Microdialysis measurement of intratumoral temozolomide concentration after cediranib, a pan-VEGF receptor tyrosine kinase inhibitor, in a U87 glioma model
Microdialysis measurement of intratumoral temozolomide concentration after cediranib, a pan-VEGF receptor tyrosine kinase inhibitor, in a U87 glioma model
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DOI：
10.1007/s00280-013-2172-3
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发表时间：
2013-07-01
影响因子：
3
通讯作者：
Brem, Henry
中科院分区：
文献类型：
--
作者：
Grossman, Rachel;Tyler, Betty;Brem, Henry
联合使用抗血管生成药物和细胞毒药物治疗恶性胶质瘤可能会通过使血脑屏障（BBB）正常化来影响细胞毒药物的分布。本研究检测了在存在和不存在泛VEGF受体酪氨酸激酶抑制剂西地尼布的情况下替莫唑胺（TMZ）的瘤内浓度。肿瘤种植后10天，口服TMZ（50 mg/kg）。TMZ给药后6 h，通过微透析评估肿瘤内TMZ的细胞外液（ECF）浓度。然后口服西地尼布（6 mg/kg），12 h后，再次给予TMZ，随后进行微透析收集。在接种后第12天和第21天，在西地尼布治疗之前和之后，一个动物亚组也进行了功能性MRI以评估体内血管生成。仅口服TMZ给药后，肿瘤内ECF-TMZ平均C（max）和浓度曲线下面积（AUC（0-a））分别为0.59 μ g/mL和1.82 μ g h/mL。西地尼布给药后，肿瘤内ECF-TMZ平均-C（max）和AUC（0-a）分别为0.83 μ g/mL和3.72 +/- A 0.61 μ g h/mL。这表示西地尼布给药后ECF-TMZ C（max）和AUC（0-a）分别增加1.4倍（p = 0.3）和2.0倍（p = 0.06）。在U87脑内胶质瘤模型中，在西地尼布给药的第一天内，肿瘤ECF中TMZ的肿瘤内浓度与单独TMZ治疗相比略有增加，但无统计学显著性，具有正常化BBB的放射学证据。
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-a)) within the tumor were 0.59 mu g/mL and 1.82 mu g h/mL, respectively. Post-cediranib, ECF-TMZ mean-C (max) and AUC(0-a) were 0.83 mu g/mL and 3.72 +/- A 0.61 mu g 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-a), 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.