Department of Neurosurgery, Johns Hopkins University School of Medicine Baltimore, Baltimore, MD 21231, USA.
Cancer Chemother Pharmacol. 2013 Jul;72(1):93-100. doi: 10.1007/s00280-013-2172-3. Epub 2013 May 7.
Combining anti-angiogenesis agents with cytotoxic agents for the treatment of malignant gliomas may affect the cytotoxic drug distribution by normalizing the blood-brain barrier (BBB). This study examines the intratumoral concentration of temozolomide (TMZ) in the presence and absence of the pan-VEGF receptor tyrosine kinase inhibitor, cediranib.
Seven nude rats bearing U87 intracerebral gliomas had a microdialysis probe centered within the tumor. Ten-days after tumor implantation, TMZ (50 mg/kg) was given orally. The extracellular fluid (ECF) concentrations of TMZ within the tumor were assessed via microdialysis for 6 h following TMZ administration. Cediranib (6 mg/kg) was then given orally, and 12 h later, TMZ was re-administered with subsequent microdialysis collection. A subset of animals also underwent functional MRI to assess angiogenesis in vivo at post-inoculation days 12 and 21, before and after the cediranib treatment.
After dosing of oral TMZ only, ECF-TMZ mean-C(max) and area under the concentration curve(AUC(0-∞)) within the tumor were 0.59 μg/mL and 1.82 μg h/mL, respectively. Post-cediranib, ECF-TMZ mean-C(max) and AUC(0-∞) were 0.83 μg/mL and 3.72 ± 0.61 μg h/mL within the tumor, respectively. This represented a 1.4-fold (p = 0.3) and 2.0-fold (p = 0.06) increase in the ECF-TMZ C(max) and AUC(0-∞), respectively, after cediranib administration. In vivo MRI measurements of the various vascular parameters were consistent with a BBB "normalization" profile following cediranib treatment.
In the U87 intracerebral glioma model, within the first day of administration of cediranib, the intratumoral concentrations of TMZ in tumor ECF were slightly, but not statistically significantly, increased when compared to the treatment of TMZ alone with radiographic evidence of a normalized BBB.
联合抗血管生成药物和细胞毒性药物治疗恶性脑胶质瘤可能会通过正常化血脑屏障（BBB）来影响细胞毒性药物的分布。本研究检测了 pan-VEGF 受体酪氨酸激酶抑制剂西地尼布存在和不存在时替莫唑胺（TMZ）的肿瘤内浓度。
7 只荷 U87 脑内胶质瘤的裸鼠的肿瘤内有一个微透析探针。在肿瘤植入后 10 天，给予 TMZ（50mg/kg）口服。在 TMZ 给药后 6 小时内通过微透析评估肿瘤内 TMZ 的细胞外液（ECF）浓度。然后给予西地尼布（6mg/kg）口服，12 小时后再次给予 TMZ 并随后进行微透析采集。一部分动物还进行了功能磁共振成像（fMRI），以在西地尼布治疗前后评估接种后第 12 天和第 21 天的体内血管生成情况。
仅给予口服 TMZ 后，肿瘤内 ECF-TMZ 的平均 C(max)和 AUC(0-∞)分别为 0.59μg/mL 和 1.82μg h/mL。给予西地尼布后，肿瘤内 ECF-TMZ 的平均 C(max)和 AUC(0-∞)分别为 0.83μg/mL 和 3.72±0.61μg h/mL。与西地尼布给药后 ECF-TMZ 的 C(max)和 AUC(0-∞)分别增加了 1.4 倍（p=0.3）和 2.0 倍（p=0.06）。西地尼布治疗后各种血管参数的体内 MRI 测量结果与 BBB“正常化”特征一致。
在 U87 脑内胶质瘤模型中，在给予西地尼布的第一天，与单独给予 TMZ 相比，肿瘤 ECF 中的 TMZ 浓度略有增加，但无统计学意义，影像学上显示 BBB 正常化。
