Abstract
Drug resistance remains a key obstacle to successful cancer treatment. The implementation of pharmacogenomics is widely proclaimed as a route to revolutionize the face of cancer therapy. Here we discuss the pharmacogenomics of the p53 tumor suppressor and its role in cancer chemosensitivity. It has been proposed that p53 has a profound impact on the response to chemotherapy and participates in development of drug resistance in tumor cells. This is based on the dual role of p53 as a guardian of genome integrity and as a key mediator of apoptosis. Alterations of the p53 gene occur in approximately 50% of human cancer, and human tumor cells retaining wildโtype p53 often have epigenetic defects in the p53 pathway. Extensive mechanistic studies of drug action suggest that virtually all cancer cells have a dysfunctional p53 system (including p53 and its associated proteins, both upstream regulators and downstream targets). Various experimental approaches to correct the p53 pathway defects in tumor cells are discussed. Many studies have correlated p53 status with prognosis and therapy response in tumors. However, the impact of p53 status on drug resistance of tumors is still controversial. The impact of p53 on chemosensitivity is complex and multifactorial, depending on the genotypic/phenotypic context of the cell. Recent technological achievements have fostered a renewed interest in pharmacogenomics of p53 and its association with drug response. These include highโthroughput tissue microarray analysis of p53 protein expression, single nucleotide polymorphism genotyping of the p53 gene, and gene expression profiling to identify the gene signature of p53โassociated chemoresistance. Knowledge from pharmacogenomic studies will provide an opportunity for improvements in drug efficacy through effective stratification of patients, and early identification of those individuals most likely to respond effectively to a specific therapy. Drug Dev. Res. 62:254โ272, 2004. ยฉ 2004 WileyโLiss, Inc.