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Hypoxia imaging predicts success of hypoxia-induced cytosine deaminase/5-fluorocytosine gene therapy in a murine lung tumor model

Cancer Gene Therapy volume 19, pages 255–262 (2012)Cite this article

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Abstract

Tc-99m-HL91 is a hypoxia imaging biomarker. The aim of this study was to investigate the value of Tc-99m-HL91 imaging for hypoxia-induced cytosine deaminase (CD)/5-fluorocytosine (5-FC) gene therapy in a murine lung tumor model. C57BL/6 mice were implanted with Lewis lung carcinoma cells transduced with the hypoxia-inducible promoter-driven CD gene (LL2/CD) or luciferase gene (LL2/Luc) serving as the control. When tumor volumes reached 100 mm3, pretreatment images were acquired after injection of Tc-99m-HL91. The mice were divided into low and high hypoxic groups based on the tumor-to-non-tumor ratio of Tc-99m-HL91. They were injected daily with 5-FC (500 mg kg−1) or the vehicle for 1 week. When tumor volumes reached 1000 mm3, autoradiography and histological examinations were performed. Treatment with 5-FC delayed tumor growth and enhanced the survival of mice bearing high hypoxic LL2/CD tumors. The therapeutic effect of hypoxia-induced CD/5-FC gene therapy was more pronounced in high hypoxic tumors than in low hypoxic tumors. This study provides the first evidence that Tc-99m-HL91 can serve as an imaging biomarker for predicting the treatment responses of hypoxia-regulated CD/5-FC gene therapy in animal tumor models. Our results suggest that hypoxia imaging using Tc-99m-HL91 has the predictive value for the success of hypoxia-directed treatment regimens.

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Acknowledgements

We thank Gang Ting and Shiaw-Pyng Wey for helpful conversations on experimental design. We also thank Julie Sun, Yuen-Shin Chao and Ting-Jyun Jhuo for their technical assistance, and Pei-Sing Liou for her secretarial help with the manuscript. We are grateful to Wei-Ming Wang for providing the statistical consulting services from the Biostatistics Consulting Center, National Cheng Kung University Hospital and Professor Iain Bruce for English-editing. This work was supported in part by Grants from the National Science Council (NSC96-2321-B-006-004-MY2, NSC-95-NU-7-006-001 and NSC-94-NU-7-006-003), Taiwan.

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Authors and Affiliations

  1. Department of Nuclear Medicine, National Cheng Kung University, College of Medicine and Hospital, Tainan, Taiwan

    B-F Lee & N-T Chiu

  2. Department of Microbiology and Immunology, National Cheng Kung University, College of Medicine, Tainan, Taiwan

    C-H Lee & A-L Shiau

  3. Institute of Nuclear Energy Research, Lungtan, Taiwan

    C-C Hsia & L-H Shen

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  1. B-F Lee
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Correspondence to A-L Shiau.

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Lee, BF., Lee, CH., Chiu, NT. et al. Hypoxia imaging predicts success of hypoxia-induced cytosine deaminase/5-fluorocytosine gene therapy in a murine lung tumor model. Cancer Gene Ther 19, 255–262 (2012). https://doi.org/10.1038/cgt.2011.87

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