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Cited by 136Drug Transport and Resistance MechanismsGlioma Diagnosis and TreatmentNanoparticle-Based Drug Delivery

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

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de Gooijer, Mark C., de Vries, Nienke A., Buckle, Tessa, Buil, Levi C.M., Beijnen, Jos H., Boogerd, Willem, van Tellingen, Olaf·2018·Neoplasia
DOI 10.1016/j.neo.2018.05.001PMC PMC6030392
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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 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.

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  • Temozolomide is an alkylating lipophilic agent that crosses the blood-brain barrier to treat GBM.

    “Temozolomide is an alkylating lipophilic agent that crosses the BBB to treat GBM36,37.”

    From Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system (2025) · cites this paper as [37]

    The Introduction identifies temozolomide as an alkylating agent used in standard GBM treatment and says it penetrates the blood-brain barrier. The Discussion also reports that it readily permeates membranes, but our copy does not establish the specific description “lipophilic.” (LLM, conf=0.86)

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  1. [1]Sarkaria JN Hu LS Parney IF Pafundi DH Brinkmann DH Laack NN Giannini C Burns TC Kizilbash SH Laramy JK Is the blood-brain barrier really disrupted in all glioblastomas? A critical assessment of existing clinical data Neuro Oncol 20 2 2018 184 191 29016900 PMC5777482
  2. [2]van Tellingen O Yetkin-Arik B de Gooijer MC Wesseling P Wurdinger T de Vries HE Overcoming the blood-brain tumor barrier for effective glioblastoma treatment Drug Resist Updat 19 2015 1 12 25791797
  3. [3]Pencheva N de Gooijer MC Vis DJ Wessels LFA Würdinger T van Tellingen O Bernards R Identification of a druggable pathway controlling glioblastoma invasiveness Cell Rep 20 1 2017 48 60 28683323
  4. [4]Abbott NJ Patabendige AA Dolman DE Yusof SR Begley DJ Structure and function of the blood-brain barrier Neurobiol Dis 37 1 2010 13 25 19664713
  5. [5]Durmus S Hendrikx JJMA Schinkel AH Apical ABC transporters and cancer chemotherapeutic drug disposition Adv Cancer Res 125 2015 1 41 25640265
  6. [6]Schinkel AH Jonker JW Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: an overview Adv Drug Deliv Rev 64 2012 138 153 12535572
  7. [7]Glioma Meta-analysis Trialists Group Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials Lancet 359 9311 2002 1011 1018 11937180
  8. [8]Medical Research Council Brain Tumour Working Party Randomized trial of procarbazine, lomustine, and vincristine in the adjuvant treatment of high-grade astrocytoma: a Medical Research Council trial J Clin Oncol 19 2 2001 509 518 11208845
  9. [11]Yung WKA Prados MD Yaya-Tur R Rosenfeld SS Brada M Friedman HS Albright R Olson J Chang SM O'Neill AM Multicenter Phase II trial of temozolomide in patients with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse J Clin Oncol 17 9 1999 2762 2771 10561351
  10. [12]Stupp R Hegi ME Mason WP van den Bent MJ Taphoorn MJB Janzer RC Ludwin SK Allgeier A Fisher B Belanger K Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial Lancet Oncol 10 5 2009 459 466 19269895
  11. [13]Hegi ME Diserens A-C Gorlia T Hamou M-F de Tribolet N Weller M Kros JM Hainfellner JA Mason W Mariani L MGMT gene silencing and benefit from temozolomide in glioblastoma N Engl J Med 352 10 2005 997 1003 15758010
  12. [14]Weller M van den Bent M Hopkins K Tonn JC Stupp R Falini A Cohen-Jonathan-Moyal E Frappaz D Henriksson R Balana C EANO guideline for the diagnosis and treatment of anaplastic gliomas and glioblastoma Lancet Oncol 15 9 2014 e395 e403 25079102
  13. [15]Kim H Likhari P Parker D Statkevich P Marco A Lin C-C Nomeir AA High-performance liquid chromatographic analysis and stability of anti-tumor agent temozolomide in human plasma J Pharm Biomed Anal 24 3 2001 461 468 11199225
  14. [16]Schinkel AH Wagenaar E van Deemter L Mol CA Borst P Absence of the mdr1a P-Glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A J Clin Invest 96 4 1995 1698 1705 7560060 PMC185805
  15. [17]Jonker JW Smit JW Brinkhuis RF Maliepaard M Beijnen JH Schellens JHM Schinkel AH Role of breast cancer resistance protein in the bioavailability and fetal penetration of topotecan J Natl Cancer Inst 92 20 2000 1651 1656 11036110
  16. [18]de Vries NA Zhao J Kroon E Buckle T Beijnen JH van Tellingen O P-Glycoprotein and Breast Cancer Resistance Protein: Two Dominant Transporters Working Together in Limiting the Brain Penetration of Topotecan Clin Cancer Res 13 21 2007 6440 6449 17975156
