Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
J Orthop Res. 2014 Mar;32(3):464-70. doi: 10.1002/jor.22527. Epub 2013 Nov 20.
Osteosarcoma (OS) is the most common malignant bone tumor affecting children and adolescents. Many patients are treated with a combination of chemotherapy, resection, and limb salvage protocols. Surgical reconstructions after tumor resection include structural allografts, non-cemented endoprostheses, and distraction osteogenesis (DO), which require direct bone formation. Although cisplatin (CDP) is extensively used for OS chemotherapy, the effects on bone regeneration are not well studied. The effects of CDP on direct bone formation in DO were compared using two dosing regimens and both C57BL/6 (B6) and tumor necrosis factor receptor 1 knockout (TNFR1KO) mice, as CDP toxicity is associated with elevated TNF levels. Detailed evaluation of the five-dose CDP regimen (2 mg/kg/day), demonstrated significant decreases in new bone formation in the DO gaps of CDP treated versus vehicle treated mice (p < 0.001). Further, no significant inhibitory effects from the five-dose CDP regimen were observed in TNFR1KO mice. The two-dose regimen significantly inhibited new bone formation in B6 mice. These results demonstrate that CDP has profound short term negative effects on the process of bone repair in DO. These data provide the mechanistic basis for modeling peri-operative chemotherapy doses and schedules and may provide new opportunities to identify molecules that spare normal cells from the inhibitory effects of CDP.
骨肉瘤（OS）是儿童和青少年中最常见的恶性骨肿瘤。许多患者接受化疗、切除和保肢方案的联合治疗。肿瘤切除后的手术重建包括结构性同种异体移植物、非骨水泥型假体和骨延长（DO），这些方法都需要直接骨形成。顺铂（CDP）广泛用于骨肉瘤的化疗，但对骨再生的影响尚未得到充分研究。本研究比较了两种剂量方案和 C57BL/6（B6）和肿瘤坏死因子受体 1 敲除（TNFR1KO）小鼠中 CDP 对 DO 中直接骨形成的影响，因为 CDP 毒性与 TNF 水平升高有关。对五剂量 CDP 方案（2mg/kg/天）的详细评估表明，与对照组相比，CDP 治疗组 DO 间隙中的新骨形成明显减少（p<0.001）。此外，在 TNFR1KO 小鼠中未观察到五剂量 CDP 方案的显著抑制作用。两剂量方案显著抑制了 B6 小鼠的新骨形成。这些结果表明，CDP 对 DO 中骨修复过程有短期的负面影响。这些数据为模拟围手术期化疗剂量和方案提供了机制基础，并可能为识别使正常细胞免受 CDP 抑制作用的分子提供新的机会。
