Brawer Michael K
Northwest Prostate Institute, Northwest Hospital Seattle, WA.
Rev Urol. 2007 Winter;9(1):1-8.
Docetaxel is becoming standard therapy for androgen-independent prostate cancer (AIPC), and investigational agents are being added to docetaxel to assess potential additive effects and synergy. Although one of these agents, calcitriol, has repeatedly demonstrated antiproliferative properties against cancer of the prostate, breast, colon, and lung, the antineoplastic activity of calcitriol requires superphysiologic levels. Unfortunately, chronic exposure to superphysiologic levels of calcitriol causes hypercalcemia and resulting toxicity. Therefore, a host of analogues of calcitriol have been investigated for antineoplastic function, including intermittent dose-intense calcitriol, or DN-101. Because of encouraging results from phase II studies of DN-101 combined with docetaxel, the ASCENT (AIPC Study of Calcitriol Enhancement of Taxotere) phase II trial investigated docetaxel plus DN-101 versus docetaxel plus placebo in 250 men with metastatic AIPC and an abnormal baseline prostate-specific antigen (PSA) level. Although the ASCENT trial did not achieve its primary endpoint for increased PSA response, there was a significant trend in PSA response rate in the DN-101 arm. DN-101 in combination with docetaxel seems to improve overall survival and, interestingly, has a favorable safety profile compared with docetaxel alone. The DN-101/docetaxel combination is currently being studied in a much larger international trial, ASCENT-2.
多西他赛正成为去势抵抗性前列腺癌（AIPC）的标准治疗方法，并且正在将研究性药物添加到多西他赛中，以评估潜在的相加作用和协同作用。尽管其中一种药物骨化三醇已多次证明对前列腺癌、乳腺癌、结肠癌和肺癌具有抗增殖特性，但骨化三醇的抗肿瘤活性需要超生理水平。不幸的是，长期暴露于超生理水平的骨化三醇会导致高钙血症及由此产生的毒性。因此，人们对一系列骨化三醇类似物的抗肿瘤功能进行了研究，包括间歇性高剂量骨化三醇，即DN-101。由于DN-101与多西他赛联合应用的II期研究结果令人鼓舞，ASCENT（多西他赛增强骨化三醇治疗AIPC的研究）II期试验在250例转移性AIPC且基线前列腺特异性抗原（PSA）水平异常的男性患者中，对多西他赛加DN-101与多西他赛加安慰剂进行了比较。尽管ASCENT试验未达到PSA反应增加的主要终点，但DN-101组的PSA反应率有显著趋势。DN-101与多西他赛联合应用似乎可改善总生存期，有趣的是，与单独使用多西他赛相比，其安全性更好。目前，DN-101/多西他赛联合用药正在一项规模更大的国际试验ASCENT-2中进行研究。
