Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
J Neurosurg Spine. 2012 Apr;16(4):365-72. doi: 10.3171/2011.12.SPINE11496. Epub 2012 Jan 20.
Recombinant human bone morphogenetic proteins (rhBMPs) are FDA-approved for specific spinal fusion procedures, but their use is contraindicated in spine tumor resection beds because of an unclear interaction between tumor tissue and such growth factors. Interestingly, a number of studies have suggested that BMPs may slow the growth of adenocarcinomas in vitro, and these lesions represent the majority of bony spine tumors. In this study, the authors hypothesized that rhBMP-2 placed in an intraosseous spine tumor in the rat could suppress tumor and delay the onset of paresis in such animals.
Twenty-six female nude athymic rats were randomized into an experimental group (Group 1) or a positive control group (Group 2). Group 1 (tumor + 15 μg rhBMP-2 sponge, 13 rats) underwent transperitoneal exposure and implantation of breast adenocarcinoma (CRL-1666) into the L-6 spine segment, followed by the implantation of a bovine collagen sponge impregnated with 15 μg of rhBMP-2. Group 2 (tumor + 0.9% NaCl sponge, 13 rats) underwent transperitoneal exposure and tumor implantation in the lumbar spine but no local treatment with rhBMP-2. An additional 8 animals were randomized into 2 negative control groups (Groups 3 and 4). Group 3 (15 μg rhBMP-2 sponge, 4 rats) and Group 4 (0.9% NaCl sponge, 4 rats) underwent transperitoneal exposure of the lumbar spine along with the implantation of rhBMP-2- and saline-impregnated bovine collagen sponges, respectively. Neither of the negative control groups was implanted with tumor. The Basso-Beattie-Bresnahan (BBB) scale was used to monitor daily motor function regression and the time to paresis (BBB score ≤ 7).
In comparison with the positive control animals (Group 2), the experimental animals (Group 1) had statistically significant longer mean (25.8 ± 12.2 vs 13 ± 1.4 days, p ≤ 0.001) and median (20 vs 13 days) times to paresis. In addition, the median survival time was significantly longer in the experimental animals (20 vs 13.5 days, p ≤ 0.0001). Histopathological analysis demonstrated bone growth and tumor inhibition in the experimental animals, whereas bone destruction and cord compression were observed in the positive control animals. Neither of the negative control groups (Groups 3 and 4) demonstrated any evidence of neurological deterioration, morbidity, or cord compromise on either gross or histological analysis.
This study shows that the local administration of rhBMP-2 (15 μg, 10 μl of 1.5-mg/ml solution) in a rat spine tumor model of breast cancer not only fails to stimulate local tumor growth, but also decreases local tumor growth and delays the onset of paresis in rats. This preclinical experiment is the first to show that the local placement of rhBMP-2 in a spine tumor bed may slow tumor progression and delay associated neurological decline.
重组人骨形态发生蛋白（rhBMPs）已获得 FDA 批准用于特定的脊柱融合手术，但由于肿瘤组织与这些生长因子之间的相互作用尚不清楚，其在脊柱肿瘤切除部位的使用是禁忌的。有趣的是，许多研究表明，BMPs 可能会减缓体外腺癌的生长，而这些病变是大多数骨脊柱肿瘤的代表。在这项研究中，作者假设 rhBMP-2 置于大鼠的骨内脊柱肿瘤中，可以抑制肿瘤并延迟此类动物的瘫痪发作。
将 26 只雌性无胸腺裸鼠随机分为实验组（第 1 组）或阳性对照组（第 2 组）。第 1 组（肿瘤+ 15 μg rhBMP-2 海绵，13 只大鼠）经腹膜暴露和 L-6 脊柱段植入乳腺癌（CRL-1666），然后植入牛胶原蛋白海绵，其中浸渍有 15 μg rhBMP-2。第 2 组（肿瘤+ 0.9%NaCl 海绵，13 只大鼠）经腹膜暴露并在腰椎中植入肿瘤，但局部未用 rhBMP-2 治疗。另外 8 只动物被随机分为 2 个阴性对照组（第 3 组和第 4 组）。第 3 组（15 μg rhBMP-2 海绵，4 只大鼠）和第 4 组（0.9%NaCl 海绵，4 只大鼠）分别经腹膜暴露腰椎，并植入 rhBMP-2 和生理盐水浸渍的牛胶原蛋白海绵。阴性对照组均未植入肿瘤。Basso-Beattie-Bresnahan（BBB）量表用于监测每日运动功能的消退和瘫痪的发生时间（BBB 评分≤7）。
与阳性对照组动物（第 2 组）相比，实验组动物（第 1 组）的瘫痪发生时间具有统计学意义的延长（平均 25.8±12.2 天比 13±1.4 天，p≤0.001）和中位数（20 天比 13 天）。此外，实验组的中位生存时间明显延长（20 天比 13.5 天，p≤0.0001）。组织病理学分析表明，实验组动物中存在骨生长和肿瘤抑制，而阳性对照组动物中则出现骨破坏和脊髓压迫。阴性对照组（第 3 组和第 4 组）的动物在大体或组织学分析中均未出现任何神经恶化、发病或脊髓受压的迹象。
本研究表明，在乳腺癌大鼠脊柱肿瘤模型中局部给予 rhBMP-2（15μg，1.5mg/ml 溶液 10μl）不仅不能刺激局部肿瘤生长，反而能减少局部肿瘤生长并延迟大鼠瘫痪的发生。这项临床前实验首次表明，rhBMP-2 在脊柱肿瘤床内的局部放置可能会减缓肿瘤进展并延迟相关的神经功能下降。
