骨癌疼痛机制与相关药物治疗研究进展

随着癌症诊疗技术的进步,癌症患者的生存时间明显延长,如何提高癌症患者的生活质量成为日益突出的问题.有75%～95%的晚期癌和转移痛患者都有癌症疼痛.癌症诱导的骨疼痛(简称骨癌痛)是癌症疼痛的典型代表,是一种独特的疼痛状态,严重影响癌症患者的生活质量,目前尚缺乏有效的治疗手段.随着骨癌痛动物模型的出现,骨癌痛机制研究取得了很大进展.外周因素如肿瘤生长和溶骨作用等以及中枢神经系统的相关变化都可能参与了骨癌痛的形成机制.骨癌痛的治疗药物包括非类固醇类抗炎药、阿片类药物、二膦酸盐类药物和其他尚在开发中的药物等.本文综述骨癌痛的基础研究和相关药物治疗方面的研究进展.     

大鼠骨癌痛模型的建立及组织学研究

目的建立一个有用的癌痛动物模型.方法将MRMT-1大鼠乳腺癌细胞接种到SD大鼠胫骨上段骨髓腔内,造成骨癌痛动物模型.用von Frey细丝刺激足底和后肢负重测量仪分别测量机械性痛觉超敏和痛觉过敏,放射学方法评估骨破坏,同时,组织切片镜下观察肿瘤和骨结构的破坏情况.结果造模动物在14天左右开始出现机械性痛觉超敏和痛觉过敏,胫骨X线摄片显示明显的骨破坏,组织学研究显示骨髓腔内肿瘤生长,向外侵蚀破坏骨皮质,同时伴有新生的编织骨形成.结论从疼痛行为学、放射学、组织学多方面研究的结果,表明大鼠骨癌痛模型已复制成功.该癌痛模型的建立,将为我国癌痛新药的评价,尤其是研究治疗癌痛中药的疗效及作用机制提供一个有用的工具.     

骨癌疼痛的发生机制和治疗进展

癌痛是影响肿瘤患者生活质量的最常见因素。75%~95%的晚期肿瘤患者会出现癌痛,骨癌疼痛具有典型的癌痛特点,初期多为钝痛,疼痛可持续性、进行性加重,其发生与肿瘤因素、骨组织因素及感觉神经元因素等有关。骨癌疼痛多采用药物治疗,且可选用的药物种类较多,目前尚无统一的治疗方案。对于骨癌疼痛患者,应在仔细分析骨癌疼痛发病机制的基础上,针对性选择效果明显的治疗方法,从而减轻患者的疼痛程度,改善生活质量。本研究结合已有的研究成果,对骨癌疼痛的发生机制进行分析,并总结这类患者的治疗方法及效果,以期为骨癌疼痛的治疗提供参考。     

癌痛动物模型及病理机制研究进展

近年来不断出现的癌痛动物模型为癌症机制的研究提供了有效的工具。癌痛有其独特的病理机制，与外周敏化、中枢敏化、骨溶解和肿瘤对外周神经的直接作用等有关，全文综述癌痛动物模型及癌痛机制的研究进展。     

大麻素受体2在胫骨癌痛大鼠脊髓背角细胞中的表达

目的:观察胫骨癌痛大鼠脊髓大麻素受体2(CB2)表达的变化,探讨CB2在骨癌痛中作用及其可能的脊髓机制。方法:雌性SD大鼠56只,体重160-180g,随机分为7组(n=8):对照组、假手术组、骨癌痛组,假手术组和骨癌痛组又各分为3个亚组(术后7d、14d和21d组),分别用免疫印迹法检测各组大鼠脊髓水平CB2表达的变化,激光共聚焦技术观察CB2的表达部位。结果:免疫印迹结果显示对照组基本没有CB2的表达,与对照组相比,假手术组及骨癌痛组脊髓CB2表达水平升高(P<0.05);与假手术组相比,骨癌痛7d组脊髓CB2蛋白表达明显上调(P<0.05)。激光共聚焦技术显示CB2主要表达于脊髓小胶质细胞和星形胶质细胞。结论:胫骨癌痛大鼠脊髓背角有CB2表达,早期为其表达的高峰,且主要表达于小胶质细胞和星形胶质细胞。     

