Kumar Pawan, Gao Qinghong, Ning Yu, Wang Zhuo, Krebsbach Paul H, Polverini Peter J
Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, 1011 North University Avenue, Room no. 5205, Ann Arbor, MI 48109, USA.
Mol Cancer Ther. 2008 Jul;7(7):2060-9. doi: 10.1158/1535-7163.MCT-08-0287.
Therapeutic radiation is commonly used in the treatment of squamous cell carcinoma of the oral cavity and pharynx. Despite the proven efficacy of this form of anticancer therapy, high-dose radiation treatment is invariably associated with numerous unwanted side effects. This is particularly true for bone, in which radiation treatment often leads to osteoradionecrosis. The aim of this study was to investigate if treatment with arsenic trioxide (As(2)O(3)) could enhance the antitumor effect of radiotherapy whereas minimizing the destructive effects of radiation on bone. As(2)O(3) treatment induced a dose-dependent (1-20 mumol/L) inhibition of endothelial and tumor cell (OSCC-3 and UM-SCC-74A) survival and significantly enhanced radiation-induced endothelial cell and tumor cell death. In contrast, As(2)O(3) treatment (0.5-7.5 mumol/L) induced the proliferation of osteoblasts and also protected osteoblasts against radiation-induced cell death. Furthermore, As(2)O(3) treatment was able to significantly enhance radiation-induced inhibition of endothelial cell tube formation and tumor cell colony formation. To test the effectiveness of As(2)O(3) and radiation treatment in vivo, we used a severe combined immunodeficiency mouse model that has a bone ossicle and tumor growing side by side subcutaneously. Animals treated with As(2)O(3) and radiation showed a significant inhibition of tumor growth, tumor angiogenesis, and tumor metastasis to the lungs as compared with As(2)O(3) treatment or radiation treatment alone. In contrast, As(2)O(3) treatment protected bone ossicles from radiation-induced bone loss. These results suggest a novel strategy to enhance the therapeutic efficacy of radiation treatment while protecting bone from the adverse effects of therapeutic radiation.
放射治疗常用于口腔和咽鳞状细胞癌的治疗。尽管这种抗癌治疗形式已被证实有效，但高剂量放射治疗总是伴随着许多不良副作用。对于骨骼来说尤其如此，放射治疗常常导致放射性骨坏死。本研究的目的是调查三氧化二砷（As₂O₃）治疗是否能增强放射治疗的抗肿瘤效果，同时将辐射对骨骼的破坏作用降至最低。As₂O₃治疗诱导内皮细胞和肿瘤细胞（OSCC - 3和UM - SCC - 74A）存活呈剂量依赖性（1 - 20 μmol/L）抑制，并显著增强辐射诱导的内皮细胞和肿瘤细胞死亡。相比之下，As₂O₃治疗（0.5 - 7.5 μmol/L）诱导成骨细胞增殖，并保护成骨细胞免受辐射诱导的细胞死亡。此外，As₂O₃治疗能够显著增强辐射诱导的内皮细胞管形成抑制和肿瘤细胞集落形成抑制。为了在体内测试As₂O₃和放射治疗的有效性，我们使用了一种严重联合免疫缺陷小鼠模型，该模型皮下同时生长有骨小体和肿瘤。与单独使用As₂O₃治疗或放射治疗相比，接受As₂O₃和放射治疗的动物显示出肿瘤生长、肿瘤血管生成以及肿瘤向肺部转移均受到显著抑制。相比之下，As₂O₃治疗保护骨小体免受辐射诱导的骨质流失。这些结果提示了一种新的策略，可增强放射治疗的疗效，同时保护骨骼免受放射治疗的不良影响。
