Health & Environmental Research Online (HERO)


Print Feedback Export to File
9292599 
Journal Article 
Abcc4 together with abcb1 and abcg2 form a robust cooperative drug efflux system that restricts the brain entry of camptothecin analogues 
Lin, Fan; Marchetti, S; Pluim, D; Iusuf, D; Mazzanti, R; Schellens, JanHM; Beijnen, JosH; van Tellingen, O; , 
2013 
1 
Clinical Cancer Research
ISSN: 1078-0432
EISSN: 1557-3265 
AMER ASSOC CANCER RESEARCH 
PHILADELPHIA 
2084-2095 
English 
23461902 
WOS:000317597500018 
Multidrug resistance-associated protein 4 (ABCC4) shares many features with P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2), including broad substrate affinity and expression at the blood-brain barrier (BBB). However, the pharmacologic relevance of ABCC4 at the BBB is difficult to evaluate, as most drugs are also substrates of ABCB1 and/or ABCG2.We have created a mouse strain in which all these alleles are inactivated to assess their impact on brain delivery of camptothecin analogues, an important class of antineoplastic agents and substrates of these transporters. Wild-type (WT), Abcg2(-/-), Abcb1a/b(-/-), Abcc4(-/-), Abcb1a/b;Abcg2(-/-), Abcg2;Abcc4(-/-), and Abcb1a/b;Abcg2;Abcc4(-/-) mice received i.v. topotecan, irinotecan, SN-38, or gimatecan alone or with concomitant oral elacridar. Drug levels were analyzed by high-performance liquid chromatography (HPLC).We found that additional deficiency of Abcc4 in Abcb1a/b;Abcg2(-/-) mice significantly increased the brain concentration of all camptothecin analogues by 1.2-fold (gimatecan) to 5.8-fold (SN-38). The presence of Abcb1a/b or Abcc4 alone was sufficient to reduce the brain concentration of SN-38 to the level in WT mice. Strikingly, the brain distribution of gimatecan in brain of WT mice was more than 220- and 40-fold higher than that of SN-38 and topotecan, respectively.Abcc4 limits the brain penetration of camptothecin analogues and teams up with Abcb1a/b and Abcg2 to form a robust cooperative drug efflux system. This concerted action limits the usefulness of selective ABC transport inhibitors to enhance drug entry for treatment of intracranial diseases. Our results also suggest that gimatecan might be a better candidate than irinotecan for clinical evaluation against intracranial tumors.