title: Variations in 5-fluorouracil concentrations of colorectal tissues as compared with dihydropyrimidine dehydrogenase (DPD) enzyme activities and DPD messenger RNA levels.
abstract: Dihydropyrimidine dehydrogenase (DPD) is the initial key enzyme in 5-fluorouracil (5-FU) catabolism. We measured DPD activities represented as DPD protein levels (units/mg protein) and the associated mRNA levels in tumorous and normal tissues from 40 colorectal cancer patients, and we studied the relation to 5-FU concentrations in the same samples after treatment with doxifluridine, a prodrug of 5-FU. DPD mRNA levels were also measured in biopsy samples before treatment for comparison with those in surgical samples. 5-FU concentrations in tumors were higher than those in normal tissues (P < 0.05) and were inversely associated with DPD protein levels (r = -0.463; P < 0.05). DPD activities in tumorous and normal tissues showed a significant correlation (r = 0.527; P < 0.01). DPD protein levels correlated with their mRNA levels detected by semiquantitative reverse transcription-PCR in tumor tissues (r = 0.740; P < 0.01). DPD mRNA levels in tumor biopsy specimens correlated with those in surgical specimens (r = 0.366; P < 0.05). These results suggest DPD activities in tumors to be predictive of 5-FU levels in colorectal cancer tissues and are reflected by DPD mRNA levels as measured by reverse transcription-PCR.
authors.affiliation: Department of Surgery I, Nippon Medical School, Tokyo 113-8603, Japan. motoko-t@nms.ac.jp
authors.forename: M
authors.initials: M
authors.lastname: Tanaka-Nozaki
authors.forename: M
authors.initials: M
authors.lastname: Onda
authors.forename: N
authors.initials: N
authors.lastname: Tanaka
authors.forename: S
authors.initials: S
authors.lastname: Kato
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000378:metabolism / Q000627:therapeutic use; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D042943:Dihydrouracil Dehydrogenase (NADP); D004305:Dose-Response Relationship, Drug; D005260:Female; D005467:Floxuridine / Q000378:metabolism / Q000627:therapeutic use; D005472:Fluorouracil / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010088:Oxidoreductases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D012007:Rectum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D000964:Antimetabolites, Antineoplastic; D012333:RNA, Messenger; D005467:Floxuridine; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil; C025034:doxifluridine