Effects of L-Histidinol on the Susceptibility of P815 Mastocytoma Cells to Selected Anticancer Drugs In Vitro and in DBA/2J Mice2

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Abstract
The effects of L-histidinol on the susceptibility of the transplantable murine mast-cell neoplasm P815 mastocytoma to selected anticancer drugs have been evaluated on cells growing in culture and in syngeneic DBA/2J mice. Combinations of L-histidinol and anticancer drugs of either phase specificity [cytarabine (ara-C) and vinblastine sulfate] or cycle specificity [5-fluorouracil (FUra) and methotrexate] had diverse effects on cultured mastocytoma cells as scored by clonogenic cell survival assays. Flow cytometric analysis of randomly proliferating P815 mastocytoma cells revealed that although exposure to L-histidinol did not preclude cells from traversing the cell cycle, the analogue nonetheless conferred a dose-dependent and apparently nonspecific delay of cell cycle transit. DBA/2J mice bearing intraperitoneal P815 mastocytoma cells were used to evaluate the in vivo efficacy of L-histidinol-ara-C and of L-histidinol-FUra combinations. Quantitative cell survival assays of murine bone marrow cells and of clonogenic tumor cells obtained from treated animals demonstrated that L-histidinol eliminated the bone marrow toxicity otherwise attending the use of the drugs ara-C and FUra. Simultaneously, the inclusion of L-histidinol provided a statistically significant increase in the capacity of these two anticancer drugs to eradicate intraperitoneal mastocytoma cells.