Bone-specific growth inhibition of prostate cancer metastasis by atrasentan
Bone-specific growth inhibition of prostate cancer metastasis by atrasentan
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DOI：
10.4161/cbt.9.8.11112
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发表时间：
2010-04-15
影响因子：
3.6
通讯作者：
Henry, Michael D.
中科院分区：
文献类型：
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作者：
Drake, Justin M.;Danke, Joshua R.;Henry, Michael D.
晚期前列腺癌经常转移到骨骼，仍然是一种无法治愈的疾病。最近的一种实验性治疗涉及内皮素受体A（ETA）拮抗剂（例如，例如，在一个实施例中，阿曲生坦）。迄今为止的临床结果喜忧参半，阿曲生坦在III期试验中未达到其主要终点。它仍然是一个悬而未决的问题，一些患者是否可能受益于这种疗法，而其他人可能不会。临床前数据支持这样的概念：内皮素信号轴可能对骨肿瘤生长特别重要，但它在多大程度上参与前列腺癌其他器官部位的转移性定植仍不清楚。在这里，我们评估阿曲生坦在前列腺癌转移性定殖的小鼠模型中的功效。使用生物发光成像，我们表明阿曲生坦确实抑制心内注射的22 Rv 1前列腺癌细胞中骨部位的肿瘤生长，但不抑制骨部位的初始定植。然而，阿曲生坦在软组织如肾上腺或肝脏中显示出很小的功效。我们的研究表明，阿曲生坦是否表现出显著的总体抗肿瘤功效和存活益处取决于该动物中明显的骨转移的存在。虽然与以前的研究结果相反，但在前列腺肿瘤模型中的疗效是明显的，该模型可诱发混合性成骨细胞/溶骨性病变。这些数据证实了阿曲生坦可能表现出对前列腺癌骨转移的选择性活性的观点，反映了临床发现，并表明内皮素信号传导在骨转移中的作用可能比以前认识到的更复杂。这里描述的模型可以为解开这种复杂性提供一个有价值的工具。
Advanced prostate cancer frequently metastasizes to bone and remains an incurable disease. One recent experimental therapy involves endothelin receptor A (ETA) antagonists (e. g., atrasentan). Clinical results to date have been mixed, with atrasentan not meeting its primary endpoints in a Phase III trial. It remains an open question whether some patients might benefit from this therapy, while others may not. Preclinical data supports the concept that the endothelin signaling axis may be particularly important for tumor growth in bone, but the extent to which it is involved in metastatic colonization of other organ sites in prostate cancer remains unclear. Here we evaluate the efficacy of atrasentan in a mouse model of prostate cancer metastatic colonization. Using bioluminescence imaging, we show that atrasentan does inhibit tumor growth in, but not the initial colonization of, bony sites in intracardially-injected 22Rv1 prostate cancer cells. However, atrasentan shows little efficacy in soft tissues such as adrenal gland or liver. Our studies show that whether atrasentan exhibits significant overall antitumor efficacy and survival benefit depends on the presence of bone metastasis evident in that animal. Though in contrast to previous findings efficacy is apparent in a prostate tumor model that elicits mixed osteoblastic/osteolytic lesions. These data confirm the notion that atrasentan may exhibit selective activity against prostate cancer bone metastasis, mirroring clinical findings, and suggest that the role of endothelin signaling in bone metastasis may be more complex than previously appreciated. The model described here may provide a valuable tool for unraveling this complexity.