Doxorubicin and cyclosporin A affect murine lymphoid cells expressing different antigenic determinants

Cyclosporin A (CsA) enhances the antitumor activity of doxorubicin (Dox) as well as that of some other cytotoxic drugs against drug-resistant tumor variants. In some cases, however, such combination treatments result in severe unexplained toxicities. In this study the possibility was explored that the effects of CsA and Dox on lymphoid cells may be instrumental, at least in part, in determining their toxicological effects. Subsets of spleen and thymus lymphoid cells, from mice with or without Dox or CsA treatment, were identified by flow cytometry based upon their plasma membrane antigenic determinants. The results indicate that there is essentially no cross-sensitivity/resistance between the two agents. The most Dox-susceptible cells were immature (non-proliferating) CD4+CD8+ thymocytes and CD3-B220- as well as CD3-B220+ splenocytes. These populations were intact following CsA treatment, but the numbers of mature CD4+CD8- and CD4-CD8+ cells were substantially reduced. Similar "mirror image" differences were found for other populations examined. When considered together, these findings suggest that in combination Dox and CsA would affect nearly all subsets of lymphoid cells, providing one possible explanation of why increased leukopenia, toxicity and immunosuppression are found after their combined administration. Since leukemias, lymphomas and, to a more limited extent, certain solid tumors express these same phenotypic markers, similar analyses should be considered for monitoring and perhaps even predicting neoplastic cell sensitivity to treatment with such agents.