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Fluorodeoxyuridine Improves Imaging of Human Glioblastoma Xenografts with Radiolabeled Iododeoxyuridine¹

Divisions of Nuclear Medicine [Y. M. D., D. O. S., F. B.], Neurosurgery [N. D. T.], and Nutrition [Y. M. D., C. P.] and Department of Morphology [M. V.], University Medical Center of Geneva, CH-1211 Geneva 14, and Department of Biochemistry [J-P. M.], University of Lausanne, CH-1066 Epalinges, Switzerland

Use of radiolabeled nucleotides for tumor imaging is hampered by rapid in vivo degradation and low DNA-incorporation rates. We evaluated whether blocking of thymidine (dThd) synthesis by 5-fluoro-2'-deoxyuridine (FdUrd) could improve scintigraphy with radio-dThd analogues, such as 5-iodo-2'-deoxyuridine (IdUrd). We first show in vitro that coincubation with FdUrd substantially increased incorporation of [¹²⁵I]IdUrd and [³H]dThd in the three tested human glioblastoma lines. Flow cytometry analysis showed that a short coincubation with FdUrd (1 h) produces a signal increase per labeled cell. We then measured biodistribution 24 h after i.v. injection of [¹²⁵I]IdUrd in nude mice s.c. xenografted with the three glioblastoma lines. Compared with animals given [¹²⁵I]IdUrd alone, i.v. preadminsitration for 1 h of 10 mg/kg FdUrd increased the uptake of [¹²⁵I]IdUrd in the three tumors 4.8–6.8-fold. Compatible with previous reports, there were no side effects in mice observed for 2 months after receiving such a treatment. The tumor uptake of [¹²⁵I]IdUrd was increased 13.6-fold when FdUrd preadministration was stepwise reduced to 1.1 mg/kg. Uptake increases remained lower (between 1.7- and 5.8-fold) in normal proliferating tissues (i.e., bone marrow, spleen, and intestine) and negligible in quiescent tissues. DNA extraction showed that 72–80% of radioactivity in tumor and intestine was bound to DNA. Scintigraphy of xenografted mice was performed at different times after i.v. injection of 3.7 MBq [¹²⁵I]IdUrd. Tumor detection was significantly improved after FdUrd preadministration while still equivocal after 24 h in mice given [¹²⁵I]IdUrd alone. Furthermore, background activity could be greatly reduced by p.o. administration of KClO₄ in addition to potassium iodide. We conclude that FdUrd preadministration may improve positron or single photon emission tomography with cell division tracers, such as radio-IdUrd and possibly other dThd analogues.

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