Interaction between 5-fluorouracil, [6RS]leucovorin, and recombinant human interferon-alpha 2a in cultured colon adenocarcinoma cells.
Recombinant human interferon-alpha 2a (rIFN-alpha 2a; 500 or 5,000 IU/mL) or [6RS] leucovorin ([6RS]LV; 1 microM) each potentiated the cytotoxic activity of 5-fluorouracil (FUra) by 2.6- to 3.2-fold during 72 hr exposures in two human colon adenocarcinoma cell lines (GC3/c1; VRC5/c1). When all three agents were combined, FUra cytotoxicity was further potentiated by 3.2- to 4.3-fold (total 10- to 14-fold). Potentiation of FUra cytotoxicity occurred at clinically achieveable concentrations of rIFN-alpha 2a and [6RS]LV. Effects were reversed by dThd (20 microM), although the activity of CB3717, a quinazoline-based, specific inhibitor of thymidylate synthase, was not potentiated by rIFN-alpha 2a. Data suggest the requirement of a 5-fluoropyrimidine for biochemical modulation and interaction at the level of thymidylate synthase or DNA.
Houghton
J A
JA
Department of Biochemical and Clinical Pharmacology, St. Jude Children's Research Hospital, Memphis, TN 38101.
Adkins
D A
DA
Rahman
A
A
Houghton
P J
PJ
D000230:Adenocarcinoma; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms; D004357:Drug Synergism; D005472:Fluorouracil / Q000008:administration & dosage*; D005492:Folic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D007370:Interferon Type I / Q000008:administration & dosage / Q000494:pharmacology*; D002955:Leucovorin / Q000008:administration & dosage / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology; D011994:Recombinant Proteins; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors; D014407:Tumor Cells, Cultured / Q000187:drug effects*
D007370:Interferon Type I; D011799:Quinazolines; D011994:Recombinant Proteins; C031662:CB 3717; D005492:Folic Acid; D013940:Thymidylate Synthase; D002955:Leucovorin; D005472:Fluorouracil