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Diffusion MRI detects early events in the response of a glioma model to the yeast cytosine deaminase gene therapy strategy

Gene Therapy volume 7, pages 1005–1010 (2000)Cite this article

Abstract

Detection of a therapeutic response early in the course of cancer treatment, before tumor growth delay or regression, is not currently possible in experimental models or clinical medicine. New interim measures of therapeutic response would be particularly useful in the development of cancer chemosensitization gene therapy by facilitating optimization of gene transfer protocols and prodrug dosing schedules. Diffusion MRI is a sensitive technique producing quantitative and noninvasive images of the apparent mobility of water within a tissue. We investigated the utility of diffusion MRI for detecting early changes associated with a refined cytosine deaminase (CD)/5-fluorocytosine (5FC) chemosensitization gene therapy paradigm in orthotopic 9L gliomas stably expressing the recently cloned S. cerevisiae CD gene. Mean tumor diffusion increased 31% within 8 days of initiating 5-FC treatment, preceding tumor growth arrest and regression. Complete regression of the intracranial tumor was observed in four of five treated animals, and recurrent tumor in the remaining animal exhibited water diffusion behavior similar to primary, untreated tumors. These results demonstrate the efficacy of the yCD/5FC strategy for glioma and suggest that increased tumor water diffusion is an indicator of active therapeutic intervention.

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Acknowledgements

This work was supported in part by research grants from the NIH to BDR (CA59009), AR (CA73904). We thank Raphia Taha for her technical assistance and helpful discussions. We acknowledge Dr Els Kievit for help with the enzyme assays.

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Authors and Affiliations

  1. Department of Radiology, University of Michigan Medical School, 1150 West Medical Center Drive, Medical Sciences Research Building III, Room 9303, Ann Arbor, 48109-0648, MI, USA

    LD Stegman, SJ Jonas, KL Stout, TL Chenevert & BD Ross

  2. Department of Biological Chemistry, University of Michigan Medical School, 1150 West Medical Center Drive, Medical Sciences Research Building III, Room 9303, Ann Arbor, 48109-0648, MI, USA

    LD Stegman, SJ Jonas, KL Stout & BD Ross

  3. Department of Department of Radiation Oncology, University of Michigan Medical School, 1150 West Medical Center Drive, Medical Sciences Research Building III, Room 9303, Ann Arbor, 48109-0648, MI, USA

    A Rehemtulla, DA Hamstra & DJ Rice

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Stegman, L., Rehemtulla, A., Hamstra, D. et al. Diffusion MRI detects early events in the response of a glioma model to the yeast cytosine deaminase gene therapy strategy. Gene Ther 7, 1005–1010 (2000). https://doi.org/10.1038/sj.gt.3301199

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