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基因介导的免疫预防与微束放射治疗对晚期大鼠脑内9L胶质肉瘤的协同作用。

Synergy of gene-mediated immunoprophylaxis and microbeam radiation therapy for advanced intracerebral rat 9L gliosarcomas.

作者信息

Smilowitz H M, Blattmann H, Bräuer-Krisch E, Bravin A, Di Michiel M, Gebbers J-O, Hanson A L, Lyubimova N, Slatkin D N, Stepanek J, Laissue J A

机构信息

Department of Pharmacology, UCHC, Farmington, CT, USA.

出版信息

J Neurooncol. 2006 Jun;78(2):135-43. doi: 10.1007/s11060-005-9094-9. Epub 2006 Apr 6.

Abstract

PURPOSE

Microbeam radiation therapy (MRT), a novel experimental radiosurgery that largely spares the developing CNS and other normal tissues, is tolerated well by developing animals and palliates advanced 9LGS tumors. This report, to our knowledge, is the first demonstration that gene-mediated immunotherapy (GMIMPR) enhances the efficacy of MRT for advanced 9LGS tumors.

METHODS

Seventy-six male Fischer 344 rats were implanted ic with 10(4)9LGS cells on d0. By d14, the cells had generated approximately approximately 40 mm3 ic 9LGS tumours, experimental models for therapy of moderately aggressive human malignant astrocytomas. Each of the 14 untreated (control) rats died from a large (>100 mg) ic tumor before d29 (median, d21). On d14, the remaining 62 rats were given deliberately suboptimal microbeam radiation therapy (MRT) by a single lateral exposure of the tumor-bearing zone of the head to a 10.1 mm-wide, approximately approximately 11 mm-high array of 20-39 microm-wide, nearly parallel beams of synchrotron wiggler-generated radiation (mainly approximately 50-150 keV X-rays) that delivered 625 Gy peak skin doses at approximately approximately 211 microm ctc intervals in approximately approximately 300 ms either without additional treatments (MRT-only, 25 rats), with post-MRT GMIMPR (MRT+GMIMPR, 23 rats: multiple sc injections of irradiated (clonogenically-disabled) GM-CSF gene-transfected 9LGS cells), or with post-MRT IMPR (MRT+IMPR, 14 rats: multiple sc injections of irradiated (clonogenically-disabled) 9LGS cells.

RESULTS

The median post-implantation survivals of rats in the MRT-only, MRT+GMIMPR and MRT+IMPR groups were over twice that of controls; further, approximately approximately 20% of rats in MRT-only and MRT+IMPR groups survived >1 yr with no obvious disabilities. Moreover, over 40% of MRT+GMIMPR rats survived >1 yr with no obvious disabilities, a significant (P<0.04) increase over the MRT-only and MRT+IMPR groups.

SIGNIFICANCE

These data suggest that the combination of MRT+GMIMPR might be better than MRT only for unifocal CNS tumors, particularly in infants and young children.

摘要

目的

微束放射治疗(MRT)是一种新型的实验性放射外科治疗方法,在很大程度上可使发育中的中枢神经系统和其他正常组织免受辐射,发育中的动物对其耐受性良好,且能缓解晚期9LGS肿瘤。据我们所知,本报告首次证明基因介导的免疫治疗(GMIMPR)可增强MRT对晚期9LGS肿瘤的疗效。

方法

76只雄性Fischer 344大鼠于第0天经颅内植入10⁴个9LGS细胞。到第14天,这些细胞已在颅内生成了约40 mm³的9LGS肿瘤,这是治疗中度侵袭性人类恶性星形细胞瘤的实验模型。14只未接受治疗的(对照)大鼠在第29天前均死于大的(>100 mg)颅内肿瘤(中位时间为第21天)。在第14天,对其余62只大鼠进行了故意次优的微束放射治疗(MRT),通过将头部肿瘤携带区域单次侧向暴露于一个10.1 mm宽、约11 mm高的由20 - 39微米宽、近乎平行的同步加速器摆动器产生的辐射束(主要是约50 - 150 keV的X射线)阵列,以约211微米的中心到中心间隔、在约300毫秒内递送625 Gy的峰值皮肤剂量,其中一组不进行额外治疗(仅MRT组,25只大鼠),一组在MRT后进行GMIMPR(MRT + GMIMPR组,23只大鼠:多次皮下注射经照射(克隆失活)的GM - CSF基因转染的9LGS细胞),另一组在MRT后进行IMPR(MRT + IMPR组,14只大鼠:多次皮下注射经照射(克隆失活)的9LGS细胞)。

结果

仅MRT组、MRT + GMIMPR组和MRT + IMPR组大鼠植入后的中位生存期是对照组的两倍多;此外,仅MRT组和MRT + IMPR组中约20%的大鼠存活超过1年且无明显残疾。而且,超过40%的MRT + GMIMPR组大鼠存活超过一年且无明显残疾,与仅MRT组和MRT + IMPR组相比有显著(P < 0.04)增加。

意义

这些数据表明,对于单灶性中枢神经系统肿瘤,尤其是婴幼儿,MRT + GMIMPR联合治疗可能比单纯MRT更好。

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