The Rapalogue, CCI-779, improves salivary gland function following radiation.
The Rapalogue, CCI-779, improves salivary gland function following radiation.
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DOI：
10.1371/journal.pone.0113183
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Limesand KH
中科院分区：
文献类型：
--
作者：
Morgan-Bathke M;Harris ZI;Arnett DG;Klein RR;Burd R;Ann DK;Limesand KH
头颈部癌症的标准治疗通常包括手术切除肿瘤，然后进行靶向头颈部放射治疗。然而，根据肿瘤的位置和阶段，有些病例可能不需要手术切除，而其他病例可能需要放化疗。不幸的是，这些放射治疗会对患者造成慢性负面影响。这些副作用与周围正常唾液腺组织的损伤有关，包括口干、味觉改变和营养不良。慢性辐射诱导的唾液腺功能障碍的潜在机制尚不清楚，然而，在啮齿动物模型中，持续升高的增殖与刺激的唾液流减少相关。CCI-779已用于其他细胞系统中诱导自噬和减少增殖，因此本研究的目的是确定CCI-779是否可用于改善慢性辐射诱导的唾液腺功能障碍。用靶向头部和颈部辐射处理4至6周龄的Atg 5 f/f; Aqp 5-Cre、Atg 5 +/+; Aqp 5-Cre和FVB小鼠。辐射后用CCI-779、氯喹或DMSO治疗FVB小鼠。测定刺激的唾液流率，并收集腮腺和下颌下唾液腺组织进行分析。通过唾液腺中Atg 5的条件性敲除，具有自噬缺陷的小鼠在辐射后24-72小时显示腺泡细胞隔室中的代偿性增殖增加和肥大。用治疗后CCI-779治疗的FVB小鼠在唾液腺生理学方面具有显著改善，如通过刺激的唾液流速、增殖指数和淀粉酶产生和分泌所确定的。因此，放射后使用CCI-779可以改善唾液腺功能并重建腺体稳态。由于CCI-779已经被FDA批准用于其他用途，它可能有二次用途，以减轻已完成抗肿瘤治疗的头颈癌患者的慢性副作用。
The standard of care for head and neck cancer typically includes surgical resection of the tumor followed by targeted head and neck radiation. However depending on tumor location and stage, some cases may not require surgical resection while others may be treated with chemoradiation. Unfortunately, these radiation treatments cause chronic negative side effects for patients. These side effects are associated with damage to surrounding normal salivary gland tissue and include xerostomia, changes in taste and malnutrition. The underlying mechanisms of chronic radiation-induced salivary gland dysfunction are unknown, however, in rodent models persistently elevated proliferation is correlated with reduced stimulated salivary flow. The rapalogue, CCI-779, has been used in other cell systems to induce autophagy and reduce proliferation, therefore the aim of this study was to determine if CCI-779 could be utilized to ameliorate chronic radiation-induced salivary gland dysfunction. Four to six week old Atg5f/f; Aqp5-Cre, Atg5+/+; Aqp5-Cre and FVB mice were treated with targeted head and neck radiation. FVB mice were treated with CCI-779, chloroquine, or DMSO post-radiation. Stimulated salivary flow rates were determined and parotid and submandibular salivary gland tissues were collected for analyses. Mice with a defect in autophagy, via a conditional knockout of Atg5 in the salivary glands, display increased compensatory proliferation in the acinar cell compartment and hypertrophy at 24-72 hours following radiation. FVB mice treated with post-therapy CCI-779 have significant improvements in salivary gland physiology as determined by stimulated salivary flow rates, proliferation indices and amylase production and secretion. Consequently, post-radiation use of CCI-779 allows for improvement of salivary gland function and reestablishment of glandular homeostasis. As CCI-779 is already FDA approved for other uses, it could have a secondary use to alleviate the chronic side effects in head and neck cancer patients who have completed anti-tumor therapy.
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影响因子：
5.7
作者：
Blanchard, Pierre;Baujat, Bertrand;Pignon, Jean-Pierre
通讯作者：
Pignon, Jean-Pierre
影响因子：
1.1
作者：
Cady, Jormain
通讯作者：
Cady, Jormain
影响因子：
4.8
作者：
Henson, BS;Eisbruch, A;Ship, JA
通讯作者：
Ship, JA
DOI：
10.5500/wjt.v4.i2.133
发表时间：
2014-06-24
期刊：
World journal of transplantation
影响因子：
--
作者：
Fernandez-Yunquera, Ainhoa;Ripoll, Cristina;Salcedo, Magdalena
通讯作者：
Salcedo, Magdalena
影响因子：
3.8
作者：
Grundmann O;Fillinger JL;Victory KR;Burd R;Limesand KH
通讯作者：
Limesand KH