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Differential Toxicity of cis- and trans-Diamminedichloroplatinum(II) toward Mammalian Cells: Lack of Influence of Any Difference in the Rates of Loss of Their DNA-bound Adducts¹

Department of Molecular Pharmacology, Institute of Cancer Research, Clifton Avenue, Sutton, Surrey SM2 5PX, England

DNA-bound adducts formed by cis- or trans-diamminedichloroplatinum(II) (cis-DDP or trans-DDP, respectively) have very different effects on DNA synthesis and cell cycle progression in Chinese hamster cells. When the loss of platinum from the DNA of cells treated with pulsed doses of these isomers was corrected for the different effects they produced on DNA replication and cell cycle progression, then adducts formed by either agent were lost slowly from DNA and at comparable rates. The kinetics of accumulation of platinum on the DNA of exponentially growing Chinese hamster cells differed following continuous treatment with a low dose (10 µM) of either cis-DDP or trans-DDP. However, when these DNA binding values were again corrected for the different effects of the two isomers on DNA replication and cell cycle progression, both compounds reacted with DNA to similar extents. The amounts of platinum that accumulated by 30 h on the DNA of stationary-phase Chinese hamster cells treated with a low dose (10 µM) of either cis- or trans-DDP were also similar but resulted in very different effects on cell survival. The amounts of platinum accumulating on the DNA of near confluent African green monkey cells were also similar following continuous treatment with a low dose (10 µM) of either cis-DDP or trans-DDP, after correction for the relatively small amount of DNA synthesis occurring in these cells, and they were similar to the binding of platinum to the DNA of similarly treated Chinese hamster cells. There was no rapid loss of platinum from the DNA of African green monkey cells following treatment with pulsed low or high doses of trans-DDP. It could be concluded that the different cytotoxic effects produced by cis- or trans-DDP resulted from an intrinsic difference in the effects of their respective DNA-bound adducts on DNA replication and were not due to a difference in the rate of repair of such adducts, as previously proposed (R. B. Ciccarelli et al., Biochemistry, 24: 7533–7540, 1985). The accumulation of platinum on the proteins of Chinese hamster or African green monkey kidney cells treated with cis- or trans-DDP was also consistent with the respective toxic effects of the two isomers.

¹ Financial support from the Johnson Matthey Research Centre and grants from the Medical Research Council and Cancer Research Campaign.

Received 6/19/86. Revised 9/18/86. Accepted 9/30/86.