Failure of l-Histidinol to Improve the Therapeutic Efficiency of 5-Fluorouracil against Murine Breast Tumors¹

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 nonlenkemic, solid murine tumor model, the BALB/c × 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.