Effects of cis-dichlorodiammine platinum (II) on DNA synthesis in kidney and other tissues of normal and tumour-bearing rats

Abstract

The induction of renal tubular damage is the dose-limiting toxic effect in the treatment of human cancer with cis-dichlorodiammine platinum (II) ( cis-DDP). The effects of cis-DDP on the rate of DNA synthesis in the renal tubular epithelium has been studied in normal rats and in animals in which the rate of renal tubular DNA synthesis has been stimulated by administration of folic acid. In normal kidneys the rate of DNA synthesis is reduced to one twentieth of the control rate at 24 hr after 4 mg cis-DDP/kg but thereafter recovers rapidly and at 3 and 7 days after treatment the rate of DNA synthesis is about 16 times greater than normal. Administration of cis-DDP concurrently with, or up to 12 hr after, folate almost completely abolishes the folate-stimulated increase in renal DNA synthesis. Administration of the drug between 1 and 9 days before folate administration reduces the folate response to one quarter to one half the level observed in non-drug treated animals. Studies of the effect of the drug on DNA synthesis in a transplanted tumour and in intestinal mucosa of non-folate treated rats shows that in all tissues there is a five to seven fold reduction in the rate of DNA synthesis at 24 hr after 4 mg cis-DDP/kg but by 72 hr the rate of DNA synthesis in intestinal mucosa is increased above normal level while that in the tumour is still markedly depressed. There appears to be no simple correlation between the effect on DNA synthesis and the uptake of cis-DDP in the tissues.