Development of Drugs That Target Prostate Cancer

开发针对前列腺癌的药物

• 批准号: 7291848
• 负责人: William Douglas Figg
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7291848
• 关键词: Development; Drugs; Target; Prostate; Cancer

We are attempting to develop novel agents that alter the biology of the cancer. In order to accomplish this goal, we have initiated a collaboration with a unique computational chemistry company to design compounds that abrogate key molecular targets in the development, progression and metastasis of cancer. These studies are just being initiated but could provide valuable new agents.A successful drug development program requires a complete understanding of the clinical pharmacology of the agent(s) being evaluated. One of our interests is to utilize pharmacokinetic/pharmacodynamic concepts in the development of novel anticancer agents. This has led to attempts to optimize therapy through characterizing the pharmacogenetics of patients and appreciates for potential drug interactions. Agents that we have recently been involved with include: MS275, UCN01, perifosine, OSI774, depsipeptide, 17-DMAG, COL3, flavopiridol, phenylbutyrate, PSC833 and phenylacetate.We have found that ketoconazole exerts a cystostatic effect on panel of human prostate cancer cell lines, with IC50 values of 5 ug/mL, 12 ug/mL and 25 ug/mL for LNCaP, PC3/PC3M, and DU145 cells, respectively. This resistance was associated with a lesser degree of Raf-1 and Bcl-2 phosphorylation. Combinations of microtubule-active drugs with ketoconazole were beneficial in DU145 cancer cells. Furthermore, ketoconazole blocked the recovery of all the prostate cancer cell lines following 24 h-pulse treatment.To build on the preclinical observations above, we initiated a Phase I trial of ketoconazole plus weekly docetaxel in patients with AIPC. The primary objective of this study is to determine the side effect profile and determine the MTD. In recognition oof possible drug-drug interations, starting doses of 5 mg/m2 and 1200 mg/d were used for docetaxel and ketoconazole, respectively. Significant hepatotoxicity was noted with a docetaxel dose of 10 mg/m2. We have therefore modified the dosing regimen to 600 mg/d of ketoconazole and 10 mg/m2 of docetaxel. A total of 22 patients have been treated with this combination to date and pharmacokinetic analyses are currently ongoing.

我们正在尝试开发改变癌症生物学的新型药物。为了实现这一目标，我们已经与一家独特的计算化学公司合作，设计了消除癌症发展，进展和转移中关键分子靶标的化合物。这些研究只是开始启动，但可以提供有价值的新代理。一项成功的药物开发计划需要完全了解正在评估的药物的临床药理学。我们的兴趣之一是在新型抗癌剂的发展中利用药代动力学/药效学概念。这导致试图通过表征患者的药物遗传学并欣赏潜在的药物相互作用来优化治疗。 Agents that we have recently been involved with include: MS275, UCN01, perifosine, OSI774, depsipeptide, 17-DMAG, COL3, flavopiridol, phenylbutyrate, PSC833 and phenylacetate.We have found that ketoconazole exerts a cystostatic effect on panel of human prostate cancer cell lines, with IC50 values of 5 ug/mL, 12 LNCAP，PC3/PC3M和DU145细胞的UG/ML和25 ug/ml。这种抗性与较小程度的RAF-1和Bcl-2磷酸化有关。微管活性药物与酮康唑的组合在DU145癌细胞中是有益的。此外，酮康唑在24 h-Pulse治疗后阻止了所有前列腺癌细胞系的恢复。为了建立上述临床前观察结果，我们在AIPC患者中启动了酮康唑和每周多西他赛的I期试验。这项研究的主要目的是确定副作用谱并确定MTD。为了识别可能的药物 - 药物中间，分别将5 mg/m2和1200 mg/d的起始剂量用于多西他赛和酮康唑。多西他赛剂量为10 mg/m2。因此，我们已经将剂量方案修改为600 mg/d的酮康唑和10 mg/m2多西他赛。迄今为止，总共有22名患者接受了这种组合，目前正在进行药代动力学分析。