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cis-Diamminedichloroplatinum(II) Accumulation in Sensitive and Resistant Human Ovarian Carcinoma Cells¹

Cancer Center, University of California, San Diego, La Jolla, California 92093

We have characterized the accumulation of cisplatin (DDP) into parent and cisplatin-resistant 2008 human ovarian carcinoma cells. Accumulation of DDP at 1 h was a linear function of concentration from 0.25 to 100 µM DDP in both cell types. DDP-resistant cells that were only 3.3-fold resistant had approximately 50% less accumulated platinum at all concentrations examined. Accumulation of 1.0 µM DDP was linear for approximately 3 h and then slowed but did not reach equilibrium at up to 24 h in either cell type. The decreased DDP accumulation in resistant cells did not appear to be due to increased efflux; similar percentages of platinum were available for exodus in parent and resistant cells. Intracellular metabolites of DDP appeared to be decreased by similar amounts in the resistant cells. Native DDP was not driven uphill into cells against a concentration gradient, suggesting that DDP uptake does not involve primary active transport. The metabolic inhibitors, dinitrophenol and NaF, did not decrease DDP accumulation; iodoacetate had a stimulatory effect. Dinitrophenol, however, in combination with NaF or iodoacetate decreased DDP accumulation. A 30-min exposure to 0.2 mM ouabain also decreased DDP accumulation in both parent and resistant cells. A component of DDP accumulation thus appears to be energy dependent. These studies have identified decreased DDP accumulation as an important mechanism of resistance that is expressed early in the acquisition of DDP resistance in human ovarian carcinoma cells.

¹ Supported by Grant CA-23100 from the National Cancer Institute, Grant IN-93N from the American Cancer Society, and a grant from Bristol-Myers Co. This work was conducted in part by the Clayton Foundation for Research, California Division.

² Clayton Foundation Investigator. To whom requests for reprints should be addressed, at Cancer Center, UCSD T-012, La Jolla, CA 92093.

³ Clayton Foundation Investigator.

Received 4/15/87. Revised 9/ 9/87. Accepted 10/ 2/87.

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