Abstract

The efficacy of radiotherapy is limited ultimately by normal tissue toxicity. For many tissues, commonly-used assays of radiation injury are based on functional endpoints. A better understanding of the production and repair of radiation damage at the genomic level of both normal and tumor tissues is the key to development of nev strategies to increase the therapeutic ratio. In this project we propose to study the question using the technique of premature chromosome condensation to directly measure chromosome damage and repair in normal and tumor tissues after in vivo irradiation. In particular, we propose to determine the amount of initial in vivo chromosome damage and the rate and extent of its repair in three rodent normal tissues (lung, liver, and CNS) and two human tumor xenografts; determine the effect of fractionated radiation doses on the accumulation and repair of chromosome damage; and determine whether repair inhibition (5FU and F-AraA) can differently alter chromosome damage accumulation in normal and tumor tissues.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
3P01CA006294-34S1
Application #
5206395
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
34
Fiscal Year
1996
Total Cost
Indirect Cost

  Publications

Edmondson, Elijah F; Hunter, Nancy R; Weil, Michael M et al. (2015) Tumor Induction in Mice After Localized Single- or Fractionated-Dose Irradiation: Differences in Tumor Histotype and Genetic Susceptibility Based on Dose Scheduling. Int J Radiat Oncol Biol Phys 92:829-36
Neskey, David M; Osman, Abdullah A; Ow, Thomas J et al. (2015) Evolutionary Action Score of TP53 Identifies High-Risk Mutations Associated with Decreased Survival and Increased Distant Metastases in Head and Neck Cancer. Cancer Res 75:1527-36
Keck, Michaela K; Zuo, Zhixiang; Khattri, Arun et al. (2015) Integrative analysis of head and neck cancer identifies two biologically distinct HPV and three non-HPV subtypes. Clin Cancer Res 21:870-81
Alsbeih, Ghazi; Brock, Williams; Story, Michael (2014) Misrepair of DNA double-strand breaks in patient with unidentified chromosomal fragility syndrome and family history of radiosensitivity. Int J Radiat Biol 90:53-9
Komaki, Ritsuko; Paulus, Rebecca; Blumenschein Jr, George R et al. (2014) EGFR expression and survival in patients given cetuximab and chemoradiation for stage III non-small cell lung cancer: a secondary analysis of RTOG 0324. Radiother Oncol 112:30-6
Cortez, Maria Angelica; Valdecanas, David; Zhang, Xiaochun et al. (2014) Therapeutic delivery of miR-200c enhances radiosensitivity in lung cancer. Mol Ther 22:1494-1503
Bhardwaj, Vikas; Cascone, Tina; Cortez, Maria Angelica et al. (2013) Modulation of c-Met signaling and cellular sensitivity to radiation: potential implications for therapy. Cancer 119:1768-75
Raju, Uma; Riesterer, Oliver; Wang, Zhi-Qiang et al. (2012) Dasatinib, a multi-kinase inhibitor increased radiation sensitivity by interfering with nuclear localization of epidermal growth factor receptor and by blocking DNA repair pathways. Radiother Oncol 105:241-9
Thariat, Juliette; Ang, K Kian; Allen, Pamela K et al. (2012) Prediction of neck dissection requirement after definitive radiotherapy for head-and-neck squamous cell carcinoma. Int J Radiat Oncol Biol Phys 82:e367-74
Skinner, Heath D; Sandulache, Vlad C; Ow, Thomas J et al. (2012) TP53 disruptive mutations lead to head and neck cancer treatment failure through inhibition of radiation-induced senescence. Clin Cancer Res 18:290-300

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