大麻素受体2在胫骨癌痛大鼠脊髓背角细胞中的表达

目的：观察胫骨癌痛大鼠脊髓大麻素受体2（CB2）表达的变化,探讨CB2在骨癌痛中作用及其可能的脊髓机制。方法：雌性SD大鼠56只,体重160-180g,随机分为7组（n=8）：对照组、假手术组、骨癌痛组,假手术组和骨癌痛组又各分为3个亚组（术后7d、14d和21d组）,分别用免疫印迹法检测各组大鼠脊髓水平CB2表达的变化,激光共聚焦技术观察CB2的表达部位。结果：免疫印迹结果显示对照组基本没有CB2的表达,与对照组相比,假手术组及骨癌痛组脊髓CB2表达水平升高（P〈0.05）;与假手术组相比,骨癌痛7d组脊髓CB2蛋白表达明显上调（P〈0.05）。激光共聚焦技术显示CB2主要表达于脊髓小胶质细胞和星形胶质细胞。结论：胫骨癌痛大鼠脊髓背角有CB2表达,早期为其表达的高峰,且主要表达于小胶质细胞和星形胶质细胞。     

P物质和降钙素基因相关肽在骨癌痛-吗啡耐受模型中的表达

背景与目的:多数晚期癌症患者会经历中重度癌痛折磨。阿片药物是癌痛治疗最常用和最有效的药物,但长时间使用容易造成耐受甚至痛觉过敏。P物质(substance P,SP)和降钙素基因相关肽(calcitonin gene-related peptide,CGRP)是疼痛信号传递中最重要的神经递质,但在癌痛-阿片耐受中的表达尚不清楚。本研究拟在骨癌痛-吗啡耐受大鼠模型上,探讨SP和CGRP在背根神经节(dorsal root ganglion,DRG)水平的表达特点。方法:60只Wistar大鼠鞘内置管成功后,随机分为3组:假手术组、吗啡耐受组和骨癌痛-吗啡耐受组。吗啡耐受组和骨癌痛-吗啡耐受组分别以热灭活Walker256乳腺癌细胞和Walker256乳腺癌细胞制备胫骨癌痛模型,接种后10 d时鞘内注射吗啡20μg/kg。动物行为学测试使用Von Frey纤维丝,于不同时间点测定机械刺激引起的机械缩足阈值。研究结束时,免疫组织化学分析DGR中SP和CGRP的表达,测定积分光密度IOD值。结果:行为学证实,吗啡耐受组和骨癌痛-吗啡耐受组在吗啡治疗第5天时出现耐受,骨癌痛-吗啡耐受组缩足阈值较吗啡耐受组和对照组明显降低(P<0.001)。骨癌痛-吗啡耐受组SP和CGRP积分光密度值IOD(9 917.9±2 246.1和15 021.5±2 989.7)较吗啡耐受组(5 191.7±1 052.6和9 737.1±2 239.8)和对照组(4 821.6±843.1和8 180.3±1 242.2)明显增加(P<0.001)。结论:SP和CGRP在癌痛-吗啡耐受大鼠模型DRG中表达增强,提示这两种神经递质参与了耐受产生,这将为新药治疗癌痛-吗啡耐受提供更符合临床的科学依据。     

Walker 256乳腺癌细胞构建大鼠胫骨骨癌痛模型

目的: 探讨以Walker 256大鼠乳腺癌腹水瘤细胞制备大鼠胫骨骨癌痛模型，为骨癌痛机制和治疗研究提供有用的工具。方法：以Walker 256乳腺癌细胞接种幼年雌性SD鼠腹腔制备腹水瘤细胞，将15 μl腹水瘤细胞注入雌性成年SD鼠左侧胫骨骨髓腔制备骨癌痛模型；以注射加热灭活瘤细胞的     

