Biomodulation of 5-fluorouracil with antifolates.
The cytotoxic activity of 5-fluorouracil (5-FU) can be modulated by coadministration of antifolates or leucovorin (LV). Although a recent meta-analysis concluded that a sequential combination of methotrexate (MTX) and 5-FU was superior to 5-FU alone in terms of response rate and survival, combination MTX and 5-FU therapy has not been actively pursued by many leading cancer centers. We have subsequently investigated the combination of trimetrexate (TMTX) plus 5-FU/LV. Unlike MTX, TMTX does not compete with LV for uptake or polyglutamylation. In a phase I clinical study, combination TMTX/5-FU/LV was well tolerated and produced an overall response rate of 20% in previously treated colorectal cancer patients. In a follow-up phase II clinical study, this combination was highly active in patients with advanced colorectal cancer, demonstrating a 50% overall response rate. Currently, a phase III clinical trial is in progress comparing this regimen with combination 5-FU/LV.
Bertino
J R
JR
Program of Molecular Pharmacology and Therapeutics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D005472:Fluorouracil / Q000008:administration & dosage* / Q000627:therapeutic use; D005493:Folic Acid Antagonists / Q000008:administration & dosage* / Q000627:therapeutic use; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage* / Q000627:therapeutic use; D008727:Methotrexate / Q000008:administration & dosage* / Q000627:therapeutic use; D016597:Trimetrexate / Q000008:administration & dosage* / Q000627:therapeutic use
D000964:Antimetabolites, Antineoplastic; D005493:Folic Acid Antagonists; D002955:Leucovorin; D005472:Fluorouracil; D016597:Trimetrexate; D008727:Methotrexate