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Retinoblastoma RB94 Enhances Radiation Treatment of Head and Neck Squamous Cell Carcinoma

Authors' Affiliations: ¹ Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; ² Department of Otolaryngology-Head and Neck Surgery, University of Maryland School of Medicine, Baltimore, Maryland; ³ Bray Plastic Surgery Medical Center, Inc., Torrance, California; ⁴ Department of Oral and Maxillofacial Surgery, College of Dental Medicine, Guangxi Medical University, Nanning, Guangxi, P.R. of China; and ⁵ Department of Technology and Product Development, Titan Pharmaceuticals, Inc., South San Francisco, California

Requests for reprints: Daqing Li, Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania School of Medicine, CRB145, 415 Curie Boulevard, Philadelphia, PA 19104. Phone: 215-746-2953; Fax: 215-573-1934; E-mail: lidaqing{at}mail.med.upenn.edu.

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/XRT antitumor 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/XRT resulted 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 XRT alone, Ad-DL312/XRT and 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.