Regulation of the multidrug resistance (MDR1) gene expression.

The emergence of drug resistance poses a major obstacle to the success of chemotherapy for a large number of human cancers. Development of the multidrug resistance phenotype in human malignancies is an especially pressing problem because the tumors become cross-resistant to multiple chemotherapeutic agents that are both chemically and physically unrelated. The increased resistance to multiple cytotoxic natural product chemotherapeutic drugs is due to overexpression of the mdr gene, which encodes a plasma membrane ATP-dependent efflux pump. Expression of P-glycoprotein is tissue specific and found in a number of normal tissues, including colon, small intestine, kidney, liver and adrenal gland, as well as in the capillaries of brain and testis. The precise physiological functions in these tissue localizations is unclear at present. Intense efforts in many laboratories currently are invested on elucidating the functions of P-glycoprotein and investigating mechanisms that regulate the mdr gene expression.