Retinoblastoma RB94 enhances radiation Treatment of head and neck squamous cell carcinoma

Koji Araki, Sidrah M. Ahmad, Guoyan Li, David A. Bray, Koichiro Saito, Daiyou Wang, Uwe Wirtz, Sunil Sreedharan, Bert W. O'Malley, Daqing Li

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Abstract

Purpose: To assess whether adenovirus-mediated retinoblastoma 94 (Ad-RB94) transgene expression enhances efficacy of radiation therapy (XRT) of human head and neck squamous cell carcinoma (HNSCC). Experimental Design: The HNSCC cell lines (JHU006 and JHU012) were treated in vitro and in a nude mouse xenograft model with Ad-RB94, Ad-DL312 control vector, or untreated as mock control. Cell viability and tumor growth were evaluated and combined RB94/XRTantitumor activity was analyzed by measuring DNA double-strand breaks, apoptosis-associated early DNA fragmentation, and levels of RB-regulated cell cycle progression E2F1 transcription factor. Results: Ad-RB94/XRTresulted in significant HNSCC cell growth inhibition compared with XRT alone or Ad-RB94 alone in vitro and caused significant tumor regression compared with XRT alone and Ad-DL312/XRT in JHU006 and with XRTalone, Ad-DL312/XRTand Ad-RB94 alone in JHU012 in vivo. Neutral comet analysis revealed that DNA damage was significantly elevated in cells treated with Ad-RB94 alone and Ad-RB94/XRT. Tumors treated with Ad-RB94 alone showed a striking increase in early apoptosis DNA fragmentation, and DNA fragmentation was further enhanced with XRT. In addition, levels of E2F1 were up-regulated by Ad-RB94/XRT combination, whereas Ad-RB94 alone did not affect E2F1 levels and XRT alone led to down-regulation of E2F1. Conclusions: A potent antitumor effect has been observed after Ad-RB94/XRT combination treatment in HNSCC xenograft tumors. Enhanced tumor regression correlated with increased apoptosis. Ad-RB94 treatment enhances the efficacy of XRT through tumor cell sensitization by arresting the cells at the radiation-sensitive G2-M cell cycle and via E2F1 up-regulation.

Original languageEnglish
Pages (from-to)3514-3519
Number of pages6
JournalClinical Cancer Research
Volume14
Issue number11
DOIs
Publication statusPublished - 2008 Jun 1

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Araki, K., Ahmad, S. M., Li, G., Bray, D. A., Saito, K., Wang, D., Wirtz, U., Sreedharan, S., O'Malley, B. W., & Li, D. (2008). Retinoblastoma RB94 enhances radiation Treatment of head and neck squamous cell carcinoma. Clinical Cancer Research, 14(11), 3514-3519. https://doi.org/10.1158/1078-0432.CCR-07-4538