Multiple genetic and epigenetic interacting mechanisms contribute to clonally selection of drug-resistant tumors: current views and new therapeutic prospective.

Successful treatment of cancer requires a clear understanding of drug-resistance mechanism. Cancer patient are often treated with standard protocols without considering individual difference in chemosensitivity, whereas the efficacy of anticancer drug varies widely among individual patients. Since chemosensitivity involves multiple interacting factors, it is not sufficient to investigate a single gene or factor to fix chemoresistance. Along with affecting disease progression, the synergism between genetic and epigenetic abnormalities can contribute to convert a sensible tumor cell in a resistant one. Unlike genetic changes, epigenetic changes are potentially reversible. Therefore, treatment with DNA methylation inhibitors can reactivate the expression of genes improperly methylated and can reverse many aspect of cancer phenotype such as drug resistance. The demethylating agents are used in the treatment of several kind of tumor, but toxicity and the potential outcome on the normal methylation patterns have always been concern of researchers and clinicals. It is necessary to create individual chemosensitivity-chemoresistance maps in order to identify the combination of drugs for optimized treatments. An overview on genetic and epigenetic events contributing to clonally selection of chemotherapeutic-resistant tumors is discussed. Copyright 2005 Wiley-Liss, Inc.