Improved Brain Penetration and Antitumor Efficacy of Temozolomide by Inhibition of ABCB1 and ABCG2

Neoplasia : an International Journal for Oncology Research
Mark C de GooijerOlaf van Tellingen

Abstract

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 recip...Continue Reading

Citations

Aug 15, 2019·Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism·Yutaro HoshiTetsuya Terasaki
Jun 18, 2020·Cancers·Claudia CirottiDaniela Barilà
Mar 17, 2019·International Journal of Molecular Sciences·Malcolm LimJodi M Saunus
Nov 12, 2019·Cancer Biology & Therapy·Jonathan D StropeWilliam D Figg
Oct 12, 2019·Nature Reviews. Cancer·Costas D ArvanitisRakesh K Jain
Sep 29, 2019·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Elizabeth R GerstnerTracy Batchelor
May 23, 2019·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Stuart J SmithRuman Rahman
Feb 28, 2020·European Journal of Medicinal Chemistry·Frauke AntoniGünther Bernhardt
Apr 23, 2020·Pharmacology & Therapeutics·Eva Gil-MartinsRenata Silva
Sep 22, 2018·Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine·Martin BauerOliver Langer
Feb 20, 2020·ACS Applied Materials & Interfaces·Kaouthar BouzinabLyudmila Turyanska

❮ Previous
Next ❯

Methods Mentioned

BETA
surgical resection
xenografts
transgenic
fluorescence microscopy

Software Mentioned

SPSS
GraphPad Prism
Excel
Paravision

Related Concepts

Related Feeds

Blood Brain Barrier

The blood brain barrier is a border that separates blood from cerebrospinal fluid. Discover the latest search on this highly selective semipermeable membrane here.

Blood Brain Barrier Regulation in Health & Disease

The blood brain barrier is essential in regulating the movement of molecules and substances in and out of the brain. Disruption to the blood brain barrier and changes in permeability allow pathogens and inflammatory molecules to cross the barrier and may play a part in the pathogenesis of neurodegenerative disorders. Here is the latest research in this field.

Blood Brain Barrier Chips

The blood brain barrier (BBB) is comprised of endothelial cells that regulate the influx and outflux of plasma concentrations. Lab-on-a-chip devices allow scientists to model diseases and mechanisms such as the passage of therapeutic antibodies across the BBB. Discover the latest research on BBB chips here.

Related Papers

European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)
E M KemperOlaf van Tellingen
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Fan LinOlaf van Tellingen
© 2022 Meta ULC. All rights reserved