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Accumulation of cis-Diamminedichloroplatinum(II) and Platinum Analogues by Platinum-resistant Murine Leukemia Cells in Vitro¹

Department of Chemotherapy, Warner-Lambert/Parke-Davis Pharmaceutical Research, Ann Arbor, Michigan 48105

Three murine leukemia lines resistant to cis-diamminedichloroplatinum(II) and one line resistant to diaminocyclohexane (DACH) platinum(II) complexes were compared to their platinum-sensitive parent lines to determine whether differences in net platinum accumulation were related to the resistant phenotype. The cis-diamminedichloroplatinum(II)-resistant lines (L1210PtR4, L1210DDP5, P388PtR4) and the DACH-resistant line (L1210DACH) were incubated in vitro with cis-diamminedichloroplatinum(II), [sp-4-2-(1R,2R)]-(1,2-cyclohexanediamine-N-N')dichloroplatinum(II), [sp-4-2-(1R,2R)]-(1,2-cyclohexanediamine-N-N')[ethanedioato(2-)-O,O']platinum(II), or dianinocyclobutanedicarboxylatoplatinum(II) and the time-dependent cellular platinum levels determined by flameless atomic absorption spectrophotometry. Cell lines resistant to a given platinum complex showed a reduction in the rate of platinum accumulation when compared to the sensitive line at 37°C. Intracellular levels of diaminocyclobutanedicarboxylatoplatinum(II) were too low to confidently measure under the conditions of this study. Our data suggest that the mechanism of platinum resistance in these cell lines may be related to a reduced accumulation of the platinum-containing drug, although patterns of cross-resistance suggest other mechanisms may be operative as well.

¹ Presented in part at the 77th Annual Meeting of the American Association for Cancer Research, Los Angeles, CA (1).

² To whom requests for reprints should be addressed, at Warner-Lambert/Parke-Davis, 2800 Plymouth Road, Ann Arbor, MI 48105.

Received 8/28/86. Revised 2/24/87. Revised 8/ 6/87. Revised 9/22/87. Accepted 9/28/87.

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