Pienta K J, Smith D C
University of Michigan Comprehensive Cancer Center, Ann Arbor 48109-0680, USA.
Semin Oncol. 1997 Oct;24(5 Suppl 15):S15-72-S15-77.
We previously developed a novel and effective therapy for hormone-refractory prostate cancer using the agents estramustine and etoposide. Although neither of these agents alone is effective in the treatment of advanced, hormone-refractory prostate cancer, we predicted their activity when used in combination based on preclinical assays, and then demonstrated their effectiveness in a phase I-II clinical trial, where they were shown to produce a 50% complete and partial response rate in patients with bidimensionally measurable disease. In preclinical studies, we had demonstrated that estramustine and etoposide interact with the nuclear matrix, which is the site of DNA replication. Expanding these investigations, we determined that paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), a microtubule inhibitor, interacts with estramustine and etoposide, and the combination of these three agents had significant preclinical activity against androgen-independent prostate cancer cells. These studies led us to conduct a phase II clinical trial of paclitaxel, estramustine, and etoposide in patients with hormone-refractory prostate cancer. Preliminary results demonstrate that this is an active regimen, with 57% of patients demonstrating a response to therapy as measured by a decrease in pretreatment prostate-specific antigen levels of greater than 50%.
我们之前使用雌莫司汀和依托泊苷开发了一种针对激素难治性前列腺癌的新型有效疗法。尽管这两种药物单独使用时对晚期激素难治性前列腺癌均无效，但基于临床前试验，我们预测了它们联合使用时的活性，随后在一项I-II期临床试验中证明了其有效性，在该试验中，对于二维可测量疾病的患者，它们显示出50%的完全缓解和部分缓解率。在临床前研究中，我们已证明雌莫司汀和依托泊苷与核基质相互作用，而核基质是DNA复制的场所。扩展这些研究后，我们确定微管抑制剂紫杉醇（泰素；百时美施贵宝公司，新泽西州普林斯顿）与雌莫司汀和依托泊苷相互作用，并且这三种药物的组合对雄激素非依赖性前列腺癌细胞具有显著的临床前活性。这些研究促使我们对激素难治性前列腺癌患者进行紫杉醇、雌莫司汀和依托泊苷的II期临床试验。初步结果表明这是一种有效的治疗方案，57%的患者通过治疗前前列腺特异性抗原水平降低超过50%来衡量，显示出对治疗有反应。
