In vivo antitumor activity of intratumoral fludarabine phosphate in refractory tumors expressing E. coli purine nucleoside phosphorylase.
In vivo antitumor activity of intratumoral fludarabine phosphate in refractory tumors expressing E. coli purine nucleoside phosphorylase.
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肿瘤内磷酸氟达拉滨在表达大肠杆菌嘌呤核苷磷酸化酶的难治性肿瘤中的体内抗肿瘤活性。
DOI：
10.1007/s00280-012-1908-9
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发表时间：
2012
影响因子：
3
通讯作者：
Parker,WilliamB
中科院分区：
文献类型：
--
作者：
Sorscher,EricJ;Hong,JeongS;Allan,PaulaW;Waud,WilliamR;Parker,WilliamB
PurposeSystemically administered fludarabine phosphate (F-araAMP) slows growth of human tumor xenografts that expressEscherichia colipurine nucleoside phosphorylase (PNP). However, this treatment has been limited by the amount of F-araAMP that can be administered in vivo. The current study was designed to (1) determine whether efficacy of this overall strategy could be improved by intratumoral administration of F-araAMP, (2) test enhancement of the approach with external beam radiation, and (3) optimize recombinant adenovirus as a means to augment PNP delivery and bystander killing in vivo.MethodsThe effects of systemic or intratumoral F-araAMP in mice were investigated with human tumor xenografts (300 mg), in which 10 % of the cells expressedE. coliPNP from a lentiviral promoter. Tumors injected with an adenoviral vector expressingE. coliPNP (Ad/PNP; 2 × 1011viral particles, 2 times per day × 3 days) and the impact of radiotherapy on tumors treated by this approach were also studied. Radiolabeled F-araAMP was used to monitor prodrug activation in vivo.ResultsIntratumoral administration of F-araAMP in human tumor xenografts expressingE. coliPNP resulted in complete regressions and/or prolonged tumor inhibition. External beam radiation significantly augmented this effect. Injection of large human tumor xenografts (human glioma, nonsmall cell lung cancer, or malignant prostate tumors) with Ad/PNP followed by intratumoral F-araAMP resulted in excellent antitumor activity superior to that observed following systemic administration of prodrug.ConclusionActivation of F-araAMP byE. coliPNP results in destruction of large tumor xenografts in vivo, augments radiotherapy, and promotes robust bystander killing. Our results indicate that intratumoral injection of F-araAMP leads to ablation of tumors in vivo with minimal toxicity.
