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Effect of cis- and trans-dichlorodiammineplatinum(II) on human tumor cell proliferation in diffusion chambers in vivo.

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 transisomer, 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.