Faculty Bibliography

The uptake of cis-diamminedichloroplatinum(II) (cisplatin) has been studied in the L1210 murine lymphoid leukemia cell line. Labeled cisplatin and its aquated derivatives were resolved by high-performance liquid chromatography on a strong cationic exchange column. After 10 min of incubation of cisplatin with the cells, the major portion of the non-protein-bound platinum was in the form of cisplatin. However, a portion of this platinum was converted with time to a derivative which coeluted with the monoaquo derivative of cisplatin. With the appearance of this derivative, there was a concomitant inhibition of sodium-dependent amino acid transport as measured by the uptake of aminoisobutyric acid and methionine. Furthermore, the exposure of L1210 cells to a preparation of predominantly aquated product(s) of cisplatin inhibited amino acid uptake following a brief (2-min) incubation, whereas measurable inhibition of amino acid uptake by cisplatin required a longer preincubation period. This inhibition of aminoisobutyric acid and methionine was dependent on the concentration of platinum. Aminoisobutyric acid and methionine were shown to be concentrated in L1210 cells in the presence of sodium ions, and competition experiments suggest similar uptake systems. Since L1210 cells are methionine-auxotrophic leukemic cells, inhibition of essential amino acid transport by cisplatin may be a mechanism of cytotoxic action.

Cisplatin and its biotransformation products were analyzed in human and rat urine and in plasma from rats. Analyses were performed using high performance liquid chromatography (HPLC). Microbial mutagenesis assays were performed on effluents from the chromatographic system. After intravenous administration to man (50 mg/m2) and intravenous and intraperitoneal administration to rats (5-10 mg/kg), platinum was excreted in the urine in a form that co-eluted mainly with cisplatin. Unbound drug in the plasma co-eluted with cisplatin. Furthermore excreted platinum exhibited mutagenic and chemical reactivity similar to that of cisplatin. We conclude that the principal form of free platinum circulating in blood and excreted in urine is cisplatin.