Safety and efficacy of convection-enhanced delivery of gemcitabine or carboplatin in a malignant glioma model in rats
Safety and efficacy of convection-enhanced delivery of gemcitabine or carboplatin in a malignant glioma model in rats
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DOI：
10.3171/jns.2003.99.5.0893
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发表时间：
2003-11-01
影响因子：
4.1
通讯作者：
Lonser, RR
中科院分区：
文献类型：
--
作者：
Degen, JW;Walbridge, S;Lonser, RR
目的。对流增强递送（CED）可安全地用于以绕过血脑屏障的方式用治疗药物灌注中枢神经系统（CNS）区域（131313）。这些特性使CED成为将具有某些药代动力学特性的强效化疗药物递送至CNS肿瘤的一种潜在理想方法。为确定两种化疗药物（具有适合这种递送方法的特性）通过CED递送至CNS的安全性和有效性，作者用卡铂或吉西他滨对未处理的大鼠以及患有9L胶质瘤的大鼠进行灌注。
方法。通过CED用卡铂（0.1、1和10mg/ml）或吉西他滨（0.4、4和40mg/ml）灌注未处理大鼠的纹状体（10μl，24只大鼠）和脑干（10μl，16只大鼠）来进行剂量递增毒性研究。有效性试验包括在20只Fischer 344大鼠颅内植入9L肿瘤细胞。在植入7天后，用40μl生理盐水（对照组，4只大鼠）、1mg/ml卡铂（4只大鼠）或4mg/ml吉西他滨（4只大鼠）对肿瘤及周围区域进行灌注。8只患有9L胶质瘤的大鼠在植入7天后通过全身给予60mg/kg卡铂（4只大鼠）或150mg/kg吉西他滨（4只大鼠）进行治疗。通过临床、大体和组织学分析来确定毒性和有效性。
仅接受最高剂量卡铂或吉西他滨CED的大鼠出现毒性。在患有9L胶质瘤的大鼠中，所有对照组和全身治疗组的动物在肿瘤植入26天内死亡。两个CED治疗组均出现长期存活（120天）和肿瘤根除（卡铂组75%的大鼠和吉西他滨组50%的大鼠）。此外，患有9L胶质瘤并接受卡铂或吉西他滨瘤内CED治疗的动物比瘤内生理盐水（p < 0.01）或全身化疗（p < 0.01）治疗的对照组存活时间显著更长。
结论。使用治疗浓度的卡铂或吉西他滨可以在无毒性的情况下对大鼠脑的敏感区域进行灌注。此外，在该胶质瘤模型中，卡铂或吉西他滨对肿瘤的CED是安全的，并且具有强大的抗肿瘤作用。这些发现表明类似的治疗模式可能对人类神经胶质瘤的治疗有用。
Object. Convection-enhanced delivery (CED) can be used safely to perfuse regions of the central nervous system (CNS) with therapeutic agents in a manner that bypasses the blood-brain barrier (131313). These features make CED a potentially ideal method for the distribution of potent chemotherapeutic agents with certain pharmacokinetic properties to tumors of the CNS. To determine the safety and efficacy of the CED of two chemotherapeutic agents (with properties ideal for this method of delivery) into the CNS, the authors perfused naive rats and those harboring 9L gliomas with carboplatin or gemcitabine.Methods. Dose-escalation toxicity studies were performed by perfusing the striatum (10 mul, 24 rats) and brainstem (10 mul, 16 rats) of naive rats with carboplatin (0.1, 1, and 10 mg/ml) or gemcitabine (0.4, 4, and 40 mg/ml) via CED. Efficacy trials involved the intracranial implantation of 9L tumor cells in 20 Fischer 344 rats. The tumor and surrounding regions were perfused with 40 mul of saline (control group, four rats), I mg/ml of carboplatin (four rats), or 4 mg/ml of gemcitabine (four rats) 7 days after implantation. Eight rats harboring the 9L glioma were treated with the systemic administration of 60 mg/kg of carboplatin (four rats) or 150 mg/kg of gemcitabine (four rats) 7 days postimplantation. Clinical, gross, and histological analyses were used to determine toxicity and efficacy.Toxicity occurred in rats that had received only the highest dose of the CED of carboplatin or gemcitabine. Among rats with 9L gliomas, all control and systemically treated animals died within 26 days of tumor implantation. Longterm survival (120 days) and eradication of the tumor occurred in both CED-treated groups (75% of rats in the carboplatin group and 50% of rats in the gemcitabine group). Furthermore, animals harboring the 9L glioma and treated with intratumoral CED of carboplatin or gemcitabine survived significantly longer than controls treated with intratumoral saline (p < 0.01) or systemtic chemotherapy (p < 0.01).Conclusions. The perfusion of sensitive regions of the rat brain can be accomplished without toxicity by using therapeutic concentrations of carboplatin or gemcitabine. In addition, CED of carboplatin or gemcitabine to tumors in this glioma model is safe and has potent antitumor effects. These findings indicate that similar treatment paradigms may be useful in the treatment of glial neoplasms in humans.