Samid D, Ram Z, Hudgins W R, Shack S, Liu L, Walbridge S, Oldfield E H, Myers C E
Clinical Pharmacology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Cancer Res. 1994 Feb 15;54(4):891-5.
Phenylacetate, a deaminated metabolite of phenylalanine, has been implicated in damage to immature brain in phenylketonuria. Because primary brain tumors are highly reminiscent of the immature central nervous system, these neoplasms should be equally vulnerable. We show here that sodium phenylacetate can induce cytostasis and reversal of malignant properties of cultured human glioblastoma cells, when used at pharmacological concentrations that are well tolerated by children and adults. Treated tumor cells exhibited biochemical alterations similar to those observed in phenylketonuria-like conditions, including selective decline in de novo cholesterol synthesis from mevalonate. Because gliomas, but not mature normal brain cells, are highly dependent on mevalonate for production of sterols and isoprenoids vital for cell growth, sodium phenylacetate would be expected to affect tumor growth in vivo while sparing normal tissues. Systemic treatment of rats bearing intracranial gliomas resulted in significant tumor suppression with no apparent toxicity to the host. The data indicate that phenylacetate, acting through inhibition of protein prenylation and other mechanisms, may offer a safe and effective novel approach to treatment of malignant gliomas and perhaps other neoplasms as well.
苯乙酸是苯丙氨酸的一种脱氨基代谢产物，与苯丙酮尿症中未成熟脑损伤有关。由于原发性脑肿瘤与未成熟的中枢神经系统高度相似，这些肿瘤应该同样易受影响。我们在此表明，苯乙酸钠在儿童和成人都能良好耐受的药理浓度下使用时，可诱导培养的人胶质母细胞瘤细胞的细胞生长停滞并逆转其恶性特性。经处理的肿瘤细胞表现出与苯丙酮尿症样情况下观察到的类似生化改变，包括由甲羟戊酸从头合成胆固醇的选择性下降。由于胶质瘤而非成熟的正常脑细胞高度依赖甲羟戊酸来产生对细胞生长至关重要的甾醇和类异戊二烯，预计苯乙酸钠会在体内影响肿瘤生长，同时 sparing正常组织。对患有颅内胶质瘤的大鼠进行全身治疗导致肿瘤显著抑制，且对宿主无明显毒性。数据表明，苯乙酸通过抑制蛋白质异戊二烯化和其他机制发挥作用，可能为治疗恶性胶质瘤以及或许其他肿瘤提供一种安全有效的新方法。 （注：原文中“sparing normal tissues”表述有误，推测可能是“sparing normal tissues”，意为“ sparing正常组织”，这里按推测翻译为“ sparing正常组织”，实际可能需要结合更准确的原文来完善。）
