Identification of molecular determinants of tumor sensitivity and resistance to anticancer drugs.

Resistance to drugs is a major problem in cancer chemotherapy. Various cellular mechanisms of drug resistance have been identified in cultured tumor cell lines selected for growth in the presence of sublethal concentrations of various anticancer drugs. They involve drug transport and detoxification, qualitative or quantitative alterations of the drug target, repair of drug-induced DNA lesions, and alterations in signaling or execution of apoptosis. More recently, the possibility to simultaneously analyze the expression of thousands of genes using DNA microarrays has allowed exploring the relationships between gene expression and sensitivity to several anticancer drugs. A number of studies using microarrays for identifying genes governing tumor chemosensitivity focused on tumor cell lines. Some clinical studies have also been carried out to investigate whether tumor gene expression patterns could predict clinical response to chemotherapy. Results of these studies are encouraging, indicating that individualization of drug treatment based on multigenic response-predictive markers is feasible.