Tissue distribution and antitumor activity of topotecan delivered by intracerebral clysis in a rat glioma model.
Tissue distribution and antitumor activity of topotecan delivered by intracerebral clysis in a rat glioma model.
复制标题
在大鼠神经胶质瘤模型中通过脑内裂解递送托泊替康的组织分布和抗肿瘤活性。
DOI：
10.1093/neurosurgery/47.6.1391
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发表时间：
2000
期刊：
影响因子：
4.8
通讯作者：
J. Bruce
中科院分区：
文献类型：
--
作者：
M. Kaiser;A. Parsa;R. Fine;Jonathan S. Hall;I. Chakrabarti;J. Bruce
目的脑内灌肠是一种依靠对流强化微量输注达到脑内治疗性药物浓度的给药技术。本研究采用系统给药和脑内灌肠给药相结合的方法，对荷瘤大鼠进行治疗。我们的目的是确定通过脑内灌肠给药的拓扑替康的疗效和组织分布。方法采用C6/Wistar大鼠脑胶质瘤模型，采用胸腺嘧啶核苷掺入法测定C6细胞对拓扑替康的敏感性。动物的长期存活提供了疗效的客观衡量；治疗期间动物体重和神经状态的记录用于近似毒性。用高压液相色谱仪测定了拓扑替康在体外肿瘤及周围脑组织中的组织渗透率。结果随着剂量的增加，C6胶质瘤细胞对拓扑替康有明显的敏感性(半数致死剂量，0.19微摩尔/L)。12只携带脑内C6胶质瘤的大鼠中有11只存活超过120d的终点，未经治疗的对照组或系统治疗的大鼠存活超过26d(n=18；P<；0.005)。动物的组织病理学评估显示，经腹膜腔内处理的动物和未经处理的对照动物的大脑中有显著的肿瘤肿块。而脑内灌肠组大鼠脑内未见肿瘤残留。小剂量脑内灌肠给药(32微g/kg/d，连续5d；n=6)可显著减轻动物体重。小剂量脑内灌肠组动物均未表现出神经毒性，1只大剂量脑内灌肠组动物(160微克/公斤/天，连续2d；n=6)在随访期间死亡。在接受脑内灌肠治疗的动物中，拓扑替康被检测到远远超出肿瘤边界，甚至在对侧大脑半球也被检测到。结论拓扑替康脑内灌肠给药对大鼠脑胶质瘤模型脑瘤有较好的治疗作用。这些研究为进一步的临床前试验提供了令人信服的理由，以正式评估不同剂量计划的毒性和有效性。
OBJECTIVE Intracerebral clysis is a drug delivery technique that depends on convection-enhanced microinfusion to achieve therapeutic drug levels within the brain. In this study, brain tumor-bearing rats were treated with topotecan delivered systemically and by the intracerebral clysis method. Our objective was to determine the efficacy and tissue distribution of topotecan delivered by intracerebral clysis. METHODS The C6/Wistar rat glioma model was used after a thymidine incorporation assay determined topotecan sensitivity of C6 cells in vitro. Long-term survival of animals provided objective measurements of efficacy; records of animal weight during treatment and neurological status served to approximate toxicity. Topotecan tissue penetration was measured in samples of ex vivo tumor and surrounding brain tissue with high-pressure liquid chromatography. RESULTS Dose escalation demonstrated significant sensitivity of C6 glioma cells to topotecan (median lethal dose, 0.19 micromol/L). Eleven of 12 rats bearing established intracerebral C6 glioma and receiving topotecan by intracerebral clysis survived beyond the end point of 120 days; no untreated control or systemically treated animal survived beyond 26 days (n = 18; P < 0.005). Histopathological assessment of animals demonstrated significant tumor masses in the brains of intraperitoneally treated animals and untreated control animals. In contrast, no residual tumor was found in the brains of intracerebral clysis groups. Animal weights during treatment were markedly reduced by intraperitoneal dosing (n = 6) but not by low-dose intracerebral clysis (32 microg/kg/d for 5 d; n = 6). None of the low-dose intracerebral clysis-treated animals demonstrated neurological toxicity, and one high-dose intracerebral clysis-treated animal (160 microg/kg/d for 2 d; n = 6) died during follow-up. Topotecan was detected well beyond the boundaries of the tumor and even in the contralateral hemisphere in animals treated with intracerebral clysis. CONCLUSION Topotecan delivered by the intracerebral clysis method is effective for treatment of brain tumors in the rat glioma model. These studies provide compelling justification for further preclinical testing to formally evaluate toxicity and efficacy with variable dosing schedules.