急!!! 谁知道哪里可以买到 tetrathiomolybdate (片剂)???

heping 发表于 2008-8-28 15:13:46

转发:
密西根大学综合癌症中心的医师注意到，一项早期的药物临床试验中大有可为的结果，这种药物降低了癌症患者血液中的铜含量。     　　     现在，新的U-M实验室之研究结果确切地告诉他们，这种实验性药物如何作用，并显示它们战胜癌症的潜力。研究结果发表于最新一期的Cancer Research期刊中，指出可利用抗血管新生的方法致疗癌症。         该篇文章描述药物-tetrathiomolybdate，或TM-如何使肿瘤细胞无法发送讯号刺激新血管的生成。藉由保持铜的低含量和阻断NFkB的讯息传递路径，研究人员相信，TM可阻断血管新生或血管生成，使肿瘤无法增长和扩散。         血管新生被认为许多癌症常见的起源，使肿瘤增生并移转至身体其它部位。U-M团队研究TM利用四种小鼠和细胞的实验方法，以研究抗血管新生潜力。他们明确地表示，TM抑制了肿瘤在植入人类乳癌细胞之小鼠体内的增生，使大鼠动脉细胞新血管的生成远离癌症倾向；减少刺激血管生成之关键讯息分子的释放；并避免植入人类乳癌细胞之小鼠之肿瘤生成。         资深作者内科副教授，也是U-M乳癌和卵巢癌风险评估计划的指导者Sofia D. Merajver 医学博士指出“经过比较后，发现这些结果支持TM临床试验的初步结果，并指出铜的减少可以抑制肿瘤之血管新生，使不良影响降至最低。”她发现TM导致的铜含量减少，更甚于仅透过饮食所减少的铜含量。         Merajver已协助领导TM在U-M的癌症临床和实验室研究调查，包括最近的晚期乳腺癌患第二阶段试验。TM已经在U-M和其它研究中心进行摄护腺癌、乳癌、头及颈部的癌症、多发性骨髓瘤、肝癌、间皮细胞瘤和其它恶性肿瘤患者。         此药物最初由George Brewer医学博士研发作为医疗用途，他是U-M之Morton and Henrietta Sellner人类遗传学教授，专门研究铜含量过多所造成的罕见遗传性疾病：威尔森氏症。         由硫和钼所制成的TM可以和血液中的铜结合，并与称为白蛋白的蛋白质结合，进行螯合作用。三个组成分的复合体之后便由身体排除。         TM在U-M健康系统的一般临床研究中心拯救了许多威尔森氏症患者的生命，去除损坏他们脑部和肝脏并害死患者的铜。         自从U-M于90年代开始成功地治疗威尔森氏症，U-M的研究开始揭露铜在血管新生中所扮演的角色-身体的正常过程及癌症中未受控制的血管新生。研究人员发现铜对于各种"生长因子"是很重要的，可使细胞成为新血管的一部分。         这些发现激励Merajver和Brewer组成团队进行TM抗癌的实验室研究。而导引出各种癌症末期患者的第一阶段试验，结果发表于2000年1月的Clinical Cancer Research期刊。         这项试验的目的是测试TM的安全性和降低癌症患者同含量的能力。但是它显示出少数铜含量被减少至五分之一的患者之肿瘤稳定三个月以上的证据。         从那时候起，U-M研究人员进行TM的临床和基础研究。目前，许多患者参加U-M综合癌症中心的第二阶段试验。同时，Merajver和她的团队继续进行基本的实验室研究，以了解TM如何发挥它的抗血管新生作用。         在新研究中，他们使用二种动物模型：一种是将人类乳癌细胞移转至小鼠体内，另一种方法是特殊育种的小鼠，并确定它们在一岁时都会罹患癌症。         结果是令人震惊的。接受人类乳癌细胞”异体移植”的小鼠，TM使它们的肿瘤减小至未接受TM小鼠肿瘤之69%。接受TM的小鼠肿瘤中只有稀稀落落的血管。         至于"遗传上预先计划"乳癌的小鼠，预先给予TM后都未发生肿瘤。这具有统计上的显著意义，虽然当小鼠停止接受TM后，在二星期内均发生肿瘤。显微镜检显示，它们的乳房区域有"微肿瘤"存在，但是因为无血液供应而无法继续增生。         研究也使用了二种体外，或细胞培养的方法。在其中一项，环状切开大鼠的主动脉 (一种可能形成新血管的组织)，浸泡于发炎的乳癌细胞培养液中。         在另一项研究中，研究人员植入乳房细胞及带有一段只能由NFkB转录因子读取的基因序列之乳癌细胞核—以及可产生NFkB作用警报的DNA片段。在癌细胞培养时，NFkB的活性是乳房细胞培养的2.5倍，但是当添加TM后，NFkB的活性几乎降低癌细胞的2倍，如同正常细胞般。         当研究人员观察构成NFkB分子组成蛋白质的基因时，他们发现以TM治疗可以显著地减少那些蛋白质的生产。当他们观察介白素(interleukin)及生长因素分子时，NFkB的转录通常可获得控制，TM存在时的含量也较低。 Merajver表示“看起来，至少有一部分的TM抗血管新生作用，是藉由抑制促进血管新生因子的释放，并抑制NFkB的活性。这是令人振奋的发现，因为NFkB与癌症对于化疗和放射治疗的抵抗力有关。我们所观察的抑制作用，也建议TM在化学预防药物中，扮演一个重要的角色，可改变易受癌症影响者的基因。” 
 
