Document Detail


Recombinant AAV9-TLK1B administration ameliorates fractionated radiation-induced xerostomia.
MedLine Citation:
PMID:  23614651     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Salivary glands are highly susceptible to radiation, and patients with head and neck cancer treated with radiotherapy invariably suffer from its distressing side effect, salivary hypofunction. The reduction in saliva disrupts oral functions, and significantly impairs oral health. Previously, we demonstrated that adenoviral-mediated expression of Tousled-like kinase 1B (TLK1B) in rat submandibular glands preserves salivary function after single-dose ionizing radiation. To achieve long-term transgene expression for protection of salivary gland function against fractionated radiation, this study examines the usefulness of recombinant adeno-associated viral vector for TLK1B delivery. Lactated Ringers or AAV2/9 with either TLK1B or GFP expression cassette were retroductally delivered to rat submandibular salivary glands (10(11) vg/gland), and animals were exposed, or not, to 20 Gy in eight fractions of 2.5 Gy/day. AAV2/9 transduced predominantly the ductal cells, including the convoluted granular tubules of the submandibular glands. Transgene expression after virus delivery could be detected within 5 weeks, and stable gene expression was observed till the end of study. Pilocarpine-stimulated saliva output measured at 8 weeks after completion of radiation demonstrated >10-fold reduction in salivary flow in saline- and AAV2/9-GFP-treated animals compared with the respective nonirradiated groups (90.8% and 92.5% reduction in salivary flow, respectively). Importantly, there was no decrease in stimulated salivary output after irradiation in animals that were pretreated with AAV2/9-TLK1B (121.5% increase in salivary flow; p<0.01). Salivary gland histology was better preserved after irradiation in TLK1B-treated group, though not significantly, compared with control groups. Single preemptive delivery of AAV2/9-TLK1B averts salivary dysfunction resulting from fractionated radiation. Although AAV2/9 transduces mostly the ductal cells of the gland, their protection against radiation assists in preserving submandibular gland function. AAV2/9-TLK1B treatment could prove beneficial in attenuating xerostomia in patients with head and neck cancer undergoing radiotherapy.
Authors:
Prakash Srinivasan Timiri Shanmugam; Robert D Dayton; Senthilnathan Palaniyandi; Fleurette Abreo; Gloria Caldito; Ronald L Klein; Gulshan Sunavala-Dossabhoy
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Human gene therapy     Volume:  24     ISSN:  1557-7422     ISO Abbreviation:  Hum. Gene Ther.     Publication Date:  2013 Jun 
Date Detail:
Created Date:  2013-06-19     Completed Date:  2014-04-17     Revised Date:  2014-06-03    
Medline Journal Info:
Nlm Unique ID:  9008950     Medline TA:  Hum Gene Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  604-12     Citation Subset:  IM    
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Acinar Cells / pathology
Animals
Cell Line
Dependovirus / metabolism*
Dose Fractionation*
Genetic Vectors
HEK293 Cells
Humans
Male
Protein-Serine-Threonine Kinases / metabolism*
Radiation Injuries / physiopathology,  therapy*
Rats
Rats, Sprague-Dawley
Recombination, Genetic / genetics*
Salivation
Submandibular Gland / metabolism,  pathology,  physiopathology,  radiation effects
Transduction, Genetic
Transgenes
Xerostomia / etiology*,  physiopathology,  therapy*
Chemical
Reg. No./Substance:
EC 2.7.11.1/Protein-Serine-Threonine Kinases
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  Use of a biosimilar granulocyte colony-stimulating factor for peripheral blood stem cell mobilizatio...
Next Document:  Conversion of Aristolochic Acid I into Aristolic Acid by Reaction with Cysteine and Glutathione: Bio...