Multidrug resistance transporters and modulation

Multidrug resistance (MDR), whereby tumor cells simultaneously possess intr insic or acquired cross-resistance to diverse chemotherapeutic agents, hamp ers the effective treatment of cancer. Molecular investigations in MDR resu lted in the isolation and characterization of genes coding for several prot eins associated with MDR, including P-glycoprotein (P-gp), the multidrug re sistance associated protein (MRP1), the lung resistance protein (LRP), and, more recently, the breast cancer resistance protein (BCRP). These transmem brane proteins cause MDR either by decreasing the total intracellular reten tion of drugs or redistributing intracellular accumulation of drugs away fr om target organelles. These proteins are expressed at varying degrees in di fferent neoplasms. including the AIDS-associated non-Hodgkin lymphoma and K aposi sarcoma and are generally associated with poor prognosis. Several MDR -reversing agents are in various stages of clinical development. First-gene ration modulators such as verapamil, quinidine, and cyclosporin required hi gh doses of drugs to reverse MDR and were associated with unacceptable toxi cities. Second- and third-generation MDR inhibitors include PSC 833, GF1209 18, VX-710, and LY335979, among others. Limitations to the use of these mod ulators include multiple and redundant cellular mechanisms of resistance, a lterations in pharmacokinetics of cytotoxic agents, and clinical toxicities . Studies to validate the role of MDR reversal in the treatment of various malignancies are underway. A potential use of these agents may be to enhanc e intestinal drug absorption and increase drug penetration to biologically important protective barriers, such as the blood-brain, blood-cerebrospinal fluid, and the maternal-fetal barriers. The use of MDR modulators with dru gs such as the antiviral protease inhibitors and cytotoxics may enhance dru g accumulation in sanctuary sites that are traditionally impenetrable to th ese agents. Curr Opin Oncol 2000, 12:450-458 (C) 2000 Lippincott Williams & Wilkins, Inc.