4.5 Article

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

Journal

GENE THERAPY
Volume 7, Issue 12, Pages 1005-1010

Publisher

NATURE PUBLISHING GROUP
DOI: 10.1038/sj.gt.3301199

Keywords

diffusion MRI; yeast cytosine deaminase; 5-fluorocytosine; glioma; gene therapy

Funding

  1. NCI NIH HHS [CA73904, CA59009] Funding Source: Medline

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Defection 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 5FC 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/5FG strategy for glioma and suggest that increased tumor water diffusion is an indicator of active therapeutic intervention.

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