Inhibition of Amino Acid Transport by cis-Diamminedichloroplatinum(ll) Derivatives in L1210 Murine Leukemia Cells

The uptake of cis-diamminedichloroplatinum(ll) (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 amino-isobutyric 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.