ATP-binding cassette transporters restrict drug delivery and efficacy against brain tumors even when blood-brain barrier integrity is lost

Mark C de Gooijer; E Marleen Kemper; Levi C M Buil; Ceren H Çitirikkaya; Tessa Buckle; Jos H Beijnen; Olaf van Tellingen

doi:10.1016/j.xcrm.2020.100184

ATP-binding cassette transporters restrict drug delivery and efficacy against brain tumors even when blood-brain barrier integrity is lost

Cell Rep Med. 2021 Jan 19;2(1):100184. doi: 10.1016/j.xcrm.2020.100184.

Authors

Mark C de Gooijer^{1

2}, E Marleen Kemper³, Levi C M Buil^{1

2}, Ceren H Çitirikkaya^{1

2}, Tessa Buckle⁴, Jos H Beijnen^{1

5

6}, Olaf van Tellingen^{1

2}

Affiliations

¹ Division of Pharmacology, the Netherlands Cancer Institute, Amsterdam, the Netherlands.
² Mouse Cancer Clinic, the Netherlands Cancer Institute, Amsterdam, the Netherlands.
³ Department of Hospital Pharmacy, Academic Medical Center, Amsterdam, the Netherlands.
⁴ Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands.
⁵ Department of Pharmacy and Pharmacology, the Netherlands Cancer Institute, Amsterdam, the Netherlands.
⁶ Division of Pharmacoepidemiology and Clinical Pharmacology, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, the Netherlands.

Abstract

The impact of a compromised blood-brain barrier (BBB) on the drug treatment of intracranial tumors remains controversial. We characterize the BBB integrity in several intracranial tumor models using magnetic resonance imaging, fluorescent dyes, and autoradiography and determine the distribution and efficacy of docetaxel in brain tumors grafted in Abcb1-proficient and Abcb1-deficient mice. Leakiness of the tumor vasculature varies from extensive to absent. Regardless of the extent of leakiness, tumor blood vessels express ATP-binding cassette transporters (Abcb1 and Abcg2). A leaky vasculature results in higher docetaxel tumor levels compared to normal brain. Nevertheless, Abcb1 can reduce drug distribution and efficacy even in leaky models. Thus, BBB leakiness does not ensure the unimpeded access of ATP-binding cassette transporter substrate drugs. Therapeutic responses may be observed, but the full potential of such therapeutics may still be attenuated. Consequently, BBB-penetrable drugs with little to no affinity for efflux transporters are preferred for the treatment of intracranial tumors.

Keywords: P-glycoprotein; blood-brain barrier; brain tumor; breast cancer resistance protein; glioma; taxanes.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ATP Binding Cassette Transporter, Subfamily B, Member 1 / deficiency
ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics*
ATP Binding Cassette Transporter, Subfamily G, Member 2 / genetics
ATP Binding Cassette Transporter, Subfamily G, Member 2 / metabolism
Animals
Antineoplastic Agents / pharmacokinetics*
Antineoplastic Agents / pharmacology
Autoradiography
Biological Transport
Blood-Brain Barrier / diagnostic imaging
Blood-Brain Barrier / metabolism*
Brain / blood supply
Brain / diagnostic imaging
Brain / drug effects
Brain Neoplasms / blood supply
Brain Neoplasms / diagnostic imaging
Brain Neoplasms / drug therapy*
Brain Neoplasms / genetics*
Cerebrovascular Circulation
Docetaxel / pharmacokinetics*
Docetaxel / pharmacology
Endothelial Cells / cytology
Endothelial Cells / drug effects
Endothelial Cells / metabolism
Female
Fluorescent Dyes / metabolism
Gene Expression
Humans
Magnetic Resonance Imaging
Male
Mice
Mice, Knockout
Protein Binding
Xenograft Model Antitumor Assays

Substances

ATP Binding Cassette Transporter, Subfamily B, Member 1
ATP Binding Cassette Transporter, Subfamily G, Member 2
Abcg2 protein, mouse
Antineoplastic Agents
Fluorescent Dyes
Docetaxel