鞘内注射氟代柠檬酸和/或米诺四环素对骨癌痛小鼠脊髓胶质细胞增殖及活化的影响

[目的]研究鞘内注射星形胶质细胞抑制剂氟代柠檬酸(FC)和/或小胶质细胞特异性抑制剂米诺四环素(MI)对骨癌痛小鼠脊髓胶质细胞增殖及活化的影响。[方法]建立小鼠跟骨癌痛模型。将雄性C3H/He小鼠随机分为6组(n=10),包括:正常组、假手术组、癌痛+人工脑脊液组、癌痛+FC组、癌痛+MI组、癌痛+FC+MI组。术后每天给药1次,持续21d,并于手术当天、术后3、7、14、21d采用免疫荧光法观察各组小鼠脊髓背角小胶质细胞及星形胶质细胞的增殖及活化情况,免疫印迹半定量分析骨癌痛小鼠脊髓腰膨大段星形胶质细胞标志物GFAP及小胶质细胞标志物CD11b的蛋白含量。[结果]⑴免疫荧光法:与正常组相比,癌痛组术后3d脊髓背角小胶质细胞明显被激活,术后14d脊髓背角星形胶质细胞明显被激活。癌痛组内,与ACSF组相比,MI、MI+FC组小鼠脊髓背角术后3d小胶质细胞及MI、FC、MI+FC组术后14d星形胶质细胞的活化均明显被抑制;其中MI+FC组更为显著。⑵免疫印迹结果显示:与术前对照组比较,骨癌痛组术后3d脊髓L4～L5节段小胶质细胞标志物CD11b的蛋白含量明显增加(P<0.05),术后14d星形胶质细胞标志物GFA...     

癌痛的发生机制及其相关药物治疗的研究现状

癌痛是一种机制独特而复杂的慢性疼痛,在动物模型中表现出对痛觉过敏、超敏等疼痛相关行为,其相应的脊髓节段内发生独特的神经化学改变.癌痛的发生与外周传入神经敏化和中枢敏化有关,在癌痛早期,以肿瘤细胞、炎症细胞产生的致痛物质以及破骨细胞的持续活化所致的初级传人神经敏化为主;在癌痛后期,肿瘤生长引起的神经压迫与损伤参与了癌痛的...     

Pathophysiology of bone cancer pain

The most common cancers, such as those affecting the breast, prostate, and lung have a strong predilection to metastasize to bone. Bone metastasis frequently results in pain, pathologic fractures, hypercalcemia, and spinal cord compression. Pain can have a devastating effect on the quality of life in advanced cancer patients and is a serious complication of cancer. Although significant advances are being made in cancer treatment and diagnosis, the basic neurobiology of bone cancer pain is poorly understood. New insights into the mechanisms that induce cancer pain now are coming from animal models.Chemicals derived from tumor cells, inflammatory cells, and cells derived from bone appear to be involved simultaneously in driving this frequently difficult-to-control pain state. Understanding the mechanisms involved in the pathophysiology of bone cancer pain will improve both our ability to provide mechanism-based therapies and the quality of life of cancer patients.     

Bisphosphonate treatment and radiotherapy in metastatic breast cancer

Patients with advanced breast cancer frequently develop metastasis to bone. Bone metastasis results in intractable pain and high risk of pathologic fractures due to osteolysis. The treatment of breast cancer patients with bone metastases requires a multidisciplinary approach. Radiotherapy is an established treatment for metastatic bone pain. It may be delivered either as a localized low dose treatment for localized bone pain or systemically for more widespread symptoms. Bisphosphonates have been shown to reduce morbidity and bone pain from bone metastases when given to patients with metastatic bone disease. In vivo studies indicate that early bisphosphonates administration in combination with radiotherapy improves remineralization and restabilization of osteolytic bone metastases in animal tumor models. This review focused on a brief discussion about biology of bone metastases, the effects of radiotherapy and bisphosphonate therapy, and possible mechanisms of combination therapy in metastatic breast cancer patients.     

A blocking antibody to nerve growth factor attenuates skeletal pain induced by prostate tumor cells growing in bone

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.     

