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Quantitative ¹H Nuclear Magnetic Resonance Diffusion Spectroscopy of BT4C Rat Glioma during Thymidine Kinase-mediated Gene Therapy in Vivo: Identification of Apoptotic Response¹

Nuclear Magnetic Resonance Research Group (J. M. H., H. P., R. A. K.), Molecular Medicine Group (A-M. P., S. Y-H.), and Animal Biotechnology Group (S. L.), A.I. Virtanen Institute, University of Kuopio, FIN-70211 Kuopio, Finland, and Department of Pathology (L. A. P.), University of Kuopio and Kuopio University Hospital, FIN-70211 Kuopio, Finland

We have investigated the effects of thymidine kinase-mediated gene therapy in a malignant rat BT4C glioma by using ¹H nuclear magnetic resonance spectroscopy in vivo. Ganciclovir has been successfully used in thymidine kinase gene therapy as treatment for various experimental malignancies. The cell damaging effect seems to be mediated by apoptosis, optimally leading to eradication of tumor tissue. In this study, we show that ganciclovir treatment of tumors transfected with the herpes simplex thymidine kinase gene causes profound changes in water, metabolites, and macromolecules observable by diffusion spectroscopy. During treatment, a 50% reduction from 0.14 ± 0.01 x 10^-9 m²/s in the apparent diffusion coefficient of choline-containing compounds can be observed, concomitant with a 219% increase in the apparent diffusion coefficient of the rapidly diffusing water component. These changes are associated with an increase in the relative fraction of this water component from 87 to 94%. The apparent diffusion coefficients of the slowly diffusing water component and macromolecules remain unaltered. The results imply a reduction in cell size and number, a significant increase in intracellular viscosity, and a possible reduction in the hydrodynamic radii of macromolecular components, which are ascribed as biophysical signatures for apoptotic cell death.

¹ This work was supported by the Academy of Finland (J. M. H., R. A. K), Sigrid Juselius Foundation, and the Cancer Society of Finland (R. A. K), Duodecim Foundation, Finnish Cultural Foundation of Northern Savo, and Instrumentarium Science Foundation (J. M. H.).

² Present address: Department of Radiology, University of Pennsylvania, B1 Stellar Chance Building, 422 Curie Boulevard, Philadelphia PA 19104.

³ To whom requests for reprints should be addressed, Nuclear Magnetic Resonance Research Group, A.I. Virtanen Institute, University of Kuopio, Neulaniementie 2, P.O. Box 1627, FIN-70211 Kuopio, Finland. Phone: 358-17-163-045; Fax: 358-17-163-030; E-mail: kauppine@messi.uku.fi.

Received 4/ 6/98. Accepted 7/ 3/98.

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