Improved Brain Penetration and Antitumor Efficacy of Temozolomide by Inhibition of ABCB1 and ABCG2
| Autor: | de Gooijer, Mark C, de Vries, Nienke A, Buckle, Tessa, Buil, Levi C M, Beijnen, Jos H, Boogerd, Willem, van Tellingen, Olaf, Afd Pharmacoepi & Clinical Pharmacology, Pharmacoepidemiology and Clinical Pharmacology |
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| Přispěvatelé: | Afd Pharmacoepi & Clinical Pharmacology, Pharmacoepidemiology and Clinical Pharmacology |
| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Cancer Research BCRP breast cancer resistance protein Abcg2 Swine Dacarbazine/analogs & derivatives ATP-binding cassette transporter Pharmacology Subfamily G AUC area under the curve Mice 0302 clinical medicine P-gp P-glycoprotein ATP Binding Cassette Transporter Subfamily G Member 2 MGMT O6-methylguanine-DNA methyltransferase media_common Alkylating/pharmacokinetics biology Brain Neoplasms ABC ATP-binding cassette ATP Binding Cassette Transporter Subfamily B/antagonists & inhibitors lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Magnetic Resonance Imaging Neoplasm Proteins Dacarbazine Blood-Brain Barrier 030220 oncology & carcinogenesis Antineoplastic Agents Alkylating/pharmacokinetics Brain Neoplasms/diagnostic imaging Subfamily B/antagonists & inhibitors ATP Binding Cassette Transporter Subfamily G Member 2/antagonists & inhibitors Blood-Brain Barrier/metabolism medicine.drug Drug Original article ATP Binding Cassette Transporter Subfamily B Neoplasm Proteins/antagonists & inhibitors BBB blood-brain barrier ATP Binding Cassette Transporter media_common.quotation_subject Antineoplastic Agents lcsh:RC254-282 Cell Line 03 medical and health sciences Pharmacokinetics In vivo Temozolomide medicine Animals Humans Antineoplastic Agents Alkylating Animal business.industry WT wild-type In vitro Disease Models Animal 030104 developmental biology Member 2/antagonists & inhibitors Cell culture Disease Models biology.protein GBM glioblastoma business MRI magnetic resonance imaging |
| Zdroj: | Neoplasia: An International Journal for Oncology Research, Vol 20, Iss 7, Pp 710-720 (2018) Neoplasia, 20(7), 710. Elsevier Neoplasia (New York, N.Y.) |
| ISSN: | 1476-5586 1522-8002 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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