title: Inductively coupled plasma mass spectroscopy quantitation of platinum-DNA adducts in peripheral blood leukocytes of patients receiving cisplatin- or carboplatin-based chemotherapy.
abstract: Platinum-DNA adducts can be assayed in peripheral blood leukocytes by means of atomic absorption spectroscopy and ELISA, and high adduct levels have been correlated previously with favorable clinical response to platinum-based chemotherapy. Our purpose was to study adduct formation in peripheral blood leukocytes by means of a new method, inductively coupled plasma mass spectroscopy (ICP-MS), and to correlate adduct formation with clinical response and toxicity. Platinum (Pt)-DNA adducts were measured by means of ICP-MS in leukocytes of 66 patients receiving a cisplatin- or carboplatin-based chemotherapy, collected either before the beginning of treatment and incubated in vitro with cisplatin or 1 and 24 h after the administration of drug to the patient. The Pt-DNA adduct level in leukocytes from patients exposed to drug in vitro was 14.33 +/- 14.71 fmol/microgram DNA (mean +/- SD), which was not significantly different from the value of 23.4 +/- 19.53 fmol/microgram DNA observed in leukocytes from nine healthy volunteers. In samples collected after the administration of chemotherapy, Pt-DNA adducts ranged from 1.91 +/- 3.59 fmol/microgram DNA (mean +/- SD) at the 1-h time point to 2.61 +/- 3.35 fmol/microgram DNA at 24 h (P > 0.05). Adduct levels in leukocytes exposed in vitro did not correlate with adduct levels from patients treated with cisplatin-based chemotherapy (r = 0.085 and 0.011 at 1 and 24 h, respectively). At 24 h, adduct levels in patients receiving cisplatin (3.15 +/- 3.64 fmol/microgram DNA, mean +/- SD) were significantly higher (P = 0.02) than those observed in patients treated with standard dose carboplatin (0.57 +/- 0.73 fmol/microgram DNA) and also higher than those in patients receiving high-dose carboplatin (1.18 +/- 1.06 fmol/microgram DNA), although the latter difference did not reach statistical significance (P = 0.071). No differences in adduct levels (mean +/- SD) were evident between patients responsive (3.23 +/- 3.51 fmol/microgram DNA) and nonresponsive (2.34 +/- 3.01 fmol/microgram DNA) to chemotherapy. In the homogeneous group of patients treated with combination of cisplatin and 5FU, received dose intensity, hemoglobin decrease, and posttreatment creatinine could not be linked with the extent of leukocyte adduct formation. The data presented here demonstrate that ICP-MS allows the detection of adducts in patients treated with cisplatin or carboplatin and suggest that adduct formation in leukocytes is not a major determinant of response or toxicity.
authors.affiliation: Department of Medical Oncology, Azienda Ospedaliera and University of Verona, 37121 Verona, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Bonetti
authors.forename: P
authors.initials: P
authors.lastname: Apostoli
authors.forename: M
authors.initials: M
authors.lastname: Zaninelli
authors.forename: F
authors.initials: F
authors.lastname: Pavanel
authors.forename: M
authors.initials: M
authors.lastname: Colombatti
authors.forename: G L
authors.initials: GL
authors.lastname: Cetto
authors.forename: T
authors.initials: T
authors.lastname: Franceschi
authors.forename: L
authors.initials: L
authors.lastname: Sperotto
authors.forename: R
authors.initials: R
authors.lastname: Leone
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016190:Carboplatin / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002945:Cisplatin / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018736:DNA Adducts / Q000032:analysis*; D005260:Female; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010984:Platinum / Q000032:analysis*
chemical_list: D000970:Antineoplastic Agents; D018736:DNA Adducts; D010984:Platinum; D016190:Carboplatin; D002945:Cisplatin