REVERSAL OF MULTIDRUG-RESISTANCE BY TACROLIMUS HYDRATE

Tacrolimus hydrate, a potent immunosuppressant produced by Streptomyce s tsukubaensis, was examined for its effect on epirubicin activity in multidrug-resistant P388 leukemia (P388/R) cells overexpressed P-glyco protein and the parent (P388/S) cells. In the absence of modulator, th e 50% inhibitory concentration for epirubicin after 48-h incubation, d etermined using a microculture tetrazolium assay, was 0.8 mu g/ml in P 388/S cells. P388/R cells demonstrated a 90-fold reduction in sensitiv ity to epirubicin. Tacrolimus hydrate (1 and 10 mu M) markedly enhance d epirubicin cytotoxicity by 4.2- and 26.7-fold for P388/R cells. A si gnificant increase in LDH release from cells by tacrolimus hydrate was also observed in P388/R cells treated with epirubicin. Tacrolimus hyd rate had a marked effect on epirubicin-induced G(2)/M blockade in the resistant cells. Both tacrolimus hydrate and cyclosporin. A dramatical ly increased the accumulation of epirubicin by the resistant cells, wh ile these compounds has no effect on epirubicin accumulation in the pa rent cells. Thus, tacrolimus hydrate is able to down-modulate P-glycop rotein-associated resistance through inhibition of P-glycoprotein func tion, suggesting that the drug may be a candidate for killing drug-res istant tumor cells.