Mechanisms of interaction of interferon and 5-fluorouracil in solid tumors.
Recent clinical trials demonstrate the combined activity of 5-fluorouracil (5-FU) and interferon (IFN) in advanced colon cancer. Several possibilities exist for explaining the interaction. Interferon may alter the pharmacokinetics of 5-FU infusion by increasing the steady state concentration. Interferon enhances the inhibitory effects of 5-FU for tumor cells in culture. This enhancement is blocked by thymidine. Interferon reduces the concentration of thymidylate synthetase, and this may account for the thymidine-reversible interaction. An alternative mechanism invokes the immunomodulatory effects of IFN. Interferon augments the activity of killer cells with possible anti-tumor activity, both in vitro and in vivo. Also, by increasing the expression of human leukocyte class I antigens, IFN reduces the sensitivity of tumor cell lines to cell-mediated killing, an effect termed resistance. 5-Fluorouracil reverses the resistance in a time- and dose-dependent manner. The effect is mediated through inhibition of protein synthesis, since thymidine cannot reverse it. Fluorouridine is more active in reversing resistance than fluorodeoxyuridine. 5-Fluorouracil also reverses the induction of human leukocyte antigens by IFN. Studies in the resistance model suggest that high doses of 5-FU by infusion for several days might be the optimal method for modulation of IFN-induced effects.
Neefe
J R
JR
Markey Cancer Center, University of Kentucky, Lexington 40536.
John
W
W
D002986:Clinical Trials as Topic; D004347:Drug Interactions; D005472:Fluorouracil / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007372:Interferons / Q000276:immunology / Q000494:pharmacology*; D009369:Neoplasms / Q000628:therapy*; D014407:Tumor Cells, Cultured
D007372:Interferons; D005472:Fluorouracil