title: Mass spectrometry study of hemoglobin-oxaliplatin complexes in colorectal cancer patients and potential association with chemotherapeutic responses.
abstract: Oxaliplatin is the most active platinum (Pt)-containing anticancer drug for the treatment of advanced colorectal cancer. We report here the study of potential association of the levels of oxaliplatin-protein complexes in 19 cancer patients with treatment efficacy using size-exclusion high-performance liquid chromatography with inductively coupled plasma mass spectrometry (HPLC/ICPMS) and nanoelectrospray ionization mass spectrometry (nanoESI-MS) techniques. Blood samples from 19 colorectal cancer patients were collected at 1 and 48 h after the first infusion of oxaliplatin. HPLC/ICPMS quantification of the oxaliplatin-protein complexes showed that the levels of Pt-protein complexes in plasma samples at 48 h were reduced by approximately 50% compared to those at 1 h, whereas those in hemolysates did not change significantly. The concentrations of hemoglobin (Hb)-oxaliplatin complexes determined by HPLC/ICPMS ranged from 3.1 to 8.7 microM. NanoESI-MS analysis of the patient hemolysates showed three distinct mass spectral profiles of the Hb-oxaliplatin complexes: (1) 1:1, (2) 1:1 with 1:2, and (3) multiple complexes of 1:1, 1:2, 1:3, and 1:4, corresponding to the Hb-oxaliplatin complex concentrations determined by HPLC/ICPMS. Potential association of variables including Hb-oxaliplatin complex concentrations with time to progress as the treatment efficacy indicator was analyzed using the Cox model. Multivariate analysis of the potential predictors showed that the statistically significant variables were Hb-oxaliplatin complex concentration (p = 0.02), performance status (p = 0.02), baseline neutrophil count (p = 0.05), and the site of the primary cancer (colon vs. rectal, p = 0.01). The hazard ratio for the concentration of the Hb-oxaliplatin complexes was 2.4, suggesting that the risk of cancer progression significantly increased with increasing of Hb-oxaliplatin complexes in patients. These results demonstrate that the level of the Hb-oxaliplatin complexes in erythrocytes is a potential biomarker for indicating inter-patient variations in oxaliplatin treatment efficacy.
authors.affiliation: Environmental Health Sciences, Department of Public Health Sciences, Faculty of Medicine and Dentistry, University of Alberta, 10-102 Clinical Sciences Building, Edmonton, AB Canada.
authors.forename: Rupasri
authors.initials: R
authors.lastname: Mandal
authors.forename: Michael B
authors.initials: MB
authors.lastname: Sawyer
authors.forename: Xing-Fang
authors.initials: XF
authors.lastname: Li
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism* / Q000556:secondary; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D004912:Erythrocytes / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006454:Hemoglobins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008297:Male; D013058:Mass Spectrometry / Q000379:methods*; D008832:Microchemistry / Q000379:methods; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011725:Pyridines / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods; D013054:Spectrophotometry, Atomic / Q000379:methods; D053719:Tandem Mass Spectrometry / Q000379:methods
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D006454:Hemoglobins; D009944:Organoplatinum Compounds; D011725:Pyridines; C431073:oxiplatin