Histidinol-Mediated Enhancement of the Specificity of Two Anticancer Drugs in Mice Bearing Leukemic Bone Marrow Disease2

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Abstract
The possibility was investigated that L-histidinol-anticancer drug combinations may provide increased tumor cell eradication and eliminate in vivo bone marrow toxicity of proliferation-dependent anticancer agents in animals bearing an established, intrafemoral bone marrow disease. It was previously demonstrated that L-histidinol, a structural analogue of the essential amino acid L-histidine, improves the specificity of cytarabine (ara-C) and 5-fluorouracil (FUra) in DBA/2J mice bearing intraperitoneal L1210 leukemia. Accordingly, DBA/2J mice were given iv injections of 1×106 L1210 leukemia cells 3 days before histidinol-anticancer drug treatments. During the postinjection, pretreatment interval, injected tumor cells populated the femoral marrows, shown by clonogenic assays and flow cytometric analyses. Following various drug treatments, quantitative and selective survival assays were performed of normal femoral cells and of clonogenic L1210 leukemia cells isolated from the femurs of treated mice. These experiments demonstrated that L-histidinol not only protected the marrow cell population from both ara-C and FUra, but also increased significantly the toxicities of these agents for the intrafemoral tumor cells. Thus L-histidinol mediates a substantial increase in the specificities of ara-C and FUra in mice bearing an established bone marrow leukemic condition.