a wide variation between individuals in response, owing partly to pharmacokinetic variability. The most common strategy used to restrict pharmacokinetic variability is to relate doses of drugs to the patient's body surface area (BSA). This approach is based on the assumption that each individual is capable of metabolising drugs with the same efficacy. However, BSA-based dosing strategies do not reduce variability between individuals in the pharmacokinetics of most chemotherapeutic agents.¹ Therefore, other factors must contribute to drug disposition as well as therapeutic efficacy and toxic effects.

One of the sources of variation in drug effects is differences between individuals in inherited elements of drug response.² Genetics is estimated to account for 20–95% of variability in therapeutic response and toxic effects. Research in pharmacogenomics aims to elucidate the genomic determinants of drug disposition and effect.³ Genetics affects various factors influencing drug disposition, including drug absorption, metabolism, distribution, and excretion.³ Several reviews on pharmacogenomics and cancer therapy have been published, but have focused mostly on genetic variability in phase II reaction enzymes such as UDP glucuronosyltransferase, N-acetyltransferases, and thiopurine methyltransferase.² Here, we focus on drug metabolism, specifically the role of metabolism mediated by cytochrome P450s, on cancer therapy and the endogenous and exogenous factors that influence the activity of these enzymes.

The cytochrome P450 enzymes catalyse the oxidation of many structurally unrelated compounds of endogenous and exogenous origin. They also have important roles in the extent and duration of drug effects, by catabolising drugs to inactive metabolites or by bioactivating prodrugs to their active forms. Several anticancer agents are metabolised by cytochrome P450s (table).