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Specificity, Schedule, and Proliferation Dependence of Infused L-Histidinol after 5-Fluorouracil in Mice¹

Veterans Administration Medical Center, Allen Park, Michigan 48101 [M. E.], and Department of Medicine, Division of Oncology, Wayne State University School of Medicine and Harper-Grace Hospitals, Detroit, Michigan 48201 [M. E., L. H.]

L-Histidinol, an analogue of the amino acid L-histidine, has been reported to be able to increase the specificity of 5-fluorouracil (FUra), through both protection of normal tissues at risk and potentiation of leukemic cell killing. It is postulated that this occurs through prevention of the entry of normal cells into the cell cycle through protein deficiency, while allowing malignant cells, permissive for protein starvation, to continue to cycle, thus maintaining sensitivity for cycle specific anticancer agents. Reported in this paper is the confirmation of these L-histidinol-FUra effects. However, a modification was made by which more L-histidinol could be given and more consistent protection of whole animals demonstrated. Further, an optimal schedule of L-histidinol was defined in which FUra preceded L-histidinol infusion. Finally, the specificity and proliferation dependence of this schedule was evaluated on colony forming units-spleen in resting and proliferating state, colony forming units-granulocyte-macrophage, and L1210 leukemia. This demonstrates that the FUra/L-histidinol combination indeed protects only normal cells but that the postulated proliferation dependence is absent, indicating an alternate biological mechanism.

¹ Supported by VA Medical Research funds and the Ben Kasle Trust for Medical Research.

² To whom requests for reprints should be addressed.

Received 5/13/87. Revised 8/10/87. Revised 11/23/87. Accepted 12/16/87.