CYCLOSPORINE-G INHIBITS PROLIFERATION OF A431 CELLS IN A DOSE-DEPENDENT AND TIME-DEPENDENT MANNER COMPARABLE TO CYCLOSPORINE-A

Cyclosporin A (CyA), a fungal metabolite with potent immunosuppressive activity and an antiproliferative effect on epithelial cells, i.e. no rmal and transformed keratinocytes, is currently proposed in the treat ment of psoriasis, where its use is limited mainly by possible nephrot oxicity and/or hepatotoxicity. Numerous analogs of CyA have been produ ced and studied. The most promising of these is the immunosuppressive analog cyclosporin G (CyG), in which norvaline is substituted for alph a-aminobutyric acid at the 2 position. This would maintain strong immu nological activity, with reduced to absent nephrotoxic and hepatotoxic effects. The authors compared the antiproliferative effect of CyG and CyA on the epidermoid carcinoma cell line A431 in vitro, performing t he MTT-microculture tetrazolium colorimetric assay based on the abilit y of viable cells to reduce the MTT compound to a blue formazan produc t. Subconfluent A431 cells were incubated with CyA or CyG or solvent o nly, for 24, 48, 72 or 96 h at concentrations of in vivo relevance (0. 3, 0.6, 1.25, 2.5, 5, 7.5, 10 mu g/ml). CyA and CyG showed similar ant iproliferative effects, in low-serum-containing media in a dose- and t ime-dependent manner. After 24 h of incubation, the inhibition of the growth rate was irrelevant. A striking inhibition of the growth rate a t the higher concentrations of the drugs (7.5 and 10 mu g/ml) at 72 an d 96 h of incubation was evident. Therefore CYG has been demonstrated to exercise an antiproliferative effect on the A431 cell line. These d ata suggest possible use for CyG in the treatment of immuno-mediated d isease, particularly in the treatment of dermatologic diseases charact erized by epidermal hyperplasia and/or keratinocyte hyperproliferation .