title: The selectivity of action of methotrexate in combination with 5-fluorouracil in xenografts of human colon adenocarcinomas.
abstract: This study was designed to examine the possibilities for increasing the therapeutic index in the treatment of human colon adenocarcinomas maintained as xenografts in immune-deprived mice using combinations of methotrexate (MTX) that preceded 5-fluorouracil (FUra). MTX, at a dose level of 100 mg/kg, increased the 5-phosphoribosyl-1-pyrophosphate (PRPP) concentration in three colon xenograft lines to a maximum between 14 and 24 hr after treatment. In murine bone marrow, concentrations of PRPP decreased progressively after MTX treatment, but in ileum there was a dramatic increase such that by 4 hr PRPP was 968% of control. The metabolism of [6-3H]FUra administered 24 hr after MTX was increased in ileum and resulted in an increased rate and a greater level of incorporation of [6-3H]FUra into RNA. Only a slight elevation in the incorporation of [6-3H]FUra into the RNA of one tumor line (HxELC2) was observed. The scheduling of FUra at a dose level of 25 mg/kg 24 hr after a priming dose of MTX (100 mg/kg) was at least as toxic as 100 mg of FUra per kilogram, administered alone. The dose-limiting toxicity was related to gastrointestinal damage; no bone marrow toxicity was detected. At dose levels of MTX up to 100 mg/kg, the increase in PRPP obtained in gastrointestinal tissue was greater than that observed in human colon xenografts 24 hr after treatment. A basis for increasing the therapeutic efficacy of FUra through a selective increase in tumor PRPP using MTX was not obtained in these studies.
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy*; D000818:Animals; D003110:Colonic Neoplasms / Q000188:drug therapy*; D004347:Drug Interactions; D005260:Female; D005472:Fluorouracil / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008727:Methotrexate / Q000494:pharmacology* / Q000633:toxicity; D051379:Mice; D008808:Mice, Inbred CBA; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy; D013934:Thymectomy; D013997:Time Factors
chemical_list: D005472:Fluorouracil; D008727:Methotrexate