Reversal of multidrug resistance of tumor cells.
Drug resistance to chemotherapy is rapidly emerging. Resistance to one drug carries over resistance to unrelated anticancer drugs leading to multidrug resistance (MDR). A major factor of MDR is P-glycoprotein (P-gp) mediated ABC transport found in many eukaryotic cells. P-gp acts as a drug eMux pump. The mdr1 gene involved in P-gp 170 protein production is localized in the human chromosome 7 band p2 1.0-21.1. Point mutations after cross-resistance patterns. A variety of stimuli increase the expression of the mdr1 gene: lowered extracellular pH, heat shock, arsenite, cytotoxic agents, anticancer drugs, transfection with oncogenes, HIV-I, and UV-irradiation. An alternative hypothesis to the efflux pump claims that P-gp modifies the intracellular environment to reduce accumulation of anticancer drugs in cancer cells by creating ionic or proton gradients. Chemosensitizers that block P-gp drug extrusion are generally lipid-soluble at physiological pH, possess a basic nitrogen atom and at least two co-planar rings. P-gp blocking does not depend on drug chirality. This opens the way of treating P-gp related MDR with chiral versions of drugs relatively harmless in terms of side-effects. We believe that resistance modifiers combined with cytostatics will chemotherapeutically be more effective for cancer patients.
Szabó
D
D
Department of Medical Microbiology, University of Szeged, Szeged, Hungary.
Keyzer
H
H
Kaiser
H E
HE
Molnár
J
J
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000502:physiology*; D018528:ATP-Binding Cassette Transporters / Q000502:physiology; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism; D014150:Antipsychotic Agents / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000235:genetics / Q000502:physiology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D019450:Genes, MDR / Q000502:physiology*; D006031:Glycosylation; D006801:Humans; D008968:Molecular Conformation; D010766:Phosphorylation; D014407:Tumor Cells, Cultured / Q000187:drug effects
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D014150:Antipsychotic Agents