FYI: 转发:
Copper-Lowering Drug Stabilizes Advanced Cancer: Research on Wilson's Disease Led to Discovery By depriving cancer tumors of the copper supply they need to form new blood vessels, researchers in the U-M Medical School have stopped the growth of the disease in a small group of patients with advanced cancer.
Five of six patients whose copper levels were kept at one-fifth of normal for more than 90 days had no growth of existing tumors or formation of new ones, according to a paper published in the January, 2000, issue of Clinical Cancer Research. The sixth patient had progression of only one tumor; all other tumors within her body remained stable. Twelve other patients did not achieve the target copper level, or could not stay at the target level for 90 days, because of disease progression.
The finding is the first evidence in humans that physicians might fight multiple types of cancer by targeting copper as a 'common denominator' of angiogenesis — the process by which tumors grow the blood vessels that allow them to expand beyond a tiny cluster of cells. The copper strategy is not limited to a single type of cancer, as are other anti-angiogenesis agents now being studied.
 
Sofia Merajver and George Brewer  Patients in the phase I trial at the U-M had metastatic cancer of the breast, kidney, colon, lung, skin, pancreas, prostate, throat, cartilage, blood vessels or endothelium. All had exhausted other conventional treatment options.
The U-M trial used oral doses of an inexpensive compound called tetrathiomolybdate, or TM, to lower patients' copper levels. TM was originally developed for clinical use by George J. Brewer, M.D., Morton and Henrietta Sellner Professor of Human Genetics, to treat people with Wilson's disease, a rare genetic disorder associated with excess copper. His work has shown TM to be the world's most potent anti-copper agent, and safe to use. 
Aware of earlier research indicating that copper is important for angiogenesis, Brewer did work in the early 1990s on animal cancer models treated with TM, with encouraging results. Then he teamed up with Sofia Merajver, M.D., Ph.D., associate professor of internal medicine, molecular genetics researcher, and oncologist in the Comprehensive Cancer Center.
Independently, Merajver was interested in exploring the inhibition of angiogenesis at very early stages in cancer development. Together with Brewer, she designed specific animal studies that allowed the team to test whether TM had the ability to prevent tumors from arising in animals at high risk for cancer. Her laboratory has also begun to uncover the molecular and cellular events involved in the inhibition of blood vessel growth by copper deficiency.
Their first results with humans actually came from a trial that was designed only to see how well TM could reduce copper levels in cancer patients, not to test its effect on the cancer itself. At all three daily dose levels given in the trial, copper levels were reduced to 20 percent of normal in four to six weeks. Neither the drug, nor the long-term copper deficiency, produced side effects.
"What began as a scientific hunch now appears to have potential as a simple but effective general anti-angiogenesis strategy," says Brewer. "We are proceeding with a clinical trial aimed at accelerating TM-induced copper reduction and assessing its effect on advanced-stage cancer. Later this year, we hope to test this approach in 100 patients with five types of less advanced cancer." Neither trial is currently accepting patients.
Adds Merajver, "These initial results suggest that the tactic of preventing angiogenesis through copper deficiency holds significant promise. Through this and other therapies, we may one day be able to turn cancer into a chronic or controllable disease or to contribute to its eradication. Still, much more research is needed before we can know the full potential of anti-angiogenesis."
 The chemicals pictured above are copper (blue) and several of the tetrathiomolybdate compounds currently under study. 
Angiogenesis happens in the body all the time, whether to repair a wound or help with the normal growth of children's bodies. It occurs through a so-called angiogenesis "cascade" — a series of biochemical steps by which cells make and secrete molecules that initiate the growth of capillaries. After the job is done, other molecular "factors" turn off the angiogenesis process. But cancer cells use this normal process for a nefarious purpose — creating an imbalance of angiogenesis activators that overrides the inhibitors and gives the nearby tumor ready access to a blood supply. This creates a vicious cycle of growth that allows tumors to grow faster than the body can respond.
In recent years, researchers have found that copper is a common denominator to several of the key factors that activate the angiogenesis process. Specifically, it acts as a co-factor, or helper, to molecules known as basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and angiogenin. Without copper, the molecules can't function and construction of blood vessels stops. 
That's why TM makes such a good choice, Brewer explains. It binds with copper and protein, making a stable compound that can't be used by tumor cells or any other part of the body. Taken at mealtime, TM prevents the body from processing and absorbing the copper in food as well as the copper normally found in saliva and gastric secretions. Taken between meals, TM is absorbed into the blood and binds copper to blood protein. In either case, the TM-protein-copper complex does not interact with other biological molecules and is excreted. 
The discovery of TM's potential effect on cancer grew directly out of Brewer's decades-long research on trace metals' importance to the body. He began by examining the role of zinc in sickle-cell anemia, a disorder of the red blood cells, and unexpectedly found that zinc acetate reduced the level of copper in the blood of some patients. This gave him the idea to test the compound's effect on the dangerously high copper levels in the systems of patients with Wilson's disease, a potentially fatal recessive genetic condition that strikes 5,000 teen-agers and young adults each year. Finding that zinc acetate brought the patients' dementia, drooling, slurred speech, temper outbursts and tremors under control if taken regularly, without side effects, he sought and received FDA approval for the compound. 
But he needed a faster-acting compound to bring copper levels under control quickly. That compound turned out to be TM, now in clinical trials at the U-M General Clinical Research Center. To date, 63 Wilson's disease patients have come to the U-M for eight weeks of treatment with TM to lower their copper levels, then returned home to take zinc acetate and follow a copper-restricted diet to maintain their copper levels.
 
 
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