A reexamination of PSC 833 (Valspodar) as a cytotoxic agent and in combination with anticancer agents

Background: The cyclosporins have been thought as being mainly immunosuppre ssive agents which interfere with the function of the MDR pump and thus pla y a role in resistance to drug anticancer effects. We reexamined their cyto toxicity in defined cell lines both as single agents and in combination wit h agents which may be of value in human malignant disease. Methods: Cells w ere grown to confluence following inoculation at 5000-8000 cells/well in 96 -well dishes, and growth patterns and death were determined by an MTT assay . Median effect analysis was used to look for synergy, additive effects, or antagonism between the cyclosporins and drugs with antitumor effects in hu mans. Results: Cyclosporin A and PSC 833 were found to have cytotoxic activ ity at clinically achievable concentrations in breast, leukemia, and prosta te cell lines. Synergistic or additive effects were demonstrated in all thr ee prostate cell lines when PSC 833 was combined with estramustine, etoposi de, ketoconazole, suramin, or vinorelbine in the prostate cancer cell lines . Cell line-selective additive effects or synergism were also identified wi th bicalutamide, carboplatin, cisplatinum, cis-retinoic acid, dexamethasone , 5-fluorouracil, liarozole, and trans-retinoic acid. Conclusions: PSC 833 or cyclosporin alone or in combination with other agents may have an antica ncer effect independently of their modulatory action on MDR. Several of the synergistic combinations which are not mediated by the MDR pump need to be tested in vivo for efficacy.