Buchegger Franz, Adamer Florence, Schaffland Andreas Oliver, Kosinski Marek, Grannavel Carine, Dupertuis Yves Marc, de Tribolet Nicolas, Mach Jean-Pierre, Delaloye Angelika Bischof
Division of Nuclear Medicine, University Hospital of Lausanne, CHUV, Rue du Bugnon 46, CH-1011 Lausanne, Switzerland.
Int J Cancer. 2004 May 20;110(1):145-9. doi: 10.1002/ijc.20112.
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.
设想将胸苷（dThd）类似物放射性碘脱氧尿苷（IdUrd）瘤内（i.t.）注射用于胶质母细胞瘤的靶向俄歇电子或β放射治疗。在此，在皮下人胶质母细胞瘤异种移植瘤LN229中进行瘤内注射[(125)I]IdUrd 5小时后，评估了在不同静脉内（i.v.）用氟脱氧尿苷（FdUrd）预处理后的生物分布。已知FdUrd可阻断从头合成dThd，从而有利于放射性IdUrd掺入DNA。结果表明，在注射放射性IdUrd前0.5小时和1小时分两部分静脉注射2 mg/kg FdUrd进行预处理，导致肿瘤平均摄取量为注射剂量的19.8%（% ID），对于约0.35 g的肿瘤，相当于65.3% ID/g。未预处理小鼠中放射性IdUrd的肿瘤摄取量仅为4.1% ID。在正常非分裂和分裂组织中观察到摄取量非常低，在脾脏中测得的最大浓度为2.9% ID/g。用10 mg/kg的更高剂量FdUrd预处理可将放射性IdUrd增加的肿瘤摄取延长至5小时。在FdUrd预处理的小鼠中进行了一项竞争实验，通过瘤内共同注射过量的dThd，导致[(125)I]IdUrd在肿瘤中的滞留非常低。DNA分离实验表明，平均而言，肿瘤中>95%的(125)I活性掺入了DNA。总之，这些结果表明，在静脉内用临床相关剂量的FdUrd预处理后，瘤内注射的放射性IdUrd中有近20% ID掺入了肿瘤DNA，并且这种方法可进一步用于发射俄歇电子和/或β射线的放射性IdUrd的扩散和治疗研究。
