Direct antiproliferative effects of cyclosporin A on murine lymphoreticular tumor cells in culture.

Cyclosporin A (CSA) has been shown to prevent mouse spleen cell blast formation in response to concanavalin A (con A) and to inhibit lymphocyte proliferation. In the presence of interleukin-2 (IL-2), however, the proliferation of preformed blasts is not affected by CSA. We examined the effects of CSA on the growth in culture of several established mouse lymphoreticular tumor-cell lines proliferating independently of exogenous lymphokines. We found that CSA abolished, by direct cytolysis, growth of the T-lymphoma lines, EL4, WEHI22.1, S49.1, RL male 1, WR19L, and YAC. In contrast, growth of the non T-cell lines, S49, P388D1, RAW264.7, PU51.R, P815, P3X63Ag8, and L929, was variably retarded by a noncytocidal action of CSA. The concentration of CSA required for T-cell cytolysis was relatively high and directly related to the numbers of cells treated. Expression of Thy-1 antigen predicted for the susceptibility of a cell line to CSA-induced lysis. At the concentrations used there was no evidence of significant mitotic death following CSA treatment; cells previously exposed to CSA and then washed were able to resume a delayed but otherwise normal pattern of replication. In a preliminary experiment, CSA afforded significant protection to C57BL/6 mice transplanted with syngeneic EL4 cells. The results indicate that CSA, in vitro and in vivo, is a potent antiproliferative agent selective for T cells, and that in the absence of growth factors its inhibitory effects are not limited to early event(s) in the T-cell activation process.