Optimal scheduling of methotrexate and 5-fluorouracil in human breast cancer

C. Benz, T. Tillis, Ellen P. Tattelman, E. Cadman

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

We have shown previously that methotrexate pretreatment of murine leukemia and human colon carcinoma cell cultures results in augmented intracellular accumulation of 5-fluorouracil metabolites. Both of these drugs are commonly used for the treatment of women with breast cancer; thus, 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 μM methotrexate for 24 hr. 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 hr 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. Since these results indicated that optimal breast tumor toxicity in vitro was achieved by 18- to 24-hr 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 treatment interval and not cumulative drug dose or elevated serum methotrexate levels. These clinical results suggest that Phase II studies evaluating 24-hr-sequenced methotrexate and 5-fluorouracil in breast cancer are warranted.

Original languageEnglish (US)
Pages (from-to)2081-2086
Number of pages6
JournalCancer Research
Volume42
Issue number5
StatePublished - 1982
Externally publishedYes

Fingerprint

Methotrexate
Fluorouracil
Breast Neoplasms
Phosphoribosyl Pyrophosphate
Pharmaceutical Preparations
Antimetabolites
Mucositis
Hypoxanthine
Leucovorin
Leukopenia
Therapeutics
Organism Cloning
Appointments and Schedules
Colon
Leukemia
Cell Culture Techniques
Carcinoma
Cell Line
Serum

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Optimal scheduling of methotrexate and 5-fluorouracil in human breast cancer. / Benz, C.; Tillis, T.; Tattelman, Ellen P.; Cadman, E.

In: Cancer Research, Vol. 42, No. 5, 1982, p. 2081-2086.

Research output: Contribution to journalArticle

Benz, C, Tillis, T, Tattelman, EP & Cadman, E 1982, 'Optimal scheduling of methotrexate and 5-fluorouracil in human breast cancer', Cancer Research, vol. 42, no. 5, pp. 2081-2086.
Benz, C. ; Tillis, T. ; Tattelman, Ellen P. ; Cadman, E. / Optimal scheduling of methotrexate and 5-fluorouracil in human breast cancer. In: Cancer Research. 1982 ; Vol. 42, No. 5. pp. 2081-2086.
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