title: Biochemical modulation of fluorouracil: comparison of methotrexate, folinic acid, and fluorouracil versus folinic acid and fluorouracil in advanced colorectal cancer: a randomized trial.
abstract: Recent advances in biochemical pharmacology have revealed the basis for the biological modulation of 5-fluorouracil (5-FU) by methotrexate (MTX) and folinic acid (FA). Sequential use of MTX given 24 h prior to 5-FU has resulted in enhanced cell kill in vitro and in vivo. In addition, administration of FA prior to 5-FU has led to potentiation of 5-FU action by stabilization of the ternary complex of thymidine synthase. In the present randomized study, two groups of patients with advanced colorectal cancer were treated as follows: 43 patients (pts) in group A received 5-FU + FA, whereas 45 pts in group B received 5-FU + FA + MTX. The dosage was as follows: group A received FA i.v. at 300 mg/m2 per day, prior to i.v. 5-FU at 500 mg/m2 per day on days 1-4; group B was given MTX i.v. at 130 mg/m2 per day on day 0, followed 24 h later by FA at 15 mg q6h x 6, and 5-FU + FA was started on day 1 and given at the same doses and schedule described for group A. Objective responses were achieved by 8/43 pts in group A (1 complete response and 7 partial responses) and by 18/45 pts in group B (3 complete and 15 partial responses), all occurring in the liver. There was no significant difference in the median time to progression (group A 6.1 months, group B 6.8 months) or the median survival (group A 9.2 months, group B 10.3 months). Toxicity was significantly greater in group B [grade 2-3 mucositis 20% versus only 2% in group A (P < 0.0001); grade 3 diarrhea in group B 15% versus 3% in group A (P < 0.001)]. According to our results, double biological modulation of 5-FU with MTX + FA led to an enhanced response rate with increased toxicity as compared with the 5-FU + FA regimen given at less than its maximally tolerated dose.
authors.affiliation: First Department of Propedeutic Medicine, University of Athens School of Medicine, Laiko Hospital, Greece.
authors.forename: A
authors.initials: A
authors.lastname: Polyzos
authors.forename: N
authors.initials: N
authors.lastname: Tsavaris
authors.forename: A
authors.initials: A
authors.lastname: Giannopoulos
authors.forename: C
authors.initials: C
authors.lastname: Bacoyiannis
authors.forename: V
authors.initials: V
authors.lastname: Papadimas
authors.forename: N
authors.initials: N
authors.lastname: Kalahanis
authors.forename: G
authors.initials: G
authors.lastname: Karatzas
authors.forename: C
authors.initials: C
authors.lastname: Kosmas
authors.forename: N
authors.initials: N
authors.lastname: Sakelaropoulos
authors.forename: A
authors.initials: A
authors.lastname: Archimandritis
authors.forename: A
authors.initials: A
authors.lastname: Papachristodoulou
authors.forename: P
authors.initials: P
authors.lastname: Kosmidis
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D000328:Adult; D000368:Aged; D000931:Antidotes / Q000008:administration & dosage / Q000009:adverse effects; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001853:Bone Marrow / Q000187:drug effects; D016923:Cell Death; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004795:Enzyme Stability / Q000187:drug effects; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D007262:Infusions, Intravenous; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects; D008113:Liver Neoplasms / Q000188:drug therapy / Q000556:secondary; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects; D008875:Middle Aged
chemical_list: D000931:Antidotes; D000964:Antimetabolites, Antineoplastic; D002955:Leucovorin; D005472:Fluorouracil; D008727:Methotrexate