Highly efficient DNA incorporation of intratumourally injected [125I]iododeoxyuridine under thymidine synthesis blocking in human glioblastoma xenografts.
Intratumoural (i.t.) injection of radio-iododeoxyuridine (IdUrd), a thymidine (dThd) analogue, is envisaged for targeted Auger electron- or beta-radiation therapy of glioblastoma. Here, biodistribution of [(125)I]IdUrd was evaluated 5 hr after i.t. injection in subcutaneous human glioblastoma xenografts LN229 after different intravenous (i.v.) pretreatments with fluorodeoxyuridine (FdUrd). FdUrd is known to block de novo dThd synthesis, thus favouring DNA incorporation of radio-IdUrd. Results showed that pretreatment with 2 mg/kg FdUrd i.v. in 2 fractions 0.5 hr and 1 hr before injection of radio-IdUrd resulted in a mean tumour uptake of 19.8% of injected dose (% ID), representing 65.3% ID/g for tumours of approx. 0.35 g. Tumour uptake of radio-IdUrd in non-pretreated mice was only 4.1% ID. Very low uptake was observed in normal nondividing and dividing tissues with a maximum concentration of 2.9% ID/g measured in spleen. Pretreatment with a higher dose of FdUrd of 10 mg/kg prolonged the increased tumour uptake of radio-IdUrd up to 5 hr. A competition experiment was performed in FdUrd pretreated mice using i.t. co-injection of excess dThd that resulted in very low tumour retention of [(125)I]IdUrd. DNA isolation experiments showed that in the mean >95% of tumour (125)I activity was incorporated in DNA. In conclusion, these results show that close to 20% ID of radio-IdUrd injected i.t. was incorporated in tumour DNA after i.v. pretreatment with clinically relevant doses of FdUrd and that this approach may be further exploited for diffusion and therapy studies with Auger electron- and/or beta-radiation-emitting radio-IdUrd.
Buchegger
Franz
F
Division of Nuclear Medicine, University Hospital of Lausanne, CHUV, Rue du Bugnon 46, CH-1011 Lausanne, Switzerland. Franz.Buchegger@chuv.hospvd.ch
Adamer
Florence
F
Schaffland
Andreas Oliver
AO
Kosinski
Marek
M
Grannavel
Carine
C
Dupertuis
Yves Marc
YM
de Tribolet
Nicolas
N
Mach
Jean-Pierre
JP
Delaloye
Angelika Bischof
AB
D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism / Q000532:radiotherapy*; D004247:DNA / Q000378:metabolism*; D005467:Floxuridine / Q000627:therapeutic use; D005909:Glioblastoma / Q000378:metabolism / Q000532:radiotherapy*; D006801:Humans; D007065:Idoxuridine / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007457:Iodine Radioisotopes / Q000627:therapeutic use*; D051379:Mice; D009368:Neoplasm Transplantation; D013936:Thymidine / Q000096:biosynthesis*; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
D007457:Iodine Radioisotopes; D005467:Floxuridine; D004247:DNA; D007065:Idoxuridine; D013936:Thymidine