title: Tissue levels of reduced folates in patients with colorectal carcinoma after infusion of folinic acid at various dose levels.
abstract: OBJECTIVE
  In patients with colorectal cancer (CRC), modulation of 5-fluorouracil (5-FU) by folinic acid (FA) improves response rate and overall survival compared with 5-FU alone. However, the optimal dose of FA is still debated. We investigated reduced folate pools in various tissues from patients with CRC without and after prior administration of FA.
  
  
  METHODS
  A total of 186 specimens (normal colorectal mucosa, primary colorectal tumor, normal liver, and liver metastases) from 86 consecutive patients with CRC were obtained and investigated for levels of reduced folates. Before surgery, patients did (n = 52) or did not (n = 34) receive FA as 15-minute i.v. infusion. FA-dose levels chosen were 20, 200, or 500 mg/m2. Tissue lysates were analyzed for reduced folate levels by means of the tritium release assay.
  
  
  RESULTS
  In normal mucosa, combined pools of tetrahydrofolate and 5,10-methylenetetra-hydrofolate were significantly elevated at all FA dose levels compared with untreated controls. In primary tumor, only 200 and 500 mg/m2 FA resulted in a significant increase of reduced folates with highest values measured after 500 mg/m2 FA. In specimens from normal liver, folate levels did not increase after administration of FA. By contrast, in specimens from liver metastases, reduced folate levels were low without FA pretreatment compared with levels from normal liver samples. Infusion of 500 mg/m2 FA caused a significant increase of reduced folate levels in liver metastases.
  
  
  CONCLUSIONS
  From a pharmacologic point of view, high-dose FA should be recommended for optimal modulation of 5-FU in patients with mCRC.
authors.affiliation: Department of Internal Medicine III, Ludwig-Maximilians-University-Grobetahadern, Marchioninistr. 15, Munich, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Schlemmer
authors.forename: Michael
authors.initials: M
authors.lastname: Kuehl
authors.forename: Andreas
authors.initials: A
authors.lastname: Schalhorn
authors.forename: Josefine
authors.initials: J
authors.lastname: Rauch
authors.forename: Karl-W
authors.initials: KW
authors.lastname: Jauch
authors.forename: Marcus
authors.initials: M
authors.lastname: Hentrich
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage* / Q000378:metabolism; D013763:Tetrahydrofolates / Q000032:analysis*
chemical_list: D000970:Antineoplastic Agents; D013763:Tetrahydrofolates; C030371:5,6,7,8-tetrahydrofolic acid; D002955:Leucovorin; D005472:Fluorouracil