Virally directed cytosine deaminase/5-fluorocytosine gene therapy enhances radiation response in human cancer xenografts

Nader N. Hanna, Helena J. Mauceri, Jeffery D. Wayne, Dennis E. Hallahan, Donald W. Kufe, Ralph R. Weichselbaum*

*Corresponding author for this work

Research output: Contribution to journalArticle

83 Scopus citations

Abstract

Gene therapy combined with radiation therapy to enhance selectively radiation cytotoxicity in malignant cells represents a new approach for cancer treatment. We investigated the efficacy of adenoviral (Ad5)-directed cytosine deaminase/5-fluorocytosine (CD/5-FC) enzyme/prodrug gene therapy to enhance selectively the tumoricidal action of ionizing radiation in human cancer xenografts derived from a human squamous carcinoma cell line (SQ- 20B). Tumor xenografts grown in hindlimbs of nude mice were transfected with an adenoviral vector (Ad.CMV.CD) containing the cytosine deaminase (CD) gene under the control of a cytomegalovirus (CMV) promoter. Mice were injected i.p. with 800 mg/kg of 5-FC for 12 days, and tumors were treated with fractionated radiation at a dose of 5 Gy/day to a total dose of 50 Gy. In larger tumors with a mean volume of 1069 mm3, marked tumor regression to 11% of the original tumor volume was observed at day 21 (P = 0.01). The volumetric regression of smaller tumors with a mean volume of 199 mm3, which received the same combined treatment protocol, was significant at day 12 (P = 0.014). However, unlike large tumors, regression of the smaller tumors continued until day 36 (P = 0.01), with 43% cured at day 26. No cures or significant volumetric reduction in size was observed in tumors treated with radiation alone; Ad.CMV.CD with or without radiation; or with Ad.CMV.CD and 5-FC. These results suggest that the CD/5-FC gene therapy approach is an effective radiosensitizing strategy and may lead to substantial improvement in local tumor control that would translate into improved cure rates and better survival.

Original languageEnglish (US)
Pages (from-to)4205-4209
Number of pages5
JournalCancer Research
Volume57
Issue number19
StatePublished - Oct 1 1997

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Hanna, N. N., Mauceri, H. J., Wayne, J. D., Hallahan, D. E., Kufe, D. W., & Weichselbaum, R. R. (1997). Virally directed cytosine deaminase/5-fluorocytosine gene therapy enhances radiation response in human cancer xenografts. Cancer Research, 57(19), 4205-4209.