There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.
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.