DOXORUBICIN AND CYCLOSPORINE-A AFFECT MURINE LYMPHOID-CELLS EXPRESSING DIFFERENT ANTIGENIC DETERMINANTS

Cyclosporin A (CsA) enhances the antitumor activity of doxorubicin (Do x) as well as that of some other cytotoxic drugs against drug-resistan t 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 ef fects. 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 indicat e that there is essentially no cross-sensitivity/resistance between th e two agents. The most Dox-susceptible cells were immature (non-prolif erating) CD4(+)CD8(+) thymocytes and CD3(-)220(-) as well as CD3(-)B22 0(+) splenocytes. These populations were intact following CsA treatmen t, 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 findi ngs suggest that in combination Dox and CsA would affect nearly all su bsets of lymphoid cells, providing one possible explanation of why inc reased leukopenia, toxicity and immunosuppression are found after thei r combined administration. Since leukemias, lymphomas and, to a more l imited extent, certain solid tumors express these same phenotypic mark ers, similar analyses should be considered for monitoring and perhaps even predicting neoplastic cell sensitivity to treatment with such age nts.