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.

我们正试图开发新的药物来改变癌症的生物学特性。为了实现这一目标，我们与一家独特的计算化学公司合作，设计出能够消除癌症发展、进展和转移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计划需要对正在评估的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/药效学的概念在开发新的抗癌药物。这导致人们试图通过表征患者的药物遗传学来优化治疗，并了解潜在的药物相互作用。我们最近参与的代理商包括：我们发现酮康唑对一组人前列腺癌细胞系具有膀胱抑制作用，对LNCaP、PC 3/PC 3 M、PC 3/PC 3 M、PC 3/PC 3 M和PC 3/PC 3 M的IC 50值分别为5 μ g/mL、12 μ g/mL和25 μ g/mL，和DU 145细胞。这种抗性与Raf-1和Bcl-2磷酸化程度较低有关。微管活性药物与酮康唑的组合在DU 145癌细胞中是有益的。此外，酮康唑阻断了所有的前列腺癌细胞系的恢复后，24小时脉冲treatment.To建立在上述临床前观察，我们启动了一项I期临床试验，酮康唑加每周多西他赛与AIPC患者。本研究的主要目的是确定副作用特征并确定MTD。考虑到可能的药物相互作用，多西他赛和酮康唑的起始剂量分别为5 mg/m2和1200 mg/d。多西他赛剂量为10 mg/m2时观察到显著肝毒性。因此，我们将给药方案修改为600 mg/d酮康唑和10 mg/m2多西他赛。迄今为止，共有22例患者接受了该联合治疗，目前正在进行药代动力学分析。