The rise of DNA methylation and the importance of chromatin on multidrug resistance in cancer

In recent years, the different classes of drugs and regimens used clinically have provided an improvement in tumour management. However, treatment is often palliative for the majority of cancer patients. Transformed cells respond poorly to chemotherapy mainly due to the development of the multidrug resistance (MDR) phenotype. Response to treatment does not generally result in complete remission and disease cure is uncommon for patients presenting with advanced stage cancer. Successful treatment of cancer requires a clearer understanding of chemotherapeutic resistance. Here, we examine what is known of one of the most extensively studied mechanisms of cellular drug resistance. The human multidrug resistance gene 1 (MDR1) is associated with expression of p-glycoprotein (Pgp). A transmembrane protein, Pgp acts as an efflux pump and reduces intracellular drug levels and thus its effectiveness as an antitumor agent. The precise mechanism of transcriptional regulation has been unclear due to the complex regulatory nature of the gene. It has become increasingly apparent that trans-activation or genetic amplification is by no means the only mechanism of activation. Consequently, alternative pathways have received more attention in the area of epigenetics to help explain transcriptional competence at a higher level of organization. The goal of this article is to highlight important findings in the field of methylation and explain how they impinge on MDR1 gene regulation. In this review, we cover the current information and postulate that epigenetic modification of MDR1 chromatin influences gene transcription in leukaemia. Finally, we explore transcriptional regulation and highlight recent progress with engineered ZFP's (zinc finger proteins). (C) 2003 Elsevier Inc. All rights reserved.