The effects of cis-diamminedichloroplatinum (II) and radiation on the proliferation kinetics of mouse duodenal crypt cells and on a partially synchronized crypt cell population

Abstract

The effects of c-DDP and radiation, given alone or in combination, on the proliferation kinetics of mouse duodenal crypt cells were investigated by repeated labelling with 3H-thymidine. Crypt cells surviving a single dose of X-rays or c-DDP alone, appeared to proliferate faster than untreated controls. When both agents were given in combination, the proliferation rate of surviving crypt cells was markedly reduced as a result of a significant increase in the DNA synthesis time. The influence of the proliferation rate of crypt cells on the effects of c-DDP and X rays was analyzed using the crypt microcolony assay. Mice were given single doses or 2 fractions of X rays with 2 different time intervals (4 and 48 hours) either alone or in combination with c-DDP given 30 minutes before the second fraction. The lethal effect of the drug was approximately the same in cells that were in accelerated proliferation after the first irradiation as in unstimulated cells. A tendency for less cell killing by the drug was observed 3.5 hours after the first irradiation. To rule out cell age dependent effects of c-DDP, crypt cell survival was assessed after irradiation was given alone or in combination with the drug on a partially synchronized crypt cell population, obtained by repeated injections of hydroxyurea. A predominant lethal effect of c-DDP was found in cells in the late G1-phase. These findings are important to consider both from a mechanistic point of view as for clinical application of the agents.