The combination of adenoviral HSV TK gene therapy and radiation is effective in athymic mouse glioblastoma xenografts without increasing toxic side effects
The combination of adenoviral HSV TK gene therapy and radiation is effective in athymic mouse glioblastoma xenografts without increasing toxic side effects
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DOI：
10.1023/b:neon.0000021897.53969.ca
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发表时间：
2004-03-01
影响因子：
3.9
通讯作者：
Hochberg, FH
中科院分区：
文献类型：
--
作者：
Nestler, U;Wakimoto, H;Hochberg, FH
目的：在前列腺癌和乳腺癌小鼠模型中，腺病毒HSV TK基因治疗联合电离辐射可增强治疗效果。在本研究中，我们采用这种方法在胸腺小鼠模型中治疗人类胶质母细胞瘤异种移植物，并评估了治疗结果和毒副作用。方法：72只裸鼠脑内接种2 × 10(5)个U87 DeltaEGFR细胞。肿瘤植入后第7天，研究人群随机分为6个治疗组：(1)第7天瘤内缓冲接种，(2)第7天瘤内腺病毒载体注射（2 × 10(9) vp），(3)第9天单剂量辐射（2.1 Gy），(4)腺病毒注射+辐射，(5)腺病毒注射+更昔洛韦（GCV）（20杯/g，每天2次，第8天至第17天），(6)腺病毒注射+ GCV +辐射。在第21天，一半的动物被处死进行脑肿瘤的组织学评估，另一半进行生存评估。结果：该研究显示，GCV治疗组的中位生存时间显著延长了5天。放射的增加减少了神经系统症状的频率，延迟了缺陷的发作，而没有改变肿瘤细胞中胸苷激酶的表达。结论：腺病毒HSV TK基因治疗联合辅助放疗在胶质母细胞瘤治疗中不会增加毒副作用。延长接受基因治疗的动物的生存时间和减少受辐射小鼠神经症状的发生是联合治疗的有希望的特点。
Object: In mouse models of prostate and breast cancer therapeutic effects are enhanced when adenoviral HSV TK gene therapy is combined with ionizing radiation. In the present study, we adopted this approach for the treatment of human glioblastoma xenografts in an athymic mouse model and assessed treatment results as well as toxic side effects.Methods: About 72 nude mice received intracerebral inoculations of 2 x 10(5) U87 DeltaEGFR cells. On day 7 after tumor implantation the study population was randomized into six treatment arms: (1) intratumoral buffer inoculation on day 7, (2) intratumoral adenoviral vector injection (2 x 10(9) vp) on day 7, (3) single dose radiation (2.1 Gy) on day 9, (4) adenoviral injection + radiation, (5) adenoviral injection + ganciclovir (GCV) (20 mug/g twice daily from day 8 to 17), (6) adenoviral injection + GCV + radiation. On day 21 half of the animals were sacrificed for histological evaluation of the brain tumors, the other half was assessed for survival.Results: This study showed significantly prolonged median survival time of 5 days for the GCV treated groups. The addition of radiation decreased the frequency of neurological symptoms and delayed the onset of deficits without altering the expression of thymidine kinase in the tumor cells.Conclusions: We conclude that adenoviral HSV TK gene therapy in combination with adjuvant radiotherapy does not generate increased toxic side effects in glioblastoma treatment. The prolonged survival time of animals receiving gene therapy and the reduced occurrence of neurological symptoms in irradiated mice constitute promising features of the combined treatment.