Baum Bruce J, Zheng Changyu, Cotrim Ana P, Goldsmith Corinne M, Atkinson Jane C, Brahim Jaime S, Chiorini John A, Voutetakis Antonis, Leakan Rose Anne, Van Waes Carter, Mitchell James B, Delporte Christine, Wang Songlin, Kaminsky Stephen M, Illei Gabor G
Gene Therapy and Therapeutics Branch, Bethesda, MD 20892-1190, USA.
Biochim Biophys Acta. 2006 Aug;1758(8):1071-7. doi: 10.1016/j.bbamem.2005.11.006. Epub 2005 Dec 5.
The treatment of most patients with head and neck cancer includes ionizing radiation (IR). Salivary glands in the IR field suffer significant and irreversible damage, leading to considerable morbidity. Previously, we reported that adenoviral (Ad)-mediated transfer of the human aquaporin-1 (hAQP1) cDNA to rat [C. Delporte, B.C. O'Connell, X. He, H.E. Lancaster, A.C. O'Connell, P. Agre, B.J. Baum, Increased fluid secretion after adenoviral-mediated transfer of the aquaporin-1 cDNA to irradiated rat salivary glands. Proc. Natl. Acad. Sci. U S A. 94 (1997) 3268-3273] and miniature pig [Z. Shan, J. Li, C. Zheng, X. Liu, Z. Fan, C. Zhang, C.M. Goldsmith, R.B. Wellner, B.J Baum, S. Wang. Increased fluid secretion after adenoviral-mediated transfer of the human aquaporin-1 cDNA to irradiated miniature pig parotid glands. Mol. Ther. 11 (2005) 444-451] salivary glands approximately 16 weeks following IR resulted in a dose-dependent increase in salivary flow to > or =80% control levels on day 3. A control Ad vector was without any significant effect on salivary flow. Additionally, after administration of Ad vectors to salivary glands, no significant lasting effects were observed in multiple measured clinical chemistry and hematology values. Taken together, the findings show that localized delivery of AdhAQP1 to IR-damaged salivary glands is useful in transiently increasing salivary secretion in both small and large animal models, without significant general adverse events. Based on these results, we are developing a clinical trial to test if the hAQP1 cDNA transfer strategy will be clinically effective in restoring salivary flow in patients with IR-induced parotid hypofunction.
大多数头颈癌患者的治疗都包括电离辐射（IR）。位于辐射区域内的唾液腺会遭受严重且不可逆的损伤，从而导致相当大的发病率。此前，我们报道过，在大鼠[C. 德尔波特，B.C. 奥康奈尔，X. 何，H.E. 兰卡斯特，A.C. 奥康奈尔，P. 阿格雷，B.J. 鲍姆，腺病毒介导的水通道蛋白-1（hAQP1）cDNA转导至受辐射大鼠唾液腺后唾液分泌增加。《美国国家科学院院刊》94（1997）3268 - 3273]和小型猪[Z. 单，J. 李，C. 郑，X. 刘，Z. 范，C. 张，C.M. 戈德史密斯，R.B. 韦尔纳，B.J. 鲍姆，S. 王。腺病毒介导的人水通道蛋白-1 cDNA转导至受辐射小型猪腮腺后唾液分泌增加。《分子治疗》11（2005）444 - 451]的唾液腺中，在辐射后约16周进行腺病毒（Ad）介导的人水通道蛋白-1（hAQP1）cDNA转导，结果在第3天唾液流量呈剂量依赖性增加至对照水平的≥80%。对照腺病毒载体对唾液流量无任何显著影响。此外，在向唾液腺施用腺病毒载体后，在多项检测的临床化学和血液学值中未观察到显著的持久影响。综上所述，这些发现表明，将AdhAQP1局部递送至受辐射损伤的唾液腺，在小型和大型动物模型中均可有效短暂增加唾液分泌，且无明显的全身性不良事件。基于这些结果，我们正在开展一项临床试验，以测试hAQP1 cDNA转导策略在恢复因辐射导致腮腺功能减退患者的唾液流量方面是否具有临床疗效。
