Validation of Several Nucleoside Tracers as Proliferation Markers

Sammanfattning: Positron emission tomography (PET) is a powerful method for in vivo characterization of tumor biochemistry and clinically has been used for diagnosing and grading of malignancy. A key element in oncology is proliferation potential, a feature that is assumed to be an important indicator of tumor growth. In order to develop methods for the assessment of proliferation potential, attempts have been made using radiolabeled nucleosides and their analogues as proliferation markers.In the present studies several nucleoside tracers, 5-[76Br]bromo-2′-deoxyuridine ([76Br]BrdU), 1-(2′-deoxy-2′-fluoro-β-D-arabinofuranosyl)-5-[76Br]bromouracil ([76Br]BFU), 1-(2′-deoxy-2′-fluoro-β-D-arabinofuranosyl)-[methyl-11C]thymine ([11C]FMAU) and 3′-deoxy-3′- [18F]fluorothymidine ([18F]FLT), were investigated with respect to tissue uptake, DNA incorporation, and excretion modulation in rats, pigs and in a tumor model in mice. Experiments of DNA incorporation were also performed in multicellular tumor aggregates. Hydroxyurea, a DNA synthesis inhibitor, was used in the experiments of DNA incorporation. Cimetidine was used to modulate the excretion of the tracers. Several combinations of diuretics were used to eliminate the metabolite of [76Br]BrdU. The radioactivity content in the animal urine samples was analysed using high-pressure liquid chromatography and thin-layer chromatography.The results of this thesis suggest that [76Br]BrdU can be incorporated into DNA and allow the determination of proliferation potential in vivo using PET, but only with due consideration of a high non-specific organ radioactivity constituted by [76Br]bromide, the metabolite of [76Br]BrdU. With forced diuresis, the non-specific organ radioactivity uptake is diminished. [76Br]BFU predominantly incorporates into DNA, and has a great potential for assessment of proliferation. [76Br]BFU was eliminated quickly as intact compound by kidneys. Cimetidine can block the rapid elimination of [76Br]BFU and make a high concentration of the tracer in proliferation tissues. [11C]FMAU is a stable compound and also has potential as a proliferation marker, but the short half-life gives a limited time for observation. Although cimetidine can effectively block the elimination of [11C]FMAU, it does not increase the uptake of [11C]FMAU in organs. [18F]FLT cannot incorporate into DNA, even though the radioactivity uptake is higher in the organs with active DNA synthesis. Cimetidine does not significantly affect the uptake of [18F]FLT in organs.