Highly efficient DNA incorporation of intratumourally injected [125I]iododeoxyuridine under thymidine synthesis blocking in human glioblastoma xenografts

被引:17
作者
Buchegger, F
Adamer, F
Schaffland, AO
Kosinski, M
Grannavel, C
Dupertuis, YM
de Tribolet, N
Mach, JP
Delaloye, AB
机构
[1] Univ Lausanne Hosp, CHU Vaudois, Div Nucl Med, CH-1011 Lausanne, Switzerland
[2] Univ Hosp Geneva, Div Nucl Med, Geneva, Switzerland
[3] Univ Hosp Geneva, Div Nutr, Geneva, Switzerland
[4] Univ Hosp Geneva, Dept Neurosurg, Geneva, Switzerland
[5] Univ Lausanne, Inst Biochem, CH-1066 Epalinges, Switzerland
关键词
radio-iododeoxyuridine; fluorodeoxyuridine; proliferation targeting; glioblastoma;
D O I
10.1002/ijc.20112
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 [I-125]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 [I-125]IdUrd. DNA isolation experiments showed that in the mean >95% of tumour I-125 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. (C) 2004 Wiley-Liss, Inc.
引用
收藏
页码:145 / 149
页数:5
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