INSULIN-LIKE GROWTH FACTOR-1 PRESERVES SALIVARY GLAND FUNCTION AFTER FRACTIONATED RADIATION
INSULIN-LIKE GROWTH FACTOR-1 PRESERVES SALIVARY GLAND FUNCTION AFTER FRACTIONATED RADIATION
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DOI：
10.1016/j.ijrobp.2010.03.035
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发表时间：
2010-10-01
影响因子：
7
通讯作者：
Klein, Rob R.
中科院分区：
文献类型：
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作者：
Limesand, Kirsten H.;Avila, Jennifer L.;Klein, Rob R.
目的：头颈癌的放射治疗包括分割放射治疗，这种放射治疗会对唾液腺造成重大损害，导致慢性唾液腺功能障碍，目前预防和治疗方案有限。这项研究在临床前模型中探讨了IGF-1在分次放射治疗方案后保留唾液腺功能的可行性。方法和材料：小鼠接受分次放射治疗，评估唾液腺功能和组织学结构、细胞凋亡和增殖的分析。结果：在本研究中，我们报道了分次放射治疗后FVB小鼠明显的细胞凋亡水平，在表达Akt1的组成活性突变体(MYR-Akt1)的转基因小鼠中显著减少。照射后FVB小鼠的唾液腺功能显著降低，而MYR-Akt1转基因小鼠在相同的治疗条件下仍能保持唾液功能。向FVB小鼠注射重组胰岛素样生长因子-1(IGF-1)，可激活内源性Akt，抑制急性细胞凋亡，并在治疗后30至90天分次剂量照射后保留唾液腺功能。FVB小鼠暴露于分割辐射后90天，唾液腺泡细胞增殖细胞核抗原阳性细胞水平显著降低，这与慢性功能丧失有关。相反，每次放射治疗前注射IGF-1的FVB小鼠表现出与未治疗对照组相似的腺泡细胞增殖率。结论：这些研究表明，头颈部放射治疗前激活IGF-1介导的通路可以调节放射诱导的唾液腺功能障碍，维持腺体稳态。(C)2010年爱思唯尔公司。
Purpose: Radiotherapy for head-and-neck cancer consists of fractionated radiation treatments that cause significant damage to salivary glands leading to chronic salivary gland dysfunction with only limited prevention and treatment options currently available. This study examines the feasibility of IGF-1 in preserving salivary gland function following a fractionated radiation treatment regimen in a pre-clinical model.Methods and Materials: Mice were exposed to fractionated radiation, and salivary gland function and histological analyses of structure, apoptosis, and proliferation were evaluated.Results: In this study, we report that treatment with fractionated doses of radiation results in a significant level of apoptotic cells in FVB mice after each fraction, which is significantly decreased in transgenic mice expressing a constitutively active mutant of Akt1 (myr-Akt1). Salivary gland function is significantly reduced in FVB mice exposed to fractionated radiation; however, myr-Akt1 transgenic mice maintain salivary function under the same treatment conditions. Injection into FVB mice of recombinant insulin-like growth factor-1 (IGF-1), which activates endogenous Akt, suppressed acute apoptosis and preserved salivary gland function after fractionated doses of radiation 30 to 90 days after treatment. FVB mice exposed to fractionated radiation had significantly lower levels of proliferating cell nuclear antigen positive salivary acinar cells 90 days after treatment, which correlated with a chronic loss of function. In contrast, FVB mice injected with IGF-1 before each radiation treatment exhibited acinar cell proliferation rates similar to those of untreated controls.Conclusion: These studies suggest that activation of IGF-1-mediated pathways before head-and-neck radiation could modulate radiation-induced salivary gland dysfunction and maintain glandular homeostasis. (C) 2010 Elsevier Inc.