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The potential of 5-fluorocytosine/cytosine deaminase enzyme prodrug gene therapy in an intrahepatic colon cancer model

Gene Therapy volume 9, pages 844–849 (2002)Cite this article

Abstract

Colorectal cancer can metastasize to the liver, but remain liver confined for years. A critical step in developing treatments for intrahepatic cancer involves assessment in an orthotopic intrahepatic model. The purpose of this study was to develop a noninvasive intrahepatic tumor model to study the efficacy of 5-flucytosine/yeast cytosine deaminase (5FC/yCD)-based gene therapy for liver tumors. Luciferase expressing human colorectal carcinoma (HT-29luc) cells were generated by retroviral infection and implanted in the left liver lobe of nude mice. The bioluminescence was measured every week for a period of 1 month, then animals were killed and tumors were measured by calipers. After we found a correlation between photon counts and tumor size, animals were implanted with tumors composed of either 0%, 10%, or 100% yCD/HT-29luc cells, and treated with 5FC. Tumor bioluminescence was measured during treatment and tumor histology examined at the time of death. We found that 5FC caused significant regression of yCD expressing tumors. Furthermore, visible tumors at the time of death, which emitted little bioluminescence, contained little or no viable tumor. We then developed an adenoviral vector for yCD. Intraperitoneal administration of adenovirus containing yCD led to the production of yCD enzyme within intrahepatic tumors. These results suggest that (1) intrahepatic cancer responds to 5FC when cells express yCD; (2) the luciferin–luciferase system permits non-invasive real time imaging of viable intrahepatic cancer; and (3) this system can be used to carry out gene therapy experiments using yCD adenovirus.

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Acknowledgements

We thank Mats Ljungman for helpful suggestions, Mary Davis and Maureen Johnson for technical assistance, Amy Pace for her help in making figures for this paper and Eric Duckers, University of Michigan for adenovirus generation. This work was supported by grants from the NIH (CA80145 and CA 83099) and a Munn Research Award from the University of Michigan Cancer Center.

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Authors and Affiliations

  1. Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA

    MK Nyati, Z Symon, E Kievit, KJ Dornfeld, SD Rynkiewicz, A Rehemtulla & TS Lawrence

  2. Department of Radiology and Biological Chemistry, University of Michigan, Ann Arbor, MI, USA

    BD Ross

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  1. MK Nyati
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  2. Z Symon
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Nyati, M., Symon, Z., Kievit, E. et al. The potential of 5-fluorocytosine/cytosine deaminase enzyme prodrug gene therapy in an intrahepatic colon cancer model. Gene Ther 9, 844–849 (2002). https://doi.org/10.1038/sj.gt.3301706

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