A blocking antibody to nerve growth factor attenuates skeletal pain induced by prostate tumor cells growing in bone
A blocking antibody to nerve growth factor attenuates skeletal pain induced by prostate tumor cells growing in bone
复制标题
DOI：
10.1158/0008-5472.can-05-0826
复制
发表时间：
2005-10-15
期刊：
影响因子：
11.2
通讯作者：
Mantyh, PW
中科院分区：
文献类型：
--
作者：
Halvorson, KG;Kubota, K;Mantyh, PW
前列腺癌的独特之处在于骨通常是临床上唯一可检测到的转移部位。已经转移到骨的前列腺肿瘤经常引起骨痛，这可能难以完全控制，因为它似乎同时受到炎症、神经性和致瘤机制的驱动。由于神经生长因子（NGF）已显示在动物模型中调节炎性和一些神经性疼痛状态，因此在骨癌的前列腺模型中施用NGF螯合抗体，其中在小鼠股骨中同时发生显著的骨形成和骨破坏。给予NGF阻断抗体可显著减少早期和晚期骨癌疼痛相关行为，其效果大于或等于急性给予10或30 mg/kg硫酸吗啡所达到的效果。相反，这种疗法不影响肿瘤诱导的骨重建、成骨细胞增殖、破骨细胞生成、肿瘤生长或皮肤或骨中感觉或交感神经支配的标志物。骨感觉神经支配的一个相当独特的方面可以部分解释抗NGF治疗在缓解前列腺癌引起的骨痛中的镇痛功效，这是几乎所有支配骨的神经纤维表达trkA和p75，并且这些是NGF通过其敏化和/或激活伤害感受器的受体。目前的研究结果表明，抗神经生长因子治疗可能是有效的，在减少疼痛和提高生活质量的前列腺肿瘤引起的骨癌疼痛患者。
Prostate cancer is unique in that bone is often the only clinically detectable site of metastasis. Prostate tumors that have metastasized to bone frequently induce bone pain which can be difficult to fully control as it seems to be driven simultaneously by inflammatory, neuropathic, and tumorigenic mechanisms. As nerve growth factor (NGF) has been shown to modulate inflammatory and some neuropathic pain states in animal models, an NGF-sequestering antibody was administered in a prostate model of bone cancer where significant bone formation and bone destruction occur simultaneously in the mouse femur. Administration of a blocking antibody to NGF produced a significant reduction in both early and late stage bone cancer pain-related behaviors that was greater than or equivalent to that achieved with acute administration of 10 or 30 mg/kg of morphine sulfate. In contrast, this therapy did not influence tumor-induced bone remodeling, osteoblast proliferation, osteoclastogenesis, tumor growth, or markers of sensory or sympathetic innervation in the skin or bone. One rather unique aspect of the sensory innervation of bone, that may partially explain the analgesic efficacy of anti-NGF therapy in relieving prostate cancer-induced bone pain, is that nearly all nerve fibers that innervate the bone express trkA and p75, and these are the receptors through which NGF sensitizes and/or activates nociceptors. The present results suggest that anti-NGF therapy may be effective in reducing pain and enhancing the quality of life in patients with prostate tumor-induced bone cancer pain.