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Selective Expansion of 5,10-Methylenetetrahydrofolate Pools and Modulation of 5-Fluorouracil Antitumor Activity by Leucovorin in Vivo¹

Dana-Farber Cancer Institute, and Departments of Biological Chemistry and Molecular Pharmacology [J. E. W., A. R.], Pathology [S. A. H.], and Medicine [A. D., E. F.], Harvard Medical School, Boston, Massachusetts 02115

Expansion of CH₂THF pools in tissues of BALB/c mice bearing s.c.-implanted EMT6 mammary adenocarcinomas was measured after leucovorin administration. Twenty-four mice were treated with leucovorin at doses of 0, 45, 90, or 180 mg/kg/injection x 8 injections spaced over 48 h. Tumor and bone marrow cytosols were assayed for CH₂THF by forming ternary complexes with thymidylate synthase and [³H]FdUMP. Tumor CH₂THF pools were expanded significantly at the two higher doses. Marrow levels were not different from controls. Groups of tumor bearing mice were treated with saline, leucovorin, 5-fluorouracil or 5-fluourouracil plus leucovorin on an optimal dosage schedule. Measured from the last day of treatment, these tumors grew to 10 mm root-mean-square diameters in 3.5 ± 1.4, 5.0 ± 1.2, 6.5 ± 1.5, and 9.3 ± 1.2 days, respectively. Growth rates were significantly different from controls only in the latter two groups.

¹ This study was supported by Grant CA 19589 from the National Cancer Institute, DHHS.

² To whom requests for reprints should be addressed, at Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115.

Received 11/28/88. Revised 2/14/89. Accepted 2/20/89.

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