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Biochemical Modulation of Tumor Cell Energy: Regression of Advanced Spontaneous Murine Breast Tumors with a 5-Fluorouracil-containing Drug Combination¹

Cancer Research Department, Catholic Medical Center, Woodhaven, New York 11421 [R. L. S., J. R. C., L. D. N., D. S. M.]; Department of Medical Physics and Medical Imaging, Memorial Sloan Kettering Cancer Center, New York, New York 10021 [J. A. K.]; and Developmental Chemotherapy, Memorial Sloan Kettering Cancer Center, New York, New York 10021 [D. S. M.]

This report describes a highly active chemotherapeutic drug combination, consisting of N-(phosphonacetyl)-L-aspartate plus 6-methylmercaptopurine riboside plus 6-aminonicotinamide plus 5-fluorouracil, in CD8F₁ mice bearing spontaneous, autochthonous, breast tumors or first-passage advanced transplants of these spontaneous tumors. The combination and sequence of administration of these drugs were selected on the basis of known potentiating biochemical interactions. High performance liquid chromatography and nuclear magnetic resonance spectroscopy measurements of biochemical changes resulting from treatment with N-(phosphonacetyl)-L-aspartate plus 6-methylmercaptopurine riboside plus 6-aminonicotinamide indicated a severe depletion of cellular energy levels in the treated tumors. 6-Aminonicotinamide produced a severe block of the pentose shunt, and 5-fluorouracil severely inhibited both thymidylate synthase and thymidine kinase in the treated tumors. This quadruple drug combination, administered on a 10–11-day schedule, produced an impressive partial tumor regression rate of 67% of large, spontaneous, autochthonous, murine breast tumors and a tumor regression rate of 74% of first-passage transplants of the spontaneous breast tumors.

¹ Supported in part by USPHS Grant CA 25842 from the National Cancer Institute, NIH, Department of Health and Human Services, and the Chemotherapy Foundation of New York.

² To whom requests for reprints should be addressed, at Cancer Research Department, Catholic Medical Center, 89-15 Woodhaven Blvd., Woodhaven, NY 11421.

Received 11/11/91. Accepted 5/13/92.

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