Effects of cyclosporin A on growth and polyamine metabolism of MOLT-4 T-lymphoblastic leukaemia cells.

We have examined the effects of Cyclosporin A (CsA) on growth and polyamine metabolism of MOLT-4, human T lymphoblastic leukaemia cells to ascertain the role of the polyamine biosynthetic pathway in the antitumour action of CsA. We observed that CsA had a dose-dependent inhibitory effect on growth of the cells in vitro, decreasing protein content, cell number and the rate of incorporation of 3H-thymidine into the cells. However, CsA treatment had no significant effect on intracellular polyamine levels in the cells. Contrary to previous reports, simultaneous addition of the diamine, putrescine, with CsA did not block or lessen the growth inhibitory effects of CsA. On the other hand, ornithine decarboxylase activity, the rate limiting enzyme of polyamine biosynthesis which converts ornithine to putrescine, was decreased by CsA treatment. This decrease appeared to be reversible and contrasts with the inhibition by alpha-difluoromethyl-ornithine, which is irreversible and can be overcome by addition of putrescine. This suppression of ornithine decarboxylase by CsA is more likely to occur by indirect effects on translation and/or transcription rather than a direct effect on the enzyme. It may be a contributory factor in the overall antiproliferative effects of CsA but is more likely to be a response to these growth inhibitory effects rather than a direct effect of the drug.