Sewing A Charlotte P, Lagerweij Tonny, van Vuurden Dannis G, Meel Michaël H, Veringa Susanna J E, Carcaboso Angel M, Gaillard Pieter J, Peter Vandertop W, Wesseling Pieter, Noske David, Kaspers Gertjan J L, Hulleman Esther
Departments of 1 Pediatric Oncology.
Neuro-Oncology Research Group.
J Neurosurg Pediatr. 2017 May;19(5):518-530. doi: 10.3171/2016.9.PEDS16152. Epub 2017 Feb 17.
OBJECTIVE Pediatric high-grade gliomas (pHGGs) including diffuse intrinsic pontine gliomas (DIPGs) are primary brain tumors with high mortality and morbidity. Because of their poor brain penetrance, systemic chemotherapy regimens have failed to deliver satisfactory results; however, convection-enhanced delivery (CED) may be an alternative mode of drug delivery. Anthracyclines are potent chemotherapeutics that have been successfully delivered via CED in preclinical supratentorial glioma models. This study aims to assess the potency of anthracyclines against DIPG and pHGG cell lines in vitro and to evaluate the efficacy of CED with anthracyclines in orthotopic pontine and thalamic tumor models. METHODS The sensitivity of primary pHGG cell lines to a range of anthracyclines was tested in vitro. Preclinical CED of free doxorubicin and pegylated liposomal doxorubicin (PLD) to the brainstem and thalamus of naïve nude mice was performed. The maximum tolerated dose (MTD) was determined based on the observation of clinical symptoms, and brains were analyzed after H & E staining. Efficacy of the MTD was tested in adult glioma E98-FM-DIPG and E98-FM-thalamus models and in the HSJD-DIPG-007-Fluc primary DIPG model. RESULTS Both pHGG and DIPG cells were sensitive to anthracyclines in vitro. Doxorubicin was selected for further preclinical evaluation. Convection-enhanced delivery of the MTD of free doxorubicin and PLD in the pons was 0.02 mg/ml, and the dose tolerated in the thalamus was 10 times higher (0.2 mg/ml). Free doxorubicin or PLD via CED was ineffective against E98-FM-DIPG or HSJD-DIPG-007-Fluc in the brainstem; however, when applied in the thalamus, 0.2 mg/ml of PLD slowed down tumor growth and increased survival in a subset of animals with small tumors. CONCLUSIONS Local delivery of doxorubicin to the brainstem causes severe toxicity, even at doxorubicin concentrations that are safe in the thalamus. As a consequence, the authors could not establish a therapeutic window for treating orthotopic brainstem tumors in mice. For tumors in the thalamus, therapeutic concentrations to slow down tumor growth could be reached. These data suggest that anatomical location determines the severity of toxicity after local delivery of therapeutic agents and that caution should be used when translating data from supratentorial CED studies to treat infratentorial tumors.
目的 小儿高级别胶质瘤（pHGGs），包括弥漫性脑桥内生性胶质瘤（DIPGs），是具有高死亡率和高发病率的原发性脑肿瘤。由于其较差的脑渗透能力，全身化疗方案未能取得令人满意的效果；然而，对流增强递送（CED）可能是一种替代的给药方式。蒽环类药物是有效的化疗药物，已在临床前幕上胶质瘤模型中通过CED成功递送。本研究旨在评估蒽环类药物在体外对DIPG和pHGG细胞系的效力，并评估在原位脑桥和丘脑肿瘤模型中使用蒽环类药物进行CED的疗效。方法 在体外测试原发性pHGG细胞系对一系列蒽环类药物的敏感性。对未处理的裸鼠的脑干和丘脑进行游离阿霉素和聚乙二醇化脂质体阿霉素（PLD）的临床前CED。根据临床症状的观察确定最大耐受剂量（MTD），并在苏木精和伊红（H&E）染色后分析大脑。在成人胶质瘤E98-FM-DIPG和E98-FM-丘脑模型以及HSJD-DIPG-007-Fluc原发性DIPG模型中测试MTD的疗效。结果 pHGG和DIPG细胞在体外对蒽环类药物均敏感。选择阿霉素进行进一步的临床前评估。游离阿霉素和PLD在脑桥中的MTD的对流增强递送为0.02 mg/ml，而在丘脑中耐受的剂量高10倍（0.2 mg/ml）。通过CED给予的游离阿霉素或PLD对脑干中的E98-FM-DIPG或HSJD-DIPG-007-Fluc无效；然而，当应用于丘脑时，0.2 mg/ml的PLD减缓了肿瘤生长并提高了一小部分小肿瘤动物的存活率。结论 即使在丘脑安全的阿霉素浓度下，将阿霉素局部递送至脑干也会导致严重毒性。因此，作者无法为治疗小鼠原位脑干肿瘤建立治疗窗口。对于丘脑中的肿瘤，可以达到减缓肿瘤生长的治疗浓度。这些数据表明，解剖位置决定了局部递送治疗药物后的毒性严重程度，并且在将幕上CED研究的数据转化用于治疗幕下肿瘤时应谨慎。
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