Drug Resistance.

Chemotherapy fails to cure most cancer patients with advanced disease, particularly patients with the most common forms of solid tumors. The presence or development of resistance to anticancer agents is the major cause of this failure. Several of the mechanisms underlying drug resistance to cytotoxic drugs have been elucidated in the last two decades, largely by employing in vitro drug-selected cancer cell lines. In unselected cell lines and probably also in human cancer, multiple mechanisms are redundantly present to defend the organism from the insults of drugs. Mechanisms have been unraveled by which cross-resistance ensues to multiple drugs (multidrug resistance), similar to what is commonly seen in patients. More recently, the identification of downstream genes, intimately involved in cell-cycle checkpoints, appears also to directly contribute to determining the sensitivity to cytotoxic drugs by regulating the response of the cell to the drug damage. The identification of mechanisms of drug resistance has provided ways of attempting to revert the drug resistance. Although, so far, attempts to revert P-glycoprotein-mediated multidrug resistance have only sorted out limited efficacy, new drugs and new strategies are being devised and implemented, such as high-dose chemotherapy and gene transfer.