PURPOSE: Local failure and toxicity to adjacent critical structures is a significant problem in radiation therapy of cancers of the head and neck. We are developing a gene therapy based method of sensitizing head/neck squamous cell carcinoma (HNSCC) to radiation treatment. As patients with the rare hereditary disorder, Nijmegen breakage syndrome, show radiation sensitivity we hypothesized that tumor-specific disruption of the function of the Nbs1 protein would lead to enhanced cellular sensitivity to ionizing radiation. EXPERIMENTAL PROCEDURES: We constructed two recombinant adenoviruses by cloning the full-length Nbs1 cDNA as well as the C-terminal 300 amino acids of Nbs1 into an adenovirus backbone under the control of a CMV promoter. The resulting adenoviruses were used to infect HNSCC cell line JHU011. These cells were evaluated for expression of the viral based constructs and assayed for clonogenic survival following radiation exposure. RESULTS: Exposure of cells expressing Nbs1-300 to ionizing radiation resulted in a small reduction in survival relative to cells infected with control virus. Surprisingly, expression of full-length Nbs1 protein resulted in markedly enhanced sensitivity to ionizing radiation. Furthermore, the use of a fractionated radiation scheme following virus infection demonstrates that expression of full-length Nbs1 protein results in significant reduction in cell survival. CONCLUSIONS: These results provide a proof of principle that disruption of Nbs1 function may provide a means of enhancing the radiosensitivity of head and neck tumors. Additionally, this work highlights the Mre11 complex as an attractive target for development of radiation sensitizers.
PURPOSE:Local failure and toxicity to adjacent critical structures is a significant problem in radiation therapy of cancers of the head and neck. We are developing a gene therapy based method of sensitizing head/neck squamous cell carcinoma (HNSCC) to radiation treatment. As patients with the rare hereditary disorder, Nijmegen breakage syndrome, show radiation sensitivity we hypothesized that tumor-specific disruption of the function of the Nbs1 protein would lead to enhanced cellular sensitivity to ionizing radiation. EXPERIMENTAL PROCEDURES: We constructed two recombinant adenoviruses by cloning the full-length Nbs1 cDNA as well as the C-terminal 300 amino acids of Nbs1 into an adenovirus backbone under the control of a CMV promoter. The resulting adenoviruses were used to infect HNSCC cell line JHU011. These cells were evaluated for expression of the viral based constructs and assayed for clonogenic survival following radiation exposure. RESULTS: Exposure of cells expressing Nbs1-300 to ionizing radiation resulted in a small reduction in survival relative to cells infected with control virus. Surprisingly, expression of full-length Nbs1 protein resulted in markedly enhanced sensitivity to ionizing radiation. Furthermore, the use of a fractionated radiation scheme following virus infection demonstrates that expression of full-length Nbs1 protein results in significant reduction in cell survival. CONCLUSIONS: These results provide a proof of principle that disruption of Nbs1 function may provide a means of enhancing the radiosensitivity of head and neck tumors. Additionally, this work highlights the Mre11 complex as an attractive target for development of radiation sensitizers.
Authors: Ananya Choudhury; Louisa D Nelson; Mark T W Teo; Sameer Chilka; Selina Bhattarai; Colin F Johnston; Faye Elliott; Johanna Lowery; Claire F Taylor; Michael Churchman; Johanne Bentley; Margaret A Knowles; Patricia Harnden; Robert G Bristow; D Timothy Bishop; Anne E Kiltie Journal: Cancer Res Date: 2010-09-15 Impact factor: 12.701
Authors: Debanu Das; Davide Moiani; Herbert L Axelrod; Mitchell D Miller; Daniel McMullan; Kevin K Jin; Polat Abdubek; Tamara Astakhova; Prasad Burra; Dennis Carlton; Hsiu-Ju Chiu; Thomas Clayton; Marc C Deller; Lian Duan; Dustin Ernst; Julie Feuerhelm; Joanna C Grant; Anna Grzechnik; Slawomir K Grzechnik; Gye Won Han; Lukasz Jaroszewski; Heath E Klock; Mark W Knuth; Piotr Kozbial; S Sri Krishna; Abhinav Kumar; David Marciano; Andrew T Morse; Edward Nigoghossian; Linda Okach; Jessica Paulsen; Ron Reyes; Christopher L Rife; Natasha Sefcovic; Henry J Tien; Christine B Trame; Henry van den Bedem; Dana Weekes; Qingping Xu; Keith O Hodgson; John Wooley; Marc-André Elsliger; Ashley M Deacon; Adam Godzik; Scott A Lesley; John A Tainer; Ian A Wilson Journal: J Mol Biol Date: 2010-02-01 Impact factor: 5.469
Authors: Toshimitsu Tanaka; Anupama Munshi; Colin Brooks; Jenny Liu; Marvette L Hobbs; Raymond E Meyn Journal: Clin Cancer Res Date: 2008-02-15 Impact factor: 12.531