Adenoviral delivery of Tousled kinase for the protection of salivary glands against ionizing radiation damage

S. Palaniyandi, Y. Odaka, W. Green, F. Abreo, G. Caldito, A. D. Benedetti, G. Sunavala-Dossabhoy

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

Oral complications of salivary hypofunction often afflict cancer patients undergoing radiotherapy for head and neck cancers. Dry mouth or xerostomia is an undesirable consequence of radiotherapy that compromises normal oral functions in addition to causing odynophagia and increasing the patient's risk of oral infections and dental caries. Radiation-induced xerostomia is irreversible, and palliative measures to provide symptomatic relief remain the mainstay of treatment. Previously, we identified a splice variant of a cellular kinase, Tousled-like kinase 1B (TLK1B), which when overexpressed protects normal epithelial cells against ionizing radiation (IR)-induced cell death. To address the need to protect salivary glands in patients undergoing regional radiotherapy, we investigated whether preemptive expression of TLK1B in salivary glands protects against IR. In stably-derived salivary cell lines in vitro, TLK1B expression increased cell survival after IR. Cells expressing exogenous TLK1B were less radiosensitive (A5-TLK1B, α/Β0.67 Gy; ParC5-TLK1B, α/Β4.3 Gy) compared to control cells (A5-BK, α/Β1.7 Gy; ParC5-BK, α/Β32.7 Gy). Using a recombinant adenovirus serotype 5 viral vector for TLK1B gene transfer into rat submandibular salivary glands in vivo, we demonstrated that TLK1B protects the saliva-secreting acinar cells and better preserves salivary gland function against IR relative to control glands. After a single fraction of 16 Gy, the decline in salivary function at 8 weeks was less pronounced in TLK1B-treated animals (40%) as compared to saline-treated controls (67%). Histopathological analysis demonstrated increase in acinar atrophy, decrease in acinar cell number, and increase in inflammatory infiltrate and fibrosis in irradiated control tissues relative to TLK1B-treated glands. These results show the radioprotective benefits of TLK1B and implicate its usefulness in the management of regional radiotherapy-induced xerostomia.

Original languageEnglish
Pages (from-to)275-282
Number of pages8
JournalGene Therapy
Volume18
Issue number3
DOIs
StatePublished - Mar 2011

Bibliographical note

Funding Information:
We thank Dr John Chang and the Radiation Oncology team at LSUHSC-Shreveport for their assistance with dose calculations and radiation of animals. This study was supported by research grants from LSUHSC-Feist Weiller Cancer Center, Shreveport, LA, by the Louisiana Gene Therapy Research Consortium and by the American Cancer Society.

Keywords

  • TLK1
  • Tousled
  • radiation
  • radioresistance
  • salivary glands
  • xerostomia

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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