Analysis of the interactions of immunosuppressive drugs with cyclosporine in inhibiting DNA proliferation

Abstract

Though the high immunosuppressive efficacy of cyclosporine has revolutionized clinical transplantation, renal, hepatic, and neural toxicities limit its therapeutic potential. One approach to this problem is to combine CsA therapy with immunosuppressive agents that act synergistically with it, thereby permitting lower doses and mitigating drug-induced toxicity. The present study examines the in vitro interactions of various immunosuppressive agents—namely, 6-mercaptopurine (6MP), dexamethasone (Dexa), FK506, and Enisoprost (EP)— with CsA. These investigations dissect the impact of the drug combinations in inhibiting 3H-thymidine incorporation into DNA by normal human peripheral blood lymphocytes activated by mitogens or by alloantigens in mixed lymphocyte culture responses. The median-effect equation was used to analyze the dose-effect relationships of immunosuppressive drugs either alone or in combination. The interactions were quantified by calculation of combination indices (Cl). Cl values <1, >1, and equal to 1 represent synergistic, antagonistic, and additive interactions, respectively. In combination with CsA, 6MP showed modest and Dexa profound synergism, while EP displayed modest and FK506 marked antagonism. These findings confirm the clinical impression of in vivo synergism between CsA and Dexa. They suggest that in vitro analysis of drug interactions may distinguish synergistic drug combinations potentially applicable to clinical practice. © 1990 by Williams & Wilkins.