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 × 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 μ-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.