Maltese W A, Defendini R, Green R A, Sheridan K M, Donley D K
J Clin Invest. 1985 Nov;76(5):1748-54. doi: 10.1172/JCI112165.
3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase catalyzes the formation of mevalonate, an essential precursor for isoprenoid compounds in mammalian cells. Recent studies have shown that mevinolin, a competitive inhibitor of the reductase, inhibits cell proliferation and induces differentiation in cultured C1300 (Neuro-2A) murine neuroblastoma cells. We now report that mevinolin can inhibit neuroblastoma growth in vivo. The specific activity of HMG-CoA reductase in subcutaneous neuroblastomas increased more than 20-fold between the fifth and eighth days after tumor inoculation, and remained elevated for the remainder of the tumor lifetime in mice. The increase in reductase activity was correlated with a marked increase in tumor DNA content and exponential increase in tumor weight. Using an in vitro assay to monitor the ability of mouse serum to suppress sterol synthesis, we determined that mevinolin was inactivated or cleared from the circulation within 3-6 h after a single subcutaneous injection. However, by using subcutaneous osmotic pumps to deliver a constant infusion of mevinolin, we were able to maintain adequate blood levels of the drug for 7 d. Mevinolin (5 mg/kg per h) suppressed tumor growth (wet weight) significantly when treatment was carried out between day 1 and day 8 or between day 5 and day 12 after tumor inoculation. Histopathological examination of tumors from mevinolin-treated mice revealed few or no mitotic figures and marked cellular degeneration. Measurements of incorporation of (3H)acetate into neuroblastoma sterols and ubiquinones 24 h after implantation of osmotic pumps showed that mevinolin produced a marked inhibition of isoprenoid synthesis in the tumors in vivo. The data suggest that, in addition to their demonstrated utility as cholesterol-lowering drugs, competitive inhibitors of HMG-CoA reductase may have considerable potential as novel antineoplastic agents.
3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶催化甲羟戊酸的形成，甲羟戊酸是哺乳动物细胞中类异戊二烯化合物的必需前体。最近的研究表明，美伐他汀是该还原酶的竞争性抑制剂，可抑制培养的C1300（Neuro-2A）小鼠神经母细胞瘤细胞的增殖并诱导其分化。我们现在报告美伐他汀可在体内抑制神经母细胞瘤的生长。皮下神经母细胞瘤中HMG-CoA还原酶的比活性在肿瘤接种后第5天至第8天之间增加了20多倍，并在小鼠肿瘤生存期的剩余时间内保持升高。还原酶活性的增加与肿瘤DNA含量的显著增加和肿瘤重量的指数增加相关。通过体外试验监测小鼠血清抑制甾醇合成的能力，我们确定单次皮下注射后3-6小时内美伐他汀从循环中失活或清除。然而，通过使用皮下渗透泵持续输注美伐他汀，我们能够在7天内维持药物的足够血药浓度。当在肿瘤接种后第1天至第8天或第5天至第12天进行治疗时，美伐他汀（每小时5mg/kg）显著抑制肿瘤生长（湿重）。对美伐他汀治疗小鼠的肿瘤进行组织病理学检查发现，有丝分裂象很少或没有，且有明显的细胞变性。在植入渗透泵24小时后测量（3H）乙酸掺入神经母细胞瘤甾醇和泛醌的情况表明，美伐他汀在体内对肿瘤中的类异戊二烯合成产生了显著抑制。数据表明，除了已证明的作为降胆固醇药物的效用外，HMG-CoA还原酶的竞争性抑制剂作为新型抗肿瘤药物可能具有相当大的潜力。
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