Ram Z, Samid D, Walbridge S, Oshiro E M, Viola J J, Tao-Cheng J H, Shack S, Thibault A, Myers C E, Oldfield E H
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland 20892.
Cancer Res. 1994 Jun 1;54(11):2923-7.
Phenylacetate is a naturally occurring plasma component that suppresses the growth of tumor cells and induces differentiation in vitro. To evaluate the in vivo potential and preventive and therapeutic antitumor efficacy of sodium phenylacetate against malignant brain tumors, Fischer 344 rats (n = 50) bearing cerebral 9L gliosarcomas received phenylacetate by continuous s.c. release starting on the day of tumor inoculation (n = 10) using s.c. osmotic minipumps (550 mg/kg/day for 28 days). Rats with established brain tumors (n = 12) received continuous s.c. phenylacetate supplemented with additional daily i.p. dose (300 mg/kg). Control rats (n = 25) were treated in a similar way with saline. Rats were sacrificed during treatment for electron microscopic studies of their tumors, in vivo proliferation assays, and measurement of phenylacetate levels in the serum and cerebrospinal fluid. Treatment with phenylacetate extended survival when started on the day of tumor inoculation (P < 0.01) or 7 days after inoculation (P < 0.03) without any associated adverse effects. In the latter group, phenylacetate levels in pooled serum and cerebrospinal fluid samples after 7 days of treatment were in the therapeutic range as determined in vitro (2.45 mM in serum and 3.1 mM in cerebrospinal fluid). Electron microscopy of treated tumors demonstrated marked hypertrophy and organization of the rough endoplasmic reticulum, indicating cell differentiation, in contrast to the scant and randomly distributed endoplasmic reticulum in tumors from untreated animals. In addition, in vitro studies demonstrated dose-dependent inhibition of the rate of tumor proliferation and restoration of anchorage dependency, a marker of phenotypic reversion. Phenylacetate, used at clinically achievable concentrations, prolongs survival of rats with malignant brain tumors through induction of tumor differentiation. Its role in the treatment of brain tumors and other cancers should be explored further.
苯乙酸盐是一种天然存在的血浆成分，在体外可抑制肿瘤细胞生长并诱导分化。为评估苯乙酸钠对恶性脑肿瘤的体内潜力以及预防和治疗抗肿瘤功效，对50只接种了脑9L胶质肉瘤的Fischer 344大鼠进行实验，其中10只在肿瘤接种当天开始通过皮下持续释放给予苯乙酸盐（使用皮下渗透微型泵，剂量为550 mg/kg/天，持续28天）。对已形成脑肿瘤的12只大鼠给予皮下持续苯乙酸盐，并额外每日腹腔注射一次（剂量为300 mg/kg）。25只对照大鼠以类似方式给予生理盐水。在治疗期间处死大鼠，以对其肿瘤进行电子显微镜研究、体内增殖分析，并测量血清和脑脊液中的苯乙酸盐水平。在肿瘤接种当天开始使用苯乙酸盐进行治疗可延长生存期（P < 0.01），在接种后7天开始治疗也可延长生存期（P < 0.03），且无任何相关不良反应。在后一组中，治疗7天后合并的血清和脑脊液样本中的苯乙酸盐水平处于体外测定的治疗范围内（血清中为2.45 mM，脑脊液中为3.1 mM）。对治疗后肿瘤的电子显微镜检查显示，粗面内质网显著肥大且有序排列，表明细胞分化，而未治疗动物肿瘤中的内质网则稀少且随机分布。此外，体外研究表明，苯乙酸盐对肿瘤增殖速率具有剂量依赖性抑制作用，并恢复了贴壁依赖性，这是表型逆转的一个标志。在临床可达到的浓度下使用苯乙酸盐，可通过诱导肿瘤分化延长患有恶性脑肿瘤大鼠的生存期。其在脑肿瘤和其他癌症治疗中的作用应进一步探索。
