OPTIMAL SCHEDULING OF METHOTREXATE AND 5-FLUOROURACIL IN HUMAN-BREAST CANCER

  • 1 January 1982
    • journal article
    • research article
    • Vol. 42  (5) , 2081-2086
Abstract
Methotrexate pretreatment of cell cultures results in augmented intracellular accumulation of 5-fluorouracil metabolites. Sequencing of methotrexate before 5-fluorouracil was evaluated in vitro using a human mammary carcinoma cell line, 47-DN. Intracellular 5-fluorouracil accumulation was maximally increased 4-fold in cultures pretreated with 10 .mu.M methotrexate for 24 h. This enhancement of 5-fluorouracil metabolism was associated with increased intracellular levels of 5-phosphoribosyl 1-pyrophosphate, resulting from the antipurine effect of methotrexate. Brief exposure to exogenous hypoxanthine at physiological concentrations reversed the biochemical synergism between methotrexate and 5-fluorouracil. Other antimetabolites associated with elevations of 5-phosphoribosyl 1-pyrophosphate enhanced intracellular accumulation of 5-fluorouracil up to 2.5-fold. In cloning assays, 18 h of methotrexate pretreatment followed by 5-fluorouracil resulted in optimal synergistic cytotoxicity, which could be prevented if high concentrations of leucovorin were given between methotrexate and 5-fluorouracil administration. Optimal breast tumor toxicity in vitro was achieved by 18- to 24-h sequencing of methotrexate and 5-fluorouracil. A clinical toxicity study was carried out to assess whether this drug schedule could be tolerated. Seven patients with advanced cancer were treated with 21 courses of sequential therapy. No toxicity occurred with 38% of treatment courses; mild to moderate leukopenia and mucositis occurred with 29 and 38% of courses, respectively. Toxicity was related to retreatment interval and not cumulative drug dose or elevated serum methotrexate levels.