Antitumor Action of cis-Dichlorobis(methylamine)platinum(II)2

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Abstract
cis-Dichlorobis(methyla mine) platinum(II) (cis-DMAP) induced unbalanced growth in Escherichia coli and prolonged survival times of BALB/c mice bearing the Ehrlich ascites tumor as well as of (C57BL × DBA/2)F1 mice bearing the L1210 leukemia. In vitro, cis-DMAP inhibited the synthesis of DNA, RNA, and, to a lesser extent, protein in Ehrlich ascites tumor cells. Inhibition once conferred was irreversible when the cells were washed with fresh medium. Suspensions of tumor cells became approximately 95% nonviable after 7.5 hours of incubation with the compound at 10-4M. cis-DMAP-3H bound firmly to intact tumor cells in vitro, and the response of this interaction to various chemical and physical influences indicated that binding was not mediated enzymatically. cis-DMAP-3H, which was bound to cells, was not removed on precipitation and washing with trichloroacetic acid. cis-DMAP-3H did bind to isolated DNA and RNA but not to bovine serum albumin. Dialysis experiments with the polynucleotides of adenine (A), cytosine (C), guanine (G), and uridine (U) showed that the relative degree of binding occurred in the order poly-U> poly-G> poly-A>poly-C. About 50% of an injected dose of cis-DMAP-3H was excreted in urine by rats in 24 hours, and no appreciable amount was excreted in feces. Studies of distribution of radioactivity from cis-DMAP-3H in organs of rats showed an initially high value in kidneys and liver followed by a decline. The amount recovered in lungs was relatively constant over the 96-hour period of measurement. The relative rates of the hydrolytic aquation reactions in a series of organo-substituted square planar platinum (II) complexes may have some value in predicting the relative anti-tumor effectiveness within the series.

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