Improved Brain Penetration and Antitumor Efficacy of Temozolomide by Inhibition of ABCB1 and ABCG2.
Improved Brain Penetration and Antitumor Efficacy of Temozolomide by Inhibition of ABCB1 and ABCG2.
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DOI：
10.1016/j.neo.2018.05.001
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发表时间：
2018-07
期刊：
影响因子：
--
通讯作者：
van Tellingen O
中科院分区：
文献类型：
--
作者：
de Gooijer MC;de Vries NA;Buckle T;Buil LCM;Beijnen JH;Boogerd W;van Tellingen O
抗癌药物替莫唑胺是唯一被证明具有抗高级别神经胶质瘤活性的药物，因此已成为这些肿瘤标准治疗的一部分。 P-糖蛋白（P-gp；ABCB1）和乳腺癌耐药蛋白（BCRP；ABCG2）是转运蛋白，存在于血脑屏障处并限制大脑对底物药物的摄取。我们利用野生型、Abcg2−/−、Abcb1a/b−/− 和 Abcg2−/−、Abcb1a/b−/− 和 Abcb1a/b;Abcg2−/− 小鼠。我们在此表明，与野生型对照相比，Abcb1a/b 和 Abcg2 的联合删除使替莫唑胺的脑渗透增加了 1.5 倍 (P < .001)，而不改变全身药物暴露。此外，当将替莫唑胺与双重 P-gp/BCRP 抑制剂 elacridar (GF120918) 联合给予野生型小鼠时，也实现了相同的增加。当受体小鼠中 Abcb1a/b 和 Abcg2 基因缺陷或药理抑制时，替莫唑胺对三种不同颅内肿瘤模型的抗肿瘤功效显着增强。这些发现需要对替莫唑胺与 elacridar 联合治疗神经胶质瘤进行进一步的临床测试，因为这为进一步提高这种已经具有活性的药物的抗肿瘤功效提供了前景。
The anticancer drug temozolomide is the only drug with proven activity against high-grade gliomas and has therefore become a part of the standard treatment of these tumors. P-glycoprotein (P-gp; ABCB1) and breast cancer resistance protein (BCRP; ABCG2) are transport proteins, which are present at the blood-brain barrier and limit the brain uptake of substrate drugs. We have studied the effect of P-gp and BCRP on the pharmacokinetics and pharmacodynamics of temozolomide, making use of a comprehensive set of in vitro transport experiments and in vivo pharmacokinetic and antitumor efficacy experiments using wild-type, Abcg2−/−, Abcb1a/b−/−, and Abcb1a/b;Abcg2−/− mice. We here show that the combined deletion of Abcb1a/b and Abcg2 increases the brain penetration of temozolomide by 1.5-fold compared to wild-type controls (P < .001) without changing the systemic drug exposure. Moreover, the same increase was achieved when temozolomide was given to wild-type mice in combination with the dual P-gp/BCRP inhibitor elacridar (GF120918). The antitumor efficacy of temozolomide against three different intracranial tumor models was significantly enhanced when Abcb1a/b and Abcg2 were genetically deficient or pharmacologically inhibited in recipient mice. These findings call for further clinical testing of temozolomide in combination with elacridar for the treatment of gliomas, as this offers the perspective of further improving the antitumor efficacy of this already active agent.
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影响因子：
2.9
作者：
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