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      Cyclosporins as drug resistance modifiers

      Biochemical Pharmacology
      Elsevier BV

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          Abstract

          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.

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          Author and article information

          Journal
          Biochemical Pharmacology
          Biochemical Pharmacology
          Elsevier BV
          00062952
          January 1992
          January 1992
          : 43
          : 1
          : 109-117
          Article
          10.1016/0006-2952(92)90668-9
          1346494
          98d8567e-5cdc-4bc5-af07-97b7f4d866e8
          © 1992

          https://www.elsevier.com/tdm/userlicense/1.0/

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