GENETIC FACTORS THAT ALTER THE PHARMACODYNAMICS OF ANTINEOPLASTIC AGENTS INDEPENDENT OF ALTERATIONS IN PLASMA PHARMACOKINETICS
Open AccessMost anticancer agents are inherently toxic. The toxicity of these drugs is designed to target and kill specific populations of rapidly proliferating abnormal cells in tumors. The therapeutic index of anticancer drugs is maximized when these agents have the desired mechanism of action within tumors with minimum toxicity to otherwise healthy tissues. Drug exposure in tissues often depends on the area under the plasma concentration versus time curve (AUC), and the genetic influence on variation in AUC has been heavily studied in relation to drug efficacy and toxicity. The AUC of drugs is influenced by the polymorphic expression and function of drug transporting (e.g. ATP-binding cassette transporters) and metabolizing (e.g. Cytochromes P450) proteins expressed in the liver and other excretory organs. However, inter-individual variation in the genes encoding drug metabolizing and transporting proteins may also alter their extrahepatic expression within peripheral tissues. Although it remains poorly studied, genetic inheritance may also alter the metabolism and transport of drugs within the tissues themselves and causing variation in toxicity and efficacy. Against this background, this project will test the overarching hypothesis that if a gene is responsible for the regulation of the metabolism and distribution of a substrate drug, and the gene is expressed extrahepatically, that allelic variation in such a gene will be responsible for inter-individual variation in drug toxicity or efficacy in a manner that is independent of the plasma concentration of the drug.The purpose of this project was to identify gene-drug interactions associated with the pharmacodynamics (e.g. efficacy and toxicity) of the taxanes and romidepsin that are not related to modulations in plasma pharmacokinetics (e.g. bodily exposure to the drug); instead, these gene-drug interactions were expected to be related to extrahepatic gene expression mediating tumor and tissue metabolism and transport. This project was also intended to provide mechanistic understanding of these interactions where possible. Firstly, these data indicate that a Cytochrome P450 1B1 (CYP1B1) polymorphism (L432V; CYP1B1*3) is related to docetaxel treatment efficacy in men with androgen independent prostate cancer in a manner that does not depend on AUC exposure to docetaxel. Further experiments were carried out to test the biological plausibility of this interaction, and the data suggest that this interaction is related to alterations in CYP1B1-catalyzed estrogen metabolism within the tumor tissue. Next, the data presented herein suggest that polymorphisms in the ATP-binding cassette transporter B1 (ABCB1) are related to the toxicities of docetaxel and romidepsin in a manner that is also independent a contribution of these polymorphisms towards variation in plasma drug exposure. This project demonstrates the possibility that polymorphisms in the ABCB1 gene are responsible for variation in clinical outcome following drug administration in a manner that depends on ABCB1 expression within biological barriers (i.e. the blood-nerve, blood cell-blood, and blood-myocardium barriers).These data suggest that genetic variation influences efficacy and toxicity of the taxanes and romidepsin by altering exposure and mechanism of action within the tissues themselves, and proteins that were previously characterized as important determinants of clearance in the liver actually are also responsible for drug disposition in the tissues. If validated by larger studies, these data could cause a paradigm shift in informing clinical treatment, as dose adjustments and alternative therapy options should be reconsidered.
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