title: Platinum-DNA damage in leukocyte DNA of patients receiving carboplatin and cisplatin chemotherapy, measured by atomic absorption spectrometry.
abstract: Previous studies have shown that platinum-DNA adduct level in leukocyte DNA (measured by antibody methodology) is directly related to disease response in ovarian cancer and testicular cancer. To determine if this principle could be more broadly applied, platinum-DNA damage was studied in a blinded fashion in leukocyte DNA of 21 cancer patients who received carboplatin (day 1) and cisplatin (day 3) in a phase 1 clinical trial. Fifteen different tumor types were included in this cohort. Using atomic absorption spectrometry with Zeeman background correction, DNA-bound platinum was measured during cycles 1 (C1) and 2 (C2) of therapy for most patients. For each of two cycles of therapy, most patients developed measurable levels of adduct after carboplatin, and in most patients adduct levels increased further after cisplatin, often in a supra-additive fashion. Total mg dose levels varied by less than 2-fold, whereas individual patients differed by as much as 10(3) in their adduct measurements after C1 and after C2, and by 29-fold after the very first carboplatin dose. All patients had refractory disease at the initiation of therapy, and 19 patients were evaluable for disease response. Adduct determinations were made 24 h after the first dose of platinum therapy in 17 of these individuals. Mean adduct levels after the first dose of carboplatin were higher in six responders (50 fmol/micrograms DNA +/- 26) than in 11 non-responders (14 fmol/micrograms DNA +/- 10); Wilcoxon two sample test two-sided P = 0.0071. The six responders were patients with pleural mesothelioma (2), breast cancer, buccal mucosa cancer, esophageal cancer and ovarian cancer. Adduct levels were consistently higher in the group of responders on each day that adduct was measured, with a summary two-sided P value of 0.00011. We conclude that analysis of platinum-DNA adduct formation may help determine whether pharmacogenetics are important in cancer drug resistance; and may help to determine the relationship between DNA damage in the peripheral blood compartment and internal organ response to in vivo exposures to DNA-damaging agents.
authors.affiliation: Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: R J
authors.initials: RJ
authors.lastname: Parker
authors.forename: I
authors.initials: I
authors.lastname: Gill
authors.forename: R
authors.initials: R
authors.lastname: Tarone
authors.forename: J A
authors.initials: JA
authors.lastname: Vionnet
authors.forename: S
authors.initials: S
authors.lastname: Grunberg
authors.forename: F M
authors.initials: FM
authors.lastname: Muggia
authors.forename: E
authors.initials: E
authors.lastname: Reed
mesh_terms: D016190:Carboplatin / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D004247:DNA / Q000378:metabolism*; D004249:DNA Damage; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007962:Leukocytes / Q000378:metabolism*; D008297:Male; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010984:Platinum / Q000378:metabolism*; D011446:Prospective Studies; D013054:Spectrophotometry, Atomic
chemical_list: D010984:Platinum; D004247:DNA; D016190:Carboplatin; D002945:Cisplatin