Development of Drugs That Target Prostate Cancer

我们正试图开发能改变癌症生物学的新型制剂。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化合物，以消除癌症发展、进展和转移中的关键分子靶点。这些研究才刚刚开始，但可能会提供有价值的新药物。成功的药物开发计划需要完全了解正在评估的药物(S)的临床药理学。我们的兴趣之一是利用药代动力学/药效学的概念来开发新的抗癌药物。这导致了试图通过表征患者的药物遗传学来优化治疗，并欣赏潜在的药物相互作用。我们最近参与的药物包括：MS275，UCN01，Perifosine，OSI774，Depsitie，17-DMAG，COL3，Huang opiridol，苯丁酸酯，PSC833和苯乙酸酯。我们发现酮康唑对人前列腺癌LNCaP，PC3/PC3M和DU145细胞的IC50值分别为5ug/mL，12ug/mL和25ug/mL。这种耐药性与Raf-1和Bcl2的磷酸化程度较低有关。微管活性药物与酮康唑联合应用对DU145癌细胞是有益的。此外，酮康唑阻断了24小时脉冲治疗后所有前列腺癌细胞系的恢复。为了建立在上述临床前观察的基础上，我们启动了酮康唑联合每周多西紫杉醇在AIPC患者中的I期试验。这项研究的主要目的是确定副作用概况和MTD。为了识别可能的药物相互作用，多西紫杉醇和酮康唑的起始剂量分别为5 mg/m2和1200 mg/d。多西紫杉醇的剂量为10 mg/m2时，有明显的肝毒性。因此，我们已将给药方案修改为酮康唑600毫克/天和多西紫杉醇10毫克/平方米。到目前为止，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。

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.