It has been reported that L-
histidinol, a structural analogue of the
essential amino acid L-histidine, can transiently inhibit proliferative cycling in cells with normal phenotype while allowing continued cell cycle transit in
tumor cells. Thus, in the presence of L-
histidinol, the toxicity of a proliferation-dependent
drug such as
5-fluorouracil (FUra) was found to be reduced in normal tissue cells of the DBA/2J mouse, but not in
L1210 leukemia cells in the same mouse. Because of the potential clinical significance of this approach to reduce
chemotherapy-associated host toxicity, we evaluated the L-
histidinol-FUra combination in a nonleukemic, solid murine
tumor model, the BALB/c X DBA/8 F1 (hereafter called CD8F1)
breast tumor. The results of these studies indicate that the administration of L-
histidinol can protect the CD8F1 mouse from FUra-associated
leukopenia,
body weight loss, and ultimately, from mortality. However, in contrast to results reported in the L1210 leukemic system, L-
histidinol also reduced the cytotoxic activity of FUra against CD8F1
breast tumors. Therefore, although the dose of FUra that could be administered with safety was higher in mice receiving L-
histidinol, the therapeutic results of the combination of FUra and L-
histidinol were not superior to those obtained with FUra alone at a lower dose.