Edelstein M B, Heilbrun L K
Veterans Administration Medical Center, Allen Park, Michigan 48101.
Cancer Res. 1988 Mar 15;48(6):1470-5.
L-Histidinol, an analogue of the amino acid L-histidine, has been reported to be able to increase the specificity of 5-fluorouracil (FUra), through both protection of normal tissues at risk and potentiation of leukemic cell killing. It is postulated that this occurs through prevention of the entry of normal cells into the cell cycle through protein deficiency, while allowing malignant cells, permissive for protein starvation, to continue to cycle, thus maintaining sensitivity for cycle specific anticancer agents. Reported in this paper is the confirmation of these L-histidinol-FUra effects. However, a modification was made by which more L-histidinol could be given and more consistent protection of whole animals demonstrated. Further, an optimal schedule of L-histidinol was defined in which FUra preceded L-histidinol infusion. Finally, the specificity and proliferation dependence of this schedule was evaluated on colony forming units-spleen in resting and proliferating state, colony forming units-granulocyte-macrophage, and L1210 leukemia. This demonstrates that the FUra/L-histidinol combination indeed protects only normal cells but that the postulated proliferation dependence is absent, indicating an alternate biological mechanism.
L-组氨醇是氨基酸L-组氨酸的类似物，据报道它能够提高5-氟尿嘧啶（5-FUra）的特异性，这是通过保护有风险的正常组织以及增强对白血病细胞的杀伤作用来实现的。据推测，这一过程是通过蛋白质缺乏阻止正常细胞进入细胞周期，而允许对蛋白质饥饿有耐受性的恶性细胞继续循环，从而维持对细胞周期特异性抗癌药物的敏感性。本文报道了对这些L-组氨醇-5-FUra效应的证实。然而，进行了一项改进，使得能够给予更多的L-组氨醇，并证明对整个动物有更一致的保护作用。此外，确定了L-组氨醇的最佳给药方案，即5-FUra在输注L-组氨醇之前给药。最后，评估了该给药方案对处于静止和增殖状态的脾集落形成单位、粒细胞-巨噬细胞集落形成单位以及L1210白血病的特异性和增殖依赖性。这表明5-FUra/L-组氨醇组合确实仅保护正常细胞，但所推测的增殖依赖性并不存在，这表明存在另一种生物学机制。
