cis-Diamminedichloroplatinum(II)-induced DNA adducts in peripheral leukocytes from seven cancer patients: quantitative immunochemical detection of the adduct induction and removal after a single dose of cis-diamminedichloroplatinum(II)

Abstract

The same four platinum-containing products identified in nucleolytic digests of DNA treated with cisplatin (cisDDP) in vitro now have been shown to be present in digested DNA originating from human cells after in vivo exposure. The immunochemical detection of these products at the fmol level became possible by the application of an existing and two newly raised rabbit antisera with specificities towards the various cisDDP-DNA derived products. In DNA isolated from white blood cells of a number of cancer patients treated with the drug for the first time, intrastrand cross-links on pGpG base sequences appeared to be the main adduct, followed by the intrastrand cross-links on pApG sequences, interstrand cross-links, and/or intrastrand cross-links on two guanines separated by one or more bases and a very low amount of monofunctionally bound cisDDP to guanine; typical proportions were 65, 22, 13, and less than 1%, respectively. The induction and removal of the main adduct, the intrastrand cross-link on pGpG sequences, have been studied in DNA from blood samples of six male patients after their first cisDDP treatment. The results indicate that the susceptibility of blood cells to cisDDP-DNA adduct formation can show strong individually determined differences. From the data it is also clear that a substantial part of the adducts is removed within the first 24 h after the cisDDP-infusion.