L-histidinol protection against cytotoxic action of cytosine arabinoside and 5-fluorouracil in cultured mouse spleen cells

The effects of L-histidinol, a structural analog of the essential amino acid L-histidine, on the proliferative responses and Anticancer drug vulnerability of cultured spleen cells from male C57BL/6J mice exposed to optimal mitogenic doses of concanavalin A (Con A) or E. coli lipopolysaccharide (LPS) were investigated. By means of tritiated thymidine ([3H]dThd) incorporation into acid-insoluble material as the criterion for proliferation. L-histidinol was shown to provide a dose-dependent inhibition of mitogenic responses elicited by Con A and LPS. Total (apparent) inhibition was provided by 1-mM concentrations of the analog and, at this concentration, [3H]dThd incorporation was totally reversible even after 72 hours of sustained exposure. Simultaneous addition of L-histidinol and either of the mitogens provide a Go-like arrest for 24 hours. Thereafter, the cells appeared to begin slow cell cycle transit but did not traverse the G1/S boundary within 96 hours of incubation. These responses of cultured murine lymphocytes to L-histidinol provided dramatic and extended protection from the cell cycle phase-specific drug cytosine arabinoside and dramatic but transient protection from the cell cycle-specific drug 5-fluorouracil. In principle, these findings extend the L-histidinol Anticancer drug approach for improving the therapeutic index of antineoplastic agents, not only to both cycle- and phase-specific drugs, but also to primary cells of myeloid origin.