Molecular mechanisms of multidrug resistance in cancer chemotherapy

摘要: The occurrence of multidrug resistance (MDR) is one the main obstacles in successful chemotherapeutic treatment cancer. MDR cell lines are resistant to so-called naturally occurring anti-cancer drugs, such as anthracyclines, Vinca alkaloids and epipodophyllotoxins, but not cross-resistant alkylating agents, antimetabolites cisplatin. So far, three separate forms have been characterized more detail: classical MDR, non-Pgp atypical MDR. Although all phenotypes much common with respect cross-resistance patterns, underlying mechanisms certainly differ. Atypical associated quantitative qualitative alterations topoisomerase II alpha, a nuclear enzyme that actively participates lethal action cytotoxic drugs. cells do overexpress P-glycoprotein, unaltered their ability accumulate In this review we will focus on molecular mechanism transcriptional activation membrane-bound transport proteins. These proteins belong ATP-binding cassette (ABC) superfamily systems. phenotype by reduced due activity an energy-dependent uni-directional, membrane-bound, drug-efflux pump broad substrate specificity. drug composed transmembrane glycoprotein (P-glyco-protein-Pgp) weight 170 kD, is, man, encoded (MDR1) gene. Typically, has no P-gly-coprotein expression, yet about same pattern This caused overexpression resistance-associated protein (MRP) gene, which encodes 190 kD (MRP). MRP probably works direct extrusion drugs from and/or mediating sequestration into intracellular compartments, both leading reduction effective concentrations. For phenotype, evidence accumulating it plays role indeed, clinical resistance, especially some hematological malignancies (acute myeloid leukemia, multiple myeloma non-Hodgkin's lymphoma) solid tumors (soft tissue sarcomas neuroblastoma). association elaborated, yet, studies expression human cancer just begun. We found MRP, determined RNase protection assay well immunohistochemistry, occurs several cancers, among lung, esophagus, breast ovary, leukemias. Further indicated establish whether elevated at diagnosis unfavorable prognostic factor for outcome chemotherapy.