INFLUENCE OF CISPLATIN ON CELL-CYCLE PROGRESSION IN XENOGRAFTED HUMAN HEAD AND NECK CARCINOMAS

The scope of the present study was to examine whether the cytokinetic phenomena occurring in human tumors under the influence of cisplatin correlate with the response of the tumors to therapy with the drug. Therefore, three strains of heterotransplanted human head and neck carcinomas showing different degrees of sensitivity to cisplatin were investigated by flow cytometry at various intervals after a single administration of cisplatin at four different dose levels (3, 6, 9 or 12 mg/kg). Three types of cell-cycle alterations were observed that depended on the dose of cisplatin and the degree of drug sensitivity shown by the tumors investigated. The obviously weakest kind of tumor reaction was a delay in the G2 cell phase. This phenomenon also occurred in the case of non-responsiveness to therapy, whereby the growth, histological structure and mitotic activity of the tumors remained nearly unaltered after cisplatin treatment. With increasing cytotoxicity, additional accumulations of cells in the S phase and, finally, long-lasting blocks at the G1/S boundary were found. The latter phenomenon, which manifested at high dose levels used in sensitive tumors, was obviously irreversible, as it did not completely disappear until the tumor cells had died and been removed by immigrating macrophages. It was always accompanied by severe histological destruction, tumor cell necrotization, and marked depression of the mitotic index. Thus, the hindrance of cell traversal through the S phase obviously represents the main and significant cytokinetic event, which indicates a potent antitumor effect for cisplatin that leads to pronounced tumor regression. This finding supports the hypothesis that inhibition of DNA synthesis is the mechanism underlying the cytotoxicity of cisplatin.