Larner J, Jane J, Laws E, Packer R, Myers C, Shaffrey M
Department of Therapeutic Radiology, University of Virginia Health Sciences Center, Charlottesville 22908, USA.
Am J Clin Oncol. 1998 Dec;21(6):579-83. doi: 10.1097/00000421-199812000-00010.
Malignant gliomas are thought to be highly dependent on the mevalonate pathway for cell growth. Lovastatin, a cholesterol-lowering drug, inhibits not only the rate-limiting step in the mevalonate pathway (hepatic hydroxymethyl glutaryl coenzyme A reductase), but also the prenylation of several key regulatory proteins including ras and the small guanosine triphosphate binding proteins. Therefore, from August 1994 through March 1996, 18 patients with either anaplastic glioma or glioblastoma multiforme were entered into a trial testing the safety of high-dose lovastatin with or without radiation. Although the response data is too premature to evaluate activity, the fact that high doses of lovastatin are well tolerated with concurrent radiation suggests that central nervous system toxicity will not be a significant limiting toxicity as more selective farnesyltransferase inhibitors are brought into the clinic as radiation sensitizers.
恶性胶质瘤被认为在细胞生长方面高度依赖甲羟戊酸途径。洛伐他汀是一种降胆固醇药物，它不仅抑制甲羟戊酸途径中的限速步骤（肝脏羟甲基戊二酰辅酶A还原酶），还抑制包括ras和小GTP结合蛋白在内的几种关键调节蛋白的异戊二烯化。因此，从1994年8月到1996年3月，18例间变性胶质瘤或多形性胶质母细胞瘤患者进入了一项试验，测试高剂量洛伐他汀联合或不联合放疗的安全性。尽管反应数据还太早，无法评估活性，但高剂量洛伐他汀与同步放疗耐受性良好这一事实表明，随着更具选择性的法尼基转移酶抑制剂作为放疗增敏剂进入临床，中枢神经系统毒性不会成为显著的限制毒性。
