cis-Platinum(II) amine complexes: some structure-activity relationships for immunosuppressive, nephrotoxic and gastrointestinal (side) effects in rats.

A local graft-versus-host reaction was established to elicit lymphoid hypertrophy in F1 hybrid PVG X Lew rats. cis-Di(amine)platinum(II) complexes were given i.p. on days 1--4 in divided doses. Overnight proteinuria and measurements of renal hypertrophy on day 5 reflected the nephrotoxicity of the test compound. Stomach weights indicated the peculiar effect on pyloric stasis causing gastric distension. Weights of thymus' and spleens together with lymph-nodes showed the lymphodepressant/immunosuppressive properties of platinum compounds. Structure activity relationships for immunosuppressant, nephrotoxic and gastric-distending activities were investigated with: (a) cis-diaquo, cis-hydroxyaquo- and cis-dichlorodi(amine)platinum(II) complexes; (b) dinuclear mu-dihydroxo-bridged di(amine)platinum(II) complexes; (c) carboxylatodi(amine)platinum(II) complexes. Nephrotoxicity was minimised (with retention of immunosuppressant activity) by (a) the use of certain N-substituted amines e.g. Dach, Me4en; (b) co-administration of selected adjuncts e.g. citrate, salicylate; (c) auxiliary treatment with a penicillin mixture (Triplopen). In vitro effects of some platinum(II) compounds on isolated rat kidney tubules were also investigated.