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

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. [Display omitted] Blood-brain barrier integrity in brain tumor models varies from intact to absentBrain tumor vessels express drug efflux transportersDrug transporters can impede drug entry and efficacy, even in leaky tumorsLow-affinity ABC transporter drugs are favored candidates for treating brain tumors Whether a compromised blood-brain barrier hinders the drug treatment of intracranial tumors remains controversial. de Gooijer et al. determine how drug transporters affect the efficacy of docetaxel against several intracranial tumor models with various levels of blood-brain barrier integrity and show that ABC transporters can restrict drug efficacy even when tumor vessels are leaky.