title: Prevention of irradiation-induced salivary hypofunction by microvessel protection in mouse salivary glands.
abstract: Treatment of most head and neck cancers includes radiotherapy. Salivary glands (SGs) in the irradiation (IR) field are irreversibly damaged resulting in severe hyposalivation. We evaluated the importance of SG endothelial cells to this IR-induced injury, and whether serotype 5 adenoviral (Ad5) vector-mediated transfer of basic fibroblast growth factor (AdbFGF) or vascular endothelial growth factor (AdVEGF) complementary DNAs would afford radioprotection. Four hours after IR, microvessel density (MVD) in SGs decreased by approximately 45%. However, if mice were pre-treated with either AdVEGF or AdbFGF 48 hours before IR the loss in MVD was significantly reduced. An irrelevant vector, AdLacZ, encoding Escherichia coli beta-galactosidase, was without effect. After 8 weeks, IR reduced salivary flow by approximately 65% in untreated mice. Mice pre-treated (using 5 x 10(9) particles/gland 48 hours prior to IR) with AdLacZ exhibited a reduction in salivary flow similar to untreated mice receiving IR. However, irradiated mice pre-treated with AdbFGF or AdVEGF showed a significant improvement in their salivary flow, to approximately 70% (P < 0.01) and 80% (P < 0.01), respectively, compared to non-irradiated control mice. These results are consistent with the notion that injury to the adjacent microvasculature may play an important role in SG radiation damage. Furthermore, our results suggest that a local transient treatment directed at protecting SG endothelial cells may be beneficial for patients undergoing IR for head and neck cancer.
authors.affiliation: Gene Therapy and Therapeutics Branch, National Institute of Dental and Craniofacial Research, Bethesda, Maryland 20892-1190, USA. acotrim@nih.gov
authors.forename: Ana P
authors.initials: AP
authors.lastname: Cotrim
authors.forename: Anastasia
authors.initials: A
authors.lastname: Sowers
authors.forename: James B
authors.initials: JB
authors.lastname: Mitchell
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Baum
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000502:physiology*; D018076:DNA, Complementary; D016222:Fibroblast Growth Factor 2 / Q000235:genetics; D051379:Mice; D008809:Mice, Inbred C3H; D012469:Salivary Glands / Q000098:blood supply / Q000503:physiopathology / Q000528:radiation effects*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: D018076:DNA, Complementary; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2