Locoregional Apo2L/TRAIL eradicates intracranial human malignant glioma xenografts in athymic mice in the absence of neurotoxicity

被引:197
作者
Roth, W [1 ]
Isenmann, S
Naumann, U
Kügler, S
Bähr, M
Dichgans, J
Ashkenazi, A
Weller, M
机构
[1] Univ Tubingen, Sch Med, Dept Neurol, Mol Neurooncol Lab, Tubingen, Germany
[2] Univ Tubingen, Sch Med, Dept Neurol, Lab Neuroregenerat, Tubingen, Germany
[3] Genentech Inc, Dept Mol Oncol, S San Francisco, CA 94080 USA
关键词
Apo2L (TRAIL); apoptosis; death ligands; in vivo; malignant glioma;
D O I
10.1006/bbrc.1999.1693
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Glioblastoma multiforme is a lethal neoplasm refractory to radiochemotherapy, Although glioma cells undergo apoptosis when exposed to the death ligand, CD95 (Fas/APO-1) ligand, the therapeutic use of CD95L is considered impossible because of lethal side effects. Here, we report that the locoregional application of Apoa ligand (Apo2L) exerts strong antitumor activity on preestablished intracranially growing human U87MG glioma xenografts in athymic mice. Two repetitive intratumoral injections of 2 mu g Apo2L resulted in long-term survival of mice (>100 days), whereas the median survival of mock-treated mice was 36 days. The assessment of tumor volumes at 21 and 35 days after inoculation showed complete eradication of glioma xenografts in Apo2L-treated mice. Histology and TUNEL assay confirmed the induction of apoptosis by Apo2L in glioma cells in vivo. Importantly, the intracerebral injection of Apo2L does not result in acute or delayed neurotoxicity. We propose that a phase 1 trial of intralesional Apo2L therapy for human glioblastoma multiforme is warranted. (C) 1999 Academic Press.
引用
收藏
页码:479 / 483
页数:5
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