Multidrug resistance appears to be linked to overexpression of a cell membrane glycoprotein, termed P-glycoprotein, on the surface of cancer cells. This cell membrane glycoprotein serves as a transporter for the efflux of noxious substances, such as chemotherapeutic drugs. Its overexpression is associated with decreased accumulation of multiple chemotherapeutic drugs within the resistant cancer cells. The mdr -1 gene is expressed in several normal tissues, such as the kidney, the adrenal gland, the liver, and the colon, and its expression may be increased in the cancer cells of patients with leukemias, lymphomas, multiple myeloma, and other cancers that are resistant to chemotherapy. However, it may be that not all multidrug resistance is related to the expression of P-glycoprotein.
Circumstantial evidence suggests that some multidrug resistance is related to other proteins.
With the intention of minimizing the toxic effect of chemotherapy on bone marrow stem cells during cancer chemotherapy, the mdr -1 gene has been transfected into normal stem cells in the bone marrow of mice and that of humans in research protocols. Multidrug resistance in human cancers can be combated by noncytotoxic drugs that interact with and prevent functioning of P-glycoprotein. These agents either compete for the action of the P-glycoprotein transporter or interfere with its function. This approach inhibits the normal function of P-glycoprotein, resulting in decreased excretion of the cytotoxic agent and, possibly, in increased killing of cells. Although regression of tumors is found when this strategy is used, responses are limited.