Potentiation of 5-fluorouracil-leucovorin activity by alpha2a-interferon in colon adenocarcinoma xenografts.
Previous studies using cultured colon adenocarcinoma cells demonstrated that a mixture of the diastereoiosomers of the biologically active (6S) and inactive (6R) forms of (6RS) leucovorin or 5-formyl-H4PteGlu (LV) and recombinant human alpha2a-interferon (rIFN-alpha2a) in combination significantly increased the cytotoxicity of 5-fluorouracil (FUra) (by 10-14-fold) whereas FUra combined with single modulators was less potentiated (3-fold). Maximum cytotoxicity was achieved with 48-h drug exposures when drugs were applied continuously, and modulatory rIFN-alpha2a concentrations were obtained at >/=50 International units (IU)/ml. We therefore examined whether such interactions could occur in vivo using HxGC3/c1TK-c3 colon adenocarcinoma xenografts, deficient in thymidine salvage. Potentiation of FUra activity was significantly greater when FUra was combined with both LV and rIFN-alpha2a in comparison to the use of single modulators using a 5-day schedule for 3 courses. In mice receiving LV, the maximum level of potentiation of FUra-induced growth inhibition was independent of the rIFN-alpha2a dose between 25,000 and 600,000 IU examined in contrast to rIFN-alpha2a used as a single modulator. After administration of 25,000 IU rIFN-alpha2a, plasma rIFN-alpha2a concentrations >/=50 IU/ml were maintained for 6-8 h, comparable to exposure times achievable clinically. Data indicate that intermittent rIFN-alpha2a exposure potentiates FUra-LV activity in vivo. The efficacy of FUra combined with dual versus single modulators will thus be of importance to evaluate in randomized phase III clinical trials in patients with colorectal cancer.
Houghton
J A
JA
Department of Molecular Pharmacology and Pharmaceutical Department, St. Jude Children's Research Hospital, Memphis, Tennessee 38101, USA.
Cheshire
P J
PJ
Morton
C L
CL
Stewart
C F
CF
D000230:Adenocarcinoma / Q000473:pathology / Q000628:therapy*; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000473:pathology / Q000628:therapy*; D003131:Combined Modality Therapy; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use*; D006801:Humans; D007165:Immunosuppression Therapy / Q000379:methods; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002955:Leucovorin / Q000627:therapeutic use*; D051379:Mice; D008808:Mice, Inbred CBA; D011994:Recombinant Proteins; D013934:Thymectomy; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D014916:Whole-Body Irradiation
D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D002955:Leucovorin; D005472:Fluorouracil