Platinum-DNA adducts in leukocyte DNA correlate with disease response in ovarian cancer patients receiving platinum-based chemotherapy.

Abstract

Fifty-five ovarian cancer patients receiving platinum drug-based chemotherapy have been studied prospectively to determine the extent of formation of the bidentate intrastrand adducts of diammineplatinum covalently attached to the N7 positions of adenosine and/or guanosine in leukocyte DNA. Data for clinical response, obtained from medical records, were then correlated with the adduct values. Patients were treated with platinum-based single-agent or combination chemotherapy containing cis-diamminedichloroplatinum (II) or diamminecyclobutane-dicarboxylatoplatinum on approved experimental protocols. Adduct measurements were performed by ELISA, and disease response to therapy was assessed by standard oncologic criteria. This study comprises a total of 101 blood samples obtained after intravenous cisdiamminedichloroplatinum (II) or diamminecyclobutanedicarboxylatoplatinum infusion from 55 individuals, and in each case the highest (or "peak") adduct level for each patient was chosen for statistical analysis. Values for median adduct levels in patients grouped by complete response, partial response, and no response were 212, 193, and 62 amol of adduct per ,ug of DNA, respectively. Analysis of these data by Jonckheere's test (an extension of the Mann-Whitney test) shows that higher levels of adduct formation correlates with disease response with a two-sided P value of 0.030. Of eight patients on single-agent therapy whose buffy-coat samples did not have measurable adduct levels, none responded to therapy. Analysis of these data using the exact test for trend shows that the formation of adduct at a level of 160 amol/,ug of DNA or greater correlates with disease response with a two-sided P value of 0.032. Thus in ovarian cancer patients, the formation of the intrastrand diammineplatinum adducts in leukocyte DNA is associated with favorable disease response to cisdiamminedichloroplatinum (II) or diamminecyclobutanedicarboxylatoplatinum chemotherapy.

Xeroderma pigmentosum complementation group C single‐nucleotide polymorphisms in the nucleotide excision repair pathway correlate with prolonged progression‐free survival in advanced ovarian cancer

“…Therefore, altered NER pathway activity may correlate with improved response to platinum-based chemotherapy. [4][5][6][7] Variations in NER pathway activity can occur genetically through single-nucleotide polymorphisms (SNPs). SNPs are base-pair (bp) changes that achieve a population frequency of at least 1%.…”

Platinum-DNA adduct formation in leucocytes of children in relation to pharmacokinetics after cisplatin and carboplatin therapy

“…Together these data suggest that adduct levels after carboplatin are determined primarily by factors other than drug exposure, which could include drug uptake, reaction with glutathione or other inactivation mechanisms and DNA repair (de Graeff et al, 1988). As discussed above, Pt-DNA adduct levels in PBLs and tumour response have been shown to be related in a number of studies (Reed et al, 1986(Reed et al, , 1987(Reed et al, , 1990Fichtinger-Schepman et al, 1990;Ma et al, 1994). If low adduct levels in poor responders are due to an intracellular factor in the PBLs then the same factor must be operating in the tumour cells, i.e.…”

“…Preliminary clinical results with immunoassays for Pt-DNA adducts support the suggestion that adduct formation may relate to anti-tumour activity. Specifically, Reed and colleagues (Reed et al, 1986(Reed et al, , 1987(Reed et al, , 1988(Reed et al, , 1990 have reported that adduct levels in peripheral blood leucocytes (PBLs) correlate with response in patients receiving either cisplatin-or carboplatin-based therapy. A major limitation of these studies is that the influence of pharmacokinetic variation was not investigated.…”

Single nucleotide polymorphisms in DNA repair genes might be prognostic factors in muscle-invasive bladder cancer patients treated with chemoradiotherapy

“…These adducts are responsible for the cytotoxicity of the drug, and clinical outcome seems to be correlated with the level of platinum-DNA adducts in the circulation (Reed et al, 1987;Bosken et al, 2002). Additionally, these adducts are mainly repaired by the NER pathway (Park et al, 2001).…”