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.

我们正在尝试开发新的药剂来改变癌症的生物学特性。为了实现这一目标，我们已经开始与一家独特的计算化学公司合作，设计能够消除癌症发生、进展和转移过程中关键分子靶点的化合物。这些研究才刚刚开始，但可以提供有价值的新药物。一个成功的药物开发项目需要对被评估药物的临床药理学有全面的了解。我们的兴趣之一是利用药代动力学/药效学概念开发新的抗癌药物。这导致了通过表征患者的药物遗传学和欣赏潜在的药物相互作用来优化治疗的尝试。我们最近参与的药物包括：MS275、UCN01、perifosine、OSI774、depsipeptide、17-DMAG、COL3、flavopiridol、phenylbutyrate、PSC833和phenylacetate。我们发现酮康唑对人前列腺癌细胞具有抑囊作用，LNCaP、PC3/PC3M和DU145细胞的IC50值分别为5 ug/mL、12 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。微管活性药物联合酮康唑对DU145癌细胞有益。此外，酮康唑阻断了24 h脉冲治疗后所有前列腺癌细胞系的恢复。基于上述临床前观察，我们在AIPC患者中启动了酮康唑联合每周多西他赛的I期试验。本研究的主要目的是确定副作用概况和确定MTD。考虑到可能的药物-药物相互作用，多西他赛和酮康唑的起始剂量分别为5mg /m2和1200mg /d。多西紫杉醇剂量为10mg /m2时，观察到明显的肝毒性。因此，我们将给药方案修改为酮康唑600 mg/d和多西他赛10 mg/m2。迄今为止，共有22名患者接受了这种联合治疗，目前正在进行药代动力学分析。