L-histidinol inhibition of the proliferation and DNA biosynthesis of Ehrlich ascites carcinoma in vivo

L-histidinol, a structural analogue of the essential amino acid L-histidine, has been demonstrated to improve the selectivity and efficacy of a variety of cancer drug in several transplantable tumors. L-histidinol causes a rapid decrease in the incorporation of labeled thymidine into Ehrlich ascites carcinoma [EAC] tumor cells. The effect is expressed during 24 hours after L-histidinol treatment [250 mg/kg, 5 doses i.p., 2 hours apart] of EAC-bearing mice. The observed reduced incorporation of labeled thymidine is due to an inhibition of DNA biosynthesis. DNA synthesis was measured by an isotope dilution assay after pulse-labeling with [3H] thymidine 1 muCi/mouse and by monitoring the increase in the total amount of DNA of cell population. The data demonstrated that L-histidinol inhibits DNA biosynthesis and cell proliferation of Ehrlich ascites carcinoma in vivo

In-vitro interaction of l-histidinol and cisplatin on [3H] thymidine incorporation into DNA and the viability of cultures EAC cells

The cytotoxic activity of cisplatin and/or L-histidinol was studied on Ehrlich ascites carcinoma [EAC] cell line. Cisplatin in concentration ranged from 1-20 microM reduced cell survival of cultured EAC cells in a concentration-related manner. The concentration of cisplatin that inhibited the survival of 50% of cells [IC50] was 16 micro M. L-Histidionl [0.5-4 mM] per se did not affect the survival tumor cells, however, it significantly potentiated the cytotoxicity of cisplatin. An important observation is that with the use of L-histidinol [4 mM] in combination with cisplatin, the IC50 of cisplatin was shifted to be 4 micro M only. By means of tritiated thymidine incorporation into the cellular acid-insolube material, cisplatin [8 and 16 micro M] inhibited DNA synthesis [41% and 51% respectively] in cultured tumor cells. Also, a marked inhibition of DNA synthesis [31% and 42%] was observed with L-histidinol [2 and 4 mM respectively]. In conclusion, L-histidinol, a structural analog of the essential amino acid L-histidine, enhances cisplatin cytotoxic activity against EAC cells. These findings may reflect a potential of L-histidinol to improve the therapeutic index of cisplatin. Further studies should thoroughly investigate the mechanism[s] of enhancement of therapeutic efficacy of cisplatin by L-histidinol