title: Folate levels measured by LC-MS/MS in patients with colorectal cancer treated with different leucovorin dosages.
abstract: OBJECTIVE
  Calcium folinate (leucovorin), which is converted in vivo into biologically active folate, enhances the potency of 5-fluorouracil (5-FU)-based chemotherapy in colorectal cancer. A common dosage of leucovorin in adjuvant and palliative settings is 60 mg/m(2). The aim was to determine the levels of tetrahydrofolate (THF), 5,10-methylenetetrahydrofolate (methyleneTHF), and 5-methyltetrahydrofolate (methylTHF) in tumour and mucosa of colorectal cancer patients who received different dosages of leucovorin intravenously at time of surgery.
  
  
  METHODS
  Eighty patients scheduled for colorectal resection with indication of colorectal cancer were randomised into four groups to receive leucovorin at 0, 60, 200, or 500 mg/m(2), respectively. Blood samples were taken 10 and 30 min after leucovorin administration. Biopsy samples from tumour and mucosa were collected and snap-frozen at surgery. The levels of THF, methyleneTHF, and methylTHF in tumour and mucosa were assessed by liquid chromatography electrospray ionisation tandem mass spectrometry (LC-MS/MS) and the results were related to clinical diagnosis and therapeutic regimens.
  
  
  RESULTS
  The folate levels in tissue revealed extensive inter-individual variability. The mean methyleneTHF value for the four treatment groups were 880, 1,769, 3,024 and 3,723 pmol/gww. Only half of the patients who received 60 mg/m(2) leucovorin had higher levels of methyleneTHF in tumour than patients who received 0 mg/m(2) leucovorin. Rectal cancer patients had significantly lower levels of methyleneTHF compared with colon cancer patients.
  
  
  CONCLUSIONS
  There was a large inter-patient variability of tissue folate levels in colorectal cancer patients after supplementation with leucovorin at standardised dosage. High leucovorin doses were needed to exceed baseline methyleneTHF values, especially in rectal cancer patients. The results indicate that the standardised leucovorin dose may be insufficient to attain the full antitumour effect of 5-FU. Further studies are needed to establish whether higher dosage yields a better treatment response.
authors.affiliation: Department of Surgery, Institute of Clinical Sciences, The Sahlgrenska Academy at University of Gothenburg, The Sahlgrenska University Hospital/Östra, 41685, Gōteborg, Sweden, helena.taflin@vgregion.se.
authors.forename: Helena
authors.initials: H
authors.lastname: Taflin
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Wettergren
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Odin
authors.forename: Kristoffer
authors.initials: K
authors.lastname: Derwinger
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002853:Chromatography, Liquid / Q000379:methods; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000601:surgery; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods; D053719:Tandem Mass Spectrometry / Q000379:methods; D013763:Tetrahydrofolates / Q000032:analysis*; D014803:Vitamin B Complex / Q000008:administration & dosage / Q000627:therapeutic use
chemical_list: D013763:Tetrahydrofolates; C013123:5,10-methylenetetrahydrofolic acid; D014803:Vitamin B Complex; C030371:5,6,7,8-tetrahydrofolic acid; D002955:Leucovorin; C005984:5-methyltetrahydrofolate