Selective accumulation of platinum and formation of platinum–DNA adducts in hepatocellular carcinoma after transarterial chemoembolization with miriplatin

Abstract

Miriplatin, a lipophilic platinum complex, is a novel intra-arterial chemotherapeutic agent for hepatocellular carcinoma (HCC). Little is known about platinum-DNA adduct levels in human HCC after administration of platinum-based drugs. We investigated whether miriplatin selectively accumulates and forms platinum-DNA adducts in human HCC tumors. Using inductively coupled plasma mass spectrometry, we determined the platinum concentrations and platinum-DNA adduct levels in paired HCC tumors and non-tumor liver tissues of four patients who received transcatheter arterial chemoembolization with miriplatin and subsequently underwent hepatic resection. The mean (± standard deviation) platinum concentrations were 730 ± 350 μg/g (range, 400-1100) in HCC tumors and 16 ± 9.2 μg/g (range, 9.2-29) in non-tumor liver tissues. The concentrations were approximately 50-fold higher in HCC tumors than in non-tumor liver tissues. The mean platinum-DNA adduct levels were 54 ± 16 pg Pt/μg DNA (range, 37-69) in HCC tumors and 13 ± 13 pg Pt/μg DNA (range, 4.8-33) in non-tumor liver tissues. The adduct levels were roughly 7.6-fold higher in HCC tumors than in non-tumor liver tissues. There were no significant correlations between platinum concentrations and platinum-DNA adduct levels in HCC tumors. Our results quantitatively demonstrate that there is a selective accumulation of platinum and formation of platinum-DNA adducts in human HCC tumors after transarterial chemoembolization with miriplatin. No correlation was observed between platinum concentrations and platinum-DNA adduct levels.