Short fluorodeoxyuridine exposure of different human glioblastoma lines induces high-level accumulation of S-phase cells that avidly incorporate 125I-iododeoxyuridine.
OBJECTIVE
Radio-iododeoxyuridine (IdUrd) is a potential Auger radiation therapy agent incorporated into DNA during the synthesis phase. In this study we sought to optimise S-phase targeting by modulating cellular cycling and radio-IdUrd DNA incorporation using short non-toxic fluorodeoxyuridine (FdUrd) incubations.


METHODS
Three human glioblastoma cell lines with different p53 expression were pre-treated with various FdUrd conditions. After different intervals, (125)I-IdUrd DNA incorporation was measured. Fluorescence-activated cell sorter cell cycle analysis was performed after identical intervals post FdUrd pre-treatment.


RESULTS
The highest increase in (125)I-IdUrd DNA incorporation was induced by 1-h incubation with 1 muM FdUrd. Increase in radio-IdUrd DNA incorporation was greatest 16-24 h after FdUrd, reaching factors of >or=7.5 over baseline incorporation in the three cell lines. Furthermore, cell synchronisation in S phase was observed with a peak of >or=69.5% in the three cell lines at 16 and 24 h post FdUrd, corresponding to an increase of 2.5-4.1 over baseline.


CONCLUSIONS
FdUrd-induced thymidine synthesis inhibition led to S-phase accumulation that was maximal after an interval of 16-24 h and time-correlated with the highest radio-IdUrd DNA incorporation. These observations might allow the rational design of an Auger radiation therapy targeting a maximal number of S-phase cells in single treatment cycles.
Perillo-Adamer
Florence
F
Service of Nuclear Medicine, University Hospital of Lausanne, Rue du Bugnon 46, CH-1011, Lausanne, Switzerland. Florence.Adamer@chuv.ch
Delaloye
Angelika Bischof
AB
Genton
Céline S
CS
Schaffland
Andreas O
AO
Dupertuis
Yves M
YM
Buchegger
Franz
F
D002453:Cell Cycle / Q000187:drug effects* / Q000528:radiation effects*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005467:Floxuridine / Q000008:administration & dosage*; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D007065:Idoxuridine / Q000493:pharmacokinetics*; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics*; D008657:Metabolic Clearance Rate / Q000187:drug effects; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics
D007457:Iodine Radioisotopes; D019275:Radiopharmaceuticals; D005467:Floxuridine; D007065:Idoxuridine