Antitumor action of cis-dichlorobis(Methylamine)platmum(II)

C/s-Dichlorobis(methy lam ine) platinum(ll) (c/s-DMAP) induced unbalancedgrowth in Escherichia coli and prolonged survival times of BALB/c mice bearing the Ehrlichascites tumor as well as of (C57BL X DBA/2)Fi mice bearing the L1210 leukemia. Invitro, c/s-DMAP inhibited the synthesis ofDNA, RNA, and, to a lesser extent, protein inEhrlich ascites tumor cells. Inhibition onceconferred was irreversible when the cells werewashed with fresh medium. Suspensions oftumor cells became approximately 95% nonviable after 7.5 hours of incubation with thecompound at 10-4m. c/s-DMAP-3H bound firmlyto intact tumor cells in vitro, and the responseof this interaction to various chemical andphysical influences indicated that bindingwas not mediated enzymatically. c/s-DMAP-3H, which was bound to cells, was not removedon precipitation and washing with trichloroacetic acid. c/s-DMAP-3H did bind to isolatedDNA and RNA but not to bovine serum albumin.Dialysis experiments with the polynucleotidesof adenine (A), cytosine (C), guanine (G), anduridine (U) showed that the relative degree ofbinding occurred in the order poly-U> poly-G>poly-A>poly-C. About 50% of an injecteddose of c/s-DMAP-3H was excreted in urine byrats in 24 hours, and no appreciable amountwas excreted in feces. Studies of distributionof radioactivity from c/s-DMAP-3H in organs ofrats showed an initially high value in kidneysand liver followed by a decline. The amountrecovered in lungs was relatively constant overthe 96-hour period of measurement. Therelative rates of the hydrolytic aquation reactions in a series of organo-substituted squareplanar platinum (II) complexes may have somevalue in predicting the relative antitumor effectiveness within the series.