Walker Katharine, Medhurst Stephen J, Kidd Bruce L, Glatt Markus, Bowes Mick, Patel Sadhana, McNair Kara, Kesingland Adam, Green Jonathan, Chan Otto, Fox Alyson J, Urban Laszlo A
Purdue Biopharma LP, 201 College Road East, Princeton, NJ 08540, USA Novartis Institute for Medical Sciences, 5 Gower Place, London WC1E 6BN, UK W. Harvey Research Institute, St Bartholomew's and Royal London School of Medicine, Charterhouse Square, London, UK Novartis Pharma AG, Basel, Switzerland.
Pain. 2002 Dec;100(3):219-229. doi: 10.1016/S0304-3959(02)00040-4.
Inoculation of syngeneic MRMT-1 mammary tumour cells into one tibia of female rats produced tumour growth within the bone associated with a reduction in bone mineral density (BMD) and bone mineral content (BMC), severe radiological signs of bone destruction, together with the development of behavioural mechanical allodynia and hyperalgesia. Histological and radiological examination showed that chronic treatment with the bisphosphonate, zoledronic acid (30 microg/kg, s.c.), for 19 days significantly inhibited tumour proliferation and preserved the cortical and trabecular bone structure. In addition, BMD and BMC were preserved and a dramatic reduction of tartrate resistant acid phosphatase-positive polykaryocytes (osteoclasts) was observed. In behavioural tests, chronic treatment with zoledronic acid but not the significantly less effective bisphosphonate, pamidronate, or the selective COX-2 inhibitor, celebrex, attenuated mechanical allodynia and hyperalgesia in the affected hind paw. Zoledronic acid also attenuated mechanical hyperalgesia associated with chronic peripheral neuropathy and inflammation in the rat. In contrast, pamidronate or clodronate did not have any anti-hyperalgesic effect on mechanical hyperalgesia in the neuropathic and inflammatory pain models. We conclude that zoledronic acid, in addition to, or independent from, its anti-metastatic and bone preserving therapeutic effects, is an anti-nociceptive agent in a rat model of metastatic cancer pain. This unique property of zoledronic acid amongst the bisphosphonate class of compounds could make this drug a preferred choice for the treatment of painful bone metastases in the clinic.
将同基因MRMT - 1乳腺肿瘤细胞接种到雌性大鼠的一根胫骨中，会导致骨内肿瘤生长，同时伴有骨矿物质密度（BMD）和骨矿物质含量（BMC）降低、严重的骨破坏放射学征象，以及行为性机械性异常性疼痛和痛觉过敏的出现。组织学和放射学检查显示，用双膦酸盐唑来膦酸（30微克/千克，皮下注射）进行19天的慢性治疗可显著抑制肿瘤增殖，并保留皮质和小梁骨结构。此外，BMD和BMC得以保留，且观察到抗酒石酸酸性磷酸酶阳性多核细胞（破骨细胞）显著减少。在行为测试中，用唑来膦酸进行慢性治疗可减轻患侧后爪的机械性异常性疼痛和痛觉过敏，而用效果明显较差的双膦酸盐帕米膦酸或选择性COX - 2抑制剂塞来昔布进行慢性治疗则无此效果。唑来膦酸还可减轻与大鼠慢性周围神经病变和炎症相关的机械性痛觉过敏。相比之下，帕米膦酸或氯膦酸在神经病理性和炎症性疼痛模型中对机械性痛觉过敏没有任何抗痛觉过敏作用。我们得出结论，唑来膦酸除了具有抗转移和保骨治疗作用外，或独立于这些作用之外，在转移性癌痛大鼠模型中还是一种抗伤害感受剂。唑来膦酸在双膦酸盐类化合物中的这种独特性质可能使其成为临床上治疗疼痛性骨转移的首选药物。
