title: Diffusion MRI detects early events in the response of a glioma model to the yeast cytosine deaminase gene therapy strategy.
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.
authors.affiliation: Department of Radiology, University of Michigan Medical School, Ann Arbor, MI 48109-0648, USA.
authors.forename: L D
authors.initials: LD
authors.lastname: Stegman
authors.forename: A
authors.initials: A
authors.lastname: Rehemtulla
authors.forename: D A
authors.initials: DA
authors.lastname: Hamstra
authors.forename: D J
authors.initials: DJ
authors.lastname: Rice
authors.forename: S J
authors.initials: SJ
authors.lastname: Jonas
authors.forename: K L
authors.initials: KL
authors.lastname: Stout
authors.forename: T L
authors.initials: TL
authors.lastname: Chenevert
authors.forename: B D
authors.initials: BD
authors.lastname: Ross
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000473:pathology / Q000628:therapy*; D043525:Cytosine Deaminase; D005437:Flucytosine / Q000627:therapeutic use; D015316:Genetic Therapy; D005910:Glioma / Q000473:pathology / Q000628:therapy*; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D009368:Neoplasm Transplantation; D009700:Nucleoside Deaminases / Q000235:genetics*; D011355:Prodrugs / Q000627:therapeutic use; D051381:Rats; D011916:Rats, Inbred F344; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
chemical_list: D000935:Antifungal Agents; D011355:Prodrugs; D005437:Flucytosine; D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase