Prevention of radiation-induced salivary hypofunction following hKGF gene delivery to murine submandibular glands.
Prevention of radiation-induced salivary hypofunction following hKGF gene delivery to murine submandibular glands.
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DOI：
10.1158/1078-0432.ccr-10-2982
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发表时间：
2011-05-01
期刊：
影响因子：
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通讯作者：
Baum BJ
中科院分区：
文献类型：
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作者：
Zheng C;Cotrim AP;Rowzee A;Swaim W;Sowers A;Mitchell JB;Baum BJ
头颈部癌症患者接受放射治疗时，唾液腺会受到显著影响。我们评估了人角质细胞生长因子（hKGF）基因转移到小鼠唾液腺对预防放射诱导的唾液腺功能减退的影响。构建hKGF 5型腺病毒载体（AdLTR 2 EF 1 α-hKGF）。通过单次（15戈伊）或分次（6戈伊，5天）剂量照射8周龄雌性C3 H小鼠，以诱导唾液功能减退。在照射（IR）前，通过逆行导管滴注将AdLTR 2 EF 1 α-hKGF或AdControl（每个腺体108 - 1010个颗粒）给予两个下颌下腺（SG）。唾液流量测量后毛果芸香碱刺激。通过ELISA测量人KGF水平。SG细胞增殖用溴脱氧尿苷标记。用流式细胞术检测SGs中的内皮细胞和祖细胞或干细胞。评估SG hKGF产生对鳞状细胞癌（SCC VII）肿瘤生长的影响。在3个单独的单剂量IR实验中，AdLTR 2 EF 1 α-hKGF载体给药小鼠的唾液流速与未照射对照小鼠无显著差异（P > 0.05）。类似地，在3个单独的分级IR实验中，hKGF表达载体显著预防唾液功能减退。在血清和SG提取物中发现高水平的转基因hKGF蛋白。AdLTR 2 EF 1 α-hKGF处理的小鼠与AdControl处理的小鼠相比，细胞增殖和内皮细胞数量增加。hKGF基因转移对SCC VII肿瘤生长±放射无影响。hKGF基因转移预防小鼠中由单次或分次辐射剂量引起的唾液功能减退。研究结果表明，潜在的临床应用。
Salivary glands are significantly affected when head and neck cancer patients are treated by radiation. We evaluated the effect of human keratinocyte growth factor (hKGF) gene transfer to murine salivary glands on the prevention of radiation-induced salivary hypofunction. A hybrid serotype 5 adenoviral vector encoding hKGF (AdLTR2EF1α-hKGF) was constructed. Female C3H mice, 8 weeks old, were irradiated by single (15 Gy) or fractionated (6 Gy for 5 days) doses to induce salivary hypofunction. AdLTR2EF1α-hKGF or AdControl was administered (108 – 1010 particles per gland) to both submandibular glands (SG) by retrograde ductal instillation before irradiation (IR). Salivary flow was measured following pilocarpine stimulation. Human KGF levels were measured by ELISA. SG cell proliferation was measured with bromodeoxyuridine labeling. Endothelial and progenitor or stem cells in SGs were measured by flow cytometry. The effect of SG hKGF production on squamous cell carcinoma (SCC VII) tumor growth was assessed. In 3 separate single-dose IR experiments, salivary flow rates of mice administered the AdLTR2EF1α-hKGF vector were not significantly different from nonirradiated control mice (P > 0.05). Similarly, in 3 separate fractionated IR experiments, the hKGF-expressing vector prevented salivary hypofunction dramatically. Transgenic hKGF protein was found at high levels in serum and SG extracts. AdLTR2EF1α-hKGF–treated mice showed increased cell proliferation and numbers of endothelial cells, compared with mice treated with AdControl. hKGF gene transfer had no effect on SCC VII tumor growth ± radiation. hKGF gene transfer prevents salivary hypofunction caused by either single or fractionated radiation dosing in mice. The findings suggest a potential clinical application.