Atorvastatin, a prenylation inhibitor in acute leukemia.

描述（由申请人提供）：Ras蛋白主要参与 恶性细胞的转化、增殖和存活，包括 急性白血病和骨髓增生异常患者的原始细胞。Ras蛋白 需要翻译后修饰（异戊烯化）的活性， 其他几种关键蛋白质。异戊烯化涉及添加15- （法呢基）或20-碳（香叶基香叶基）基团，从头合成的中间体 胆固醇生物合成，以特定的CAAX基序附近的C-末端。具体 催化异戊烯化、法尼基转移酶（FT）和 香叶基香叶基转移酶-I和-II（GGT-1，GGT-II），目前在临床上 试验或临床前模型。这类抑制剂的功效可能受到以下因素的限制： 某些Ras蛋白可能被FT或GGT-1异戊烯化; 一种酶的抑制可以被另一种转移酶所规避。一个 另一种治疗策略包括HGM-CoA还原酶抑制剂 （他汀类药物），如阿托伐他汀，其阻断法呢基和阿托伐他汀的合成。 香叶基香叶基他汀类药物抑制人乳腺癌细胞异戊二烯化和增殖 白血病和其它恶性细胞系。长期目标是 我们的研究是确定抑制异戊烯化的临床效用， 急性白血病和骨髓增生异常的患者。拟议的调查 是阿托伐他汀抑制Ras的假设的初步检验， 在恶性成髓细胞中的异戊二烯化。两 具体目标是：（1）为了确定最大耐受剂量， 阿托伐他汀在急性脑梗死患者中的药代动力学和药效学 白血病或骨髓增生异常，在加速滴定I期试验中;（2.）到 确定抑制颊粘膜中的前层蛋白A的异戊烯化， 替代组织，与白血病细胞Ras异戊二烯化抑制相关 细胞具体目标1中的药效学终点包括以下作用： 阿托伐他汀对临床/实验室毒性、Ras异戊二烯化、HMG-CoA的影响 还原酶活性和甲羟戊酸水平。在具体目标2中， 将前层蛋白A异戊烯化与肿瘤中异戊烯化的抑制进行比较 组织，作为替代终点的初始验证。拟议 研究，阿托伐他汀在癌症患者中的第一个临床试验， 为随后的癌症原理验证和II期试验奠定基础 患者

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.