Animal model for mammary tumor growth in the bone microenvironment

Advanced breast cancer commonly spreads to the bones, lungs, liver or brain, and bone is the most common site of breast cancer metastasis. Nearly all patients with advanced breast cancer develop bone metastasis and suffer from serious bone metastasis-associated complications, including chronic pain, fracture, spinal cord compression and hypercalcemia. Metastasis formation in the bone is a complex process that requires cooperative reciprocal interactions between tumor cells and the cellular environment of the bone, which includes osteoclasts and osteoblasts. We have developed a murine bone invasion model of breast cancer, which required a simple surgical technique and mimics the biology of the disease. Osteolytic and/or osteoblastic lesions induced in the tumor-bone interface allowed us to explore cellular and molecular interactions between malignant cells and skeletal tissue in a syngeneic setting. In this review, we will discuss a different animal model that provides a consistent and reproducible platform for investigating the molecular mechanisms underlying tumor–bone interaction and breast cancer-induced osteolytic changes.     

Management of painful bone metastases

PURPOSE OF REVIEW: This review examines recent data on the pathophysiology and mechanisms of bone pain; it highlights the use of multiple and interdisciplinary treatments rather than sole use of traditional analgesics. RECENT FINDINGS: Bone pain has been shown to have a unique pathophysiology. Recent experimental (animal) models have revealed that, parallel to increased bone destruction, ipsilateral spinal cord segments that receive primary input from the cancerous femur exhibit several notable neurochemical changes. These mandate the use of opioid doses sufficient to inhibit the observed nociceptive behaviours; these doses are greater than those required to alleviate pain behaviours of comparable magnitude generated by inflammatory pain. Several substances have been tested in this animal model. SUMMARY: According to new preclinical data, treatment of bone cancer pain requires multidisciplinary therapies such as radiotherapy applied to the painful area along with systemic treatment (hormone therapy or chemotherapy) and supportive care (analgesic therapy and bisphosphonates). In some selected cases use of radioisotopes and other noninvasive or minimally invasive techniques may be useful in the management of metastatic bone pain. The treatment should be individualized according to the patient's clinical condition, life expectancy, and quality of life.     

小鼠跟骨癌性疼痛模型的制备

[目的]复制一个骨癌性疼痛动物模型。[方法]将NCTC2472纤维肉瘤细胞接种到C3H／He小鼠跟骨骨髓腔内,建立骨癌性疼痛动物模型。用von Frey细丝刺激小鼠足底测量机械性痛觉超敏,冷板法测量冷痛觉过敏,组织切片镜下观察肿瘤生长和骨结构的破坏情况。[结果]造模小鼠在3天左右开始出现机械性痛觉超敏，第7天出现冷痛觉过敏,组织学研究显示骨髓腔内肿瘤生长,向外侵蚀破坏骨皮质,10天左右跟骨骨皮质明显破坏。[结论]行为学、组织学研究表明，NCTC2472纤维肉瘤细胞接种到小鼠跟骨骨髓腔的癌性疼痛模型复制成功。     

Intrathecal injection of lentivirus‐mediated glial cell line‐derived neurotrophic factor RNA interference relieves bone cancer‐induced pain in rats

Bone cancer pain is a common symptom in cancer patients with bone metastases and the underlying mechanisms are largely unknown. The aim of this study is to explore the endogenous analgesic mechanisms to develop new therapeutic strategies for bone‐cancer induced pain (BCIP) as a result of metastases. MRMT‐1 tumor cells were injected into bilateral tibia of rats and X‐rays showed that the area suffered from bone destruction, accompanied by an increase in osteoclast numbers. In addition, rats with bone cancer showed apparent mechanical and thermal hyperalgesia at day 28 after intratibial MRMT‐1 inoculation. However, intrathecal injection of morphine or lentivirus‐mediated glial cell line‐derived neurotrophic factor RNAi (Lvs‐siGDNF) significantly attenuated mechanical and thermal hyperalgesia, as shown by increases in paw withdrawal thresholds and tail‐flick latencies, respectively. Furthermore, Lvs‐siGDNF interference not only substantially downregulated GDNF protein levels, but also reduced substance P immunoreactivity and downregulated the ratio of pERK/ERK, where its activation is crucial for pain signaling, in the spinal dorsal horn of this model of bone‐cancer induced pain. In this study, Lvs‐siGDNF gene therapy appeared to be a beneficial method for the treatment of bone cancer pain. As the effect of Lvs‐siGDNF to relieve pain was similar to morphine, but it is not a narcotic, the use of GDNF RNA interference may be considered as a new therapeutic strategy for the treatment of bone cancer pain in the future.