Quantitative 1H nuclear magnetic resonance diffusion spectroscopy of BT4C rat glioma during thymidine kinase-mediated gene therapy in vivo: identification of apoptotic response.

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.

Quantitative metabolite patterns of human brain tumors: detection by 1H NMR spectroscopy in vivo and in vitro.

OBJECTIVE: The aim of the present study was to investigate quantitative metabolite patterns in human brain tumors by 1H nuclear MR spectroscopy (1H MRS). MATERIALS AND METHODS: Single voxel 1H MRS was used in studying metabolites in 23 primary brain tumors in vivo. The T2 relaxation times and saturation factors were determined for N-acetylaspartate (NAA), total creatine (Cr), choline-containing compounds (Cho), and water, which was used as an internal standard in computations of metabolite concentrations in vivo. Metabolites in biopsy specimens from 75 tumors were quantified by means of 1H MRS in vitro. RESULTS: The NAA concentrations were lower in brain tumors than in normal tissue in vitro and in vivo, irrespective of the histological type. The NAA was some threefold higher in vivo than in vitro, which could be due to partial volume effect and/or contributions from other metabolites to the peak at 2.02 ppm in vivo. Ratios of Cho to Cr concentrations were elevated in tumors relative to normal brain in vivo. Absolute Cho was some 50% higher in both benign astrocytomas and oligodendrogliomas in vivo than in normal brain. However, Cho concentration in vitro was significantly higher only in pituitary adenomas than in healthy white matter. Total creatine was approximately 50% lower in malignant astrocytomas and meningiomas than in normal brain. CONCLUSION: It is concluded that absolute concentrations of metabolites in vivo yield a different picture of tumor metabolites than that derived from uncorrected metabolite ratios.