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Effect of cis- and trans-Dichlorodiammineplatinum(II) on Human Tumor Cell Proliferation in Diffusion Chambers in Vivo¹

Health and Safety Research Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37830

The cis and trans isomers of dichlorodiammineplatinum(II) (DDP) were tested for their ability to inhibit human tumor cell proliferation in vivo. Cell-impermeable diffusion chambers containing KB target cells were surgically implanted in the peritoneal cavities of Fischer rats, which were, 1 day later, given i.p. injections of cis-DDP (0.25 to 8.0 mg/kg), trans-DDP (8.0 mg/kg), or 0.9% NaCl solution. Radiolabeled cis- and trans-[^195mPt]DDPs were used to monitor the diffusion of DDP within the chamber fluid and the binding or uptake of DDP by the target cells. Cell counts following injection showed that cis-DDP induced a progressive, dose-dependent loss in cell number so that, by the second day, the chambers of animals receiving cis-DDP (8 mg/kg) contained less than 10% of the cell number found in the control or trans-DDP-treated chambers. Despite the relative lack of biological activity of the trans-isomer, between 2- and 3-fold greater levels of ^195mPt activity were detected in the fluid and target cells in chambers of animals receiving trans-[^195mPt]DDP compared to cis-[^195mPt]DDP injected animals. Scanning electron micrographs of target cells from cis-DDP treated rats showed certain morphological features (cell surface blebs and the appearance of giant cells) that were not found in control target cell populations. The diffusion chamber system was shown to be a reproducible, sensitive assay system which differentiated between cis-DDP, a potent antitumor drug, and trans-DDP, a biologically ineffective isomer. In addition, it was possible using ^195mPt-labeled DDP in this assay system to quantitate the relative concentrations of the two isomers both surrounding and within the target cells.

¹ Research sponsored by the Office of Health and Environmental Research, United States Department of Energy, under Contract W-7405-eng-26 with Union Carbide Corporation and in part by the Great Lakes Colleges Association/Associated Colleges of the Midwest program.

² To whom requests for reprints should be addressed.

³ Student in the Great Lakes Colleges Association/Associated Colleges of the Midwest program, 1978 fall semester.

Received 9/16/81. Accepted 1/22/82.