Modification of cytotoxic drug resistance by non-immuno-suppressive cyclosporins

Abstract

We have examined the ability of a series of non- or minimally-immunosuppressive analogues of cyclosporin A to modify cytotoxic drug resistance in vitro. The series includes both cyclosporins derived from naturally-occurring compounds and synthetic cyclosporins. In contrast to our previous findings, we now report that several of these analogues are highly effective modifiers of resistance to adriamycin and vincristine in a multidrug resistant subline of the human small cell lung cancer cell line NCI-H69. Two of the analogues (W8-032 and B3-243) maintain considerable activity in the dose range 1-2 micrograms ml-1 whereas little activity remains for cyclosporin A when the dose is reduced to this level. B3-243, however, in contrast to cyclosporin A and W8-032, does itself show growth inhibitory effects in this dose range. Possible clinical trial of these cyclosporins as resistance modifiers will depend upon their in vivo toxicology and pharmacokinetic properties.