Atorvastatin, a prenylation inhibitor in acute leukemia.

描述(由申请者提供)：RAS蛋白在 恶性细胞的转化、增殖和存活，包括 急性白血病和骨髓发育不良患者的原始细胞。RAS蛋白 需要翻译后修饰(苯丙基化)才能激活，就像这样 其他几种关键蛋白质。预加成包括加成15- (法尼基)或20碳(香叶基)基团，从头合成的中间体 胆固醇的生物合成，到C末端附近的特定CAAX基序。特定的 催化戊烯基化的酶抑制剂、法尼基转移酶(FT)和 香叶醛香叶醛转移酶-L和-II(GGT-1，GGT-II)，目前正在临床上 试验或临床前模型。此类抑制剂的疗效可能受到以下因素的限制 某些RAS蛋白被FT或GGT-1预基化的可能性； 一种酶的抑制可以被另一种转移酶绕过。一个 另一种治疗策略是使用hGM-CoA还原酶抑制剂 (他汀类)，如阿托伐他汀，可阻断法尼基和阿托伐他汀的合成 香叶基香叶基组。他汀类药物抑制人胸腺细胞早烯基化和增殖 白血病等恶性细胞株的体外培养。的长远目标 我们的研究是确定抑制苯丙烯化的临床效用。 急性白血病和骨髓发育不良的患者。拟议的调查 是对阿托伐他汀抑制RAS假说的初步检验 临床可耐受剂量下恶性成髓细胞的苯丙基化。二 提出了具体目标：(1)为了定义最大耐受量， 阿托伐他汀在急性心肌梗死患者中的药代动力学和药动学研究 白血病或骨髓发育不良，在加速滴定I期试验中；至 确定抑制颊粘膜中前层蛋白A的前烯基化是否 代用组织与白血病RAS预烯基化抑制相关 细胞。特定目标1的药效学终点包括 阿托伐他汀对临床/实验室毒性、RAS苯基化、HMG-CoA的影响 还原酶活性和甲氧丙戊酸水平。在具体目标2中，抑制 肿瘤中层前蛋白A的前烯基化与抑制前烯基化的比较 组织，作为代理终点的初始验证。建议数 调查，阿托伐他汀在癌症患者中的首次临床试验， 为随后的癌症原则验证和II期试验奠定基础 病人。

DESCRIPTION (provided by applicant): Ras proteins are critically involved in transformation, proliferation, and survival of malignant cells, including blasts from patients with acute leukemia and myelodysplasia. Ras proteins require post-translational modification (prenylation) for activity, as do several other critical proteins. Prenylation involves addition of 15- (farnesyl) or 20-carbon (geranylgeranyl) groups, intermediates in de-novo cholesterol biosynthesis, to specific CAAX motifs near the C-terminus. Specific inhibitors of enzymes that catalyze prenylation, farnesyltransferase (FT) and geranylgeranyltransferase-l and -II (GGT-1, GGT-II), are currently in clinical trials or preclinical models. Efficacy of such inhibitors may be limited by the potential for some Ras proteins to be prenylated by either FT or GGT-1; inhibition of one enzyme may be circumvented by the other transferase. An alternative therapeutic strategy involves HGM-CoA reductase inhibitors (statins), such as atorvastatin, which block synthesis of both farnesyl and geranylgeranyl groups. Statins inhibit prenylation and proliferation of human leukemia, and other malignant, cell lines in-vitro. The long-range objective of our research is to determine the clinical utility of inhibiting prenylation in patients with acute leukemia, and myelodysplasia. The proposed investigations are an initial test of the hypothesis that atorvastatin inhibits Ras prenylation in malignant myeloblasts at clinically tolerable doses. Two specific aims are proposed: (1.) To define the maximal tolerated dose, pharmacokinetics, and pharmacodymamics of atorvostatin in patients with acute leukemias or myelodysplasia, in an accelerated-titration phase-I trial; (2.) To determine whether inhibition of prenylation of prelamin A in buccal mucosa, a surrogate tissue, correlates with inhibition of Ras prenylation in leukemic cells. Pharmacodynamic endpoints in specific aim 1 include effects of atorvastatin on clinical / laboratory toxicities, Ras prenylation, HMG-CoA reductase activity, and mevalonate levels. In specific aim 2, inhibition of prelamin A prenylation is compared against inhibition of prenylation in tumor tissue, as initial validation of the surrogate endpoint. The proposed investigations, the first clinical trial of atorvastatin in cancer patients, lay groundwork for subsequent proof-of-principle and phase II trials in cancer patients.