Cyclosporins as drug resistance modifiers.
Cyclosporin A (CsA), a cyclic peptide of 11 amino acids isolated from the fungus Tolypoclodium inflatum Gams, is the principle drug used for immunosuppression in organ transplant patients. It is known to have a very specific effect on T-cell proliferation although the precise mechanism remains unclear. Following internalization, CsA binds to a cytosolic protein, cyclophilin, which has been shown to possess peptidyl-prolyl cis-trans isomerase activity. CsA is an effective modifier of multidrug resistance in human and rodent cells at doses in the range of 1 to 5 micrograms/mL. Although it reverses the drug accumulation deficit associated with multidrug resistance in some cell types, this is not always the case. CsA has P-glycoprotein binding activity but less specific membrane effects and inhibition of protein kinase C may also be involved in its resistance modifier action. A number of non-immunosuppressive analogues of CsA have been shown to have resistance modifier activity and some are more potent than the parent compound. One analogue from Sandoz, PSC-833, has been shown to be approximately 10-fold more potent than CsA and is expected to enter clinical trial in the near future. The use of such agents may allow a full test of the hypothesis that reversal of multidrug resistance will prove a useful clinical strategy.
MRC Clinical Oncology and Radiotherapeutics Unit, Cambridge, U.K.
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Twentyman
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002460:Cell Line / Q000187:drug effects; D002986:Clinical Trials as Topic; D003524:Cyclosporins / Q000737:chemistry / Q000494:pharmacology*; D004347:Drug Interactions; D004351:Drug Resistance / Q000235:genetics*; D006801:Humans; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008969:Molecular Sequence Data; D014407:Tumor Cells, Cultured / Q000187:drug effects
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D003524:Cyclosporins; D008562:Membrane Glycoproteins