PHASE I STUDY OF TETRATHYMOLYBDATE IN METASTATIC CANCER

描述(申请人的描述) 转移性实体瘤患者的治疗通常非常有限。 由于细胞减少性化疗的累积毒性和 抗药性。一种维持或缩小规模的新方法 转移性肿瘤包括抑制新血管生长进入 肿瘤床，这一过程被称为血管生成。正如铜已经被证明是 是动物模型中血管生成的必要条件，我们试图确定 铜的减少是导致萎缩还是减缓增长 实体瘤。已知的最有效的铜缓蚀剂是 四硫钼酸盐(TM)是由加州大学开发的 密歇根州用于治疗患有威尔逊病的患者 组织中的铜含量极高。鉴于TM已经安全地 对患有威尔逊病的人类使用，其毒性分布 转移性癌症患者尚不清楚。在这里，我们提出了第一阶段 转移性实体瘤衰竭患者TM的研究 其他治疗方案。12至18名患者将参加一项 剂量分级方案为90-120 mg/d。温和剂的主要副作用 铜缺乏是轻度贫血(红细胞压积大于基线的70%)。 本研究将确定TM在患者体内的最佳脱铜剂量 转移性疾病与TM的药效学研究 正常的合成肝功能。在有可及皮损的患者中， 治疗前后皮损标本的新生血管指数 将被测量为疗效的中间微观终点。任何 对肿瘤大小或生长速度的影响也将被注意到。这些 如果结果有希望，将有助于指导TM第二阶段遗嘱的设计 用于不同类型的癌症以及预防和佐剂。

DESCRIPTION (Applicant's Description) Patients with metastatic solid tumors often have very limited treatment options due to the cumulative toxicity of cytoreductive chemotherapy and drug resistance. A new approach to the maintenance or reduction in size of metastatic tumors consists of the inhibition of new blood vessel growth into the tumor bed, a process known as angiogenesis. As copper has been shown to be a requirement for angiogenesis in animal models, we seek to determine whether a decrease in copper causes shrinkage or slows down the growth of solid tumors. The most potent inhibitor of copper known is tetrathiomolybdate (TM) which has been developed at the University of Michigan for the treatment of patients with Wilson's disease who suffer from extremely high levels of copper in the tissues. Whereas TM has been safely administered to humans with Wilson's disease, its toxicity profile in patients with metastatic cancer is not known. Here we propose a phase I study of TM in patients with metastatic solid tumors who have exhausted other treatment options. Twelve to eighteen patients will be enrolled in a graduated dose regimen of 90-120 mg/day. The major side-effect of mild copper deficiency is mild anemia (Hct greater than 70 percent of baseline). This study will determine the optimal decoppering dose of TM in patients with metastatic disease and the pharmacodynamics of TM in patients with normal synthetic liver function. In patients with accessible lesions, the neovascularization index of the lesions sampled before and after therapy will be measured as an intermediate microscopic end-point of efficacy. Any effects on the size or rate of growth of tumors will also be noted. These results, if promising, will help guide the design of phase II wills of TM for different types of cancer and of prevention and adjuvant.