  17. [19]Lin F de Gooijer MC Roig EM Buil LC Christner SM Beumer JH Wurdinger T Beijnen JH van Tellingen O ABCB1, ABCG2, and PTEN determine the response of glioblastoma to temozolomide and ABT-888 therapy Clin Cancer Res 20 10 2014 2703 2713 24647572
  18. [20]Kemper EM Leenders W Kusters B Lyons S Buckle T Heerschap A Boogerd W Beijnen JH van Tellingen O Development of luciferase tagged brain tumour models in mice for chemotherapy intervention studies Eur J Cancer 42 18 2006 3294 3303 17027258
  19. [21]Kemper EM van Zandbergen AE Cleypool C Mos HA Boogerd W Beijnen JH van Tellingen O Increased penetration of paclitaxel into the brain by inhibition of P-glycoprotein Clin Cancer Res 9 7 2003 2849 2855 12855665
  20. [22]Zhang P de Gooijer MC Buil LC Beijnen JH Li G van Tellingen O ABCB1 and ABCG2 restrict the brain penetration of a panel of novel EZH2-Inhibitors Int J Cancer 137 8 2015 2007 2018 25868794
  21. [23]Tsang LLH Quarterman CP Gescher A Slack JA Comparison of the cytotoxicity in vitro of temozolomide and dacarbazine, prodrugs of 3-methyl-(triazen-1-yl)imidazole-4-carboxamide Cancer Chemother Pharmacol 27 5 1991 342 346 1998993
  22. [24]Yang C-H Huang C-J Yang C-S Chu Y-C Cheng A-L Whang-Peng J Yang P-C Gefitinib reverses chemotherapy resistance in gefitinib-insensitive multidrug resistant cancer cells expressing ATP-binding cassette family protein Cancer Res 65 15 2005 6943 6949 16061679
  23. [25]Stevens MFG Hickman JA Langdon SP Chubb D Vickers L Stone R Baig G Goddard C Gibson NW Slack JA Antitumor activity and pharmacokinetics in mice of 8-carbamoyl-3-methyl-imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (CCRG 81045; M & B 39831), a novel drug with potential as an alternative to dacarbazine Cancer Res 47 22 1987 5846 5852 3664486
  24. [26]de Vries NA Bruggeman SW Hulsman D de Vries HI Zevenhoven J Buckle T Hamans BC Leenders WP Beijnen JH van Lohuizen M Rapid and robust transgenic high-grade glioma mouse models for therapy intervention studies Clin Cancer Res 16 13 2010 3431 3441 20472681
  25. [27]Seelig A The role of size and charge for blood-brain barrier permeation of drugs and fatty acids J Mol Neurosci 33 1 2007 32 41 17901543
  26. [28]Peng B Dutreix C Mehring G Hayes MJ Ben-Am M Seiberling M Pokorny R Capdeville R Lloyd P Absolute bioavailability of imatinib (Glivec®) orally versus intravenous infusion J Clin Pharmacol 44 2 2004 158 162 14747424
  27. [29]Oostendorp RL Buckle T Beijnen JH van Tellingen O Schellens JH The effect of P-gp (Mdr1a/1b), BCRP (Bcrp1) and P-gp/BCRP inhibitors on the in vivo absorption, distribution, metabolism and excretion of imatinib Invest New Drugs 27 1 2009 31 40 18449471
  28. [30]Herbrink M Nuijen B Schellens JHM Beijnen JH Variability in bioavailability of small molecular tyrosine kinase inhibitors Cancer Treat Rev 41 5 2015 412 422 25818541
  29. [31]Mittapalli RK Vaidhyanathan S Dudek AZ Elmquist WF Mechanisms limiting distribution of the threonine-protein kinase B-RaFV600E inhibitor dabrafenib to the brain: implications for the treatment of melanoma brain metastases J Pharmacol Exp Ther 344 3 2012 655 664 23249624 PMC3583506
  30. [32]Kort A Durmus S Sparidans RW Wagenaar E Beijnen JH Schinkel AH Brain and testis accumulation of regorafenib is restricted by breast cancer resistance protein (BCRP/ABCG2) and P-glycoprotein (P-GP/ABCB1) Pharm Res 32 7 2015 2205 2216 25563977
  31. [33]de Gooijer MC Zhang P Thota N Mayayo-Peralta I Buil LC Beijnen JH van Tellingen O P-glycoprotein and breast cancer resistance protein restrict the brain penetration of the CDK4/6 inhibitor palbociclib Invest New Drugs 33 5 2015 1012 1019 26123925
  32. [34]Parrish KE Pokorny J Mittapalli RK Bakken K Sarkaria JN Elmquist WF Efflux transporters at the blood-brain barrier limit delivery and efficacy of cyclin-dependent kinase 4/6 inhibitor palbociclib (PD-0332991) in an orthotopic brain tumor model J Pharmacol Exp Ther 355 2 2015 264 271 26354993 PMC4613960
  33. [35]Zhuang Y Fraga CH Hubbard KE Hagedorn N Panetta JC Waters CM Stewart CF Topotecan central nervous system penetration is altered by a tyrosine kinase inhibitor Cancer Res 66 23 2006 11305 11313 17145877
  34. [36]Herbst RS Maddox A-M Rothenberg ML Small EJ Rubin EH Baselga J Rojo F Hong WK Swaisland H Averbuch SD Selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 is generally well-tolerated and has activity in non–small-cell lung cancer and other solid tumors: results of a phase I trial J Clin Oncol 20 18 2002 3815 3825 12228201
  35. [37]Xavier D Alexandra A Jean-Yves D Jean-Michel S Role of ABC transporters in the chemoresistance of human gliomas Curr Cancer Drug Targets 6 5 2006 433 445 16918310
  36. [38]Mason WP Cairncross JG Drug insight: temozolomide as a treatment for malignant glioma—impact of a recent trial Nat Clin Pract Neurol 1 2005 88 95 16932504
  37. [39]Schinkel AH Mayer U Wagenaar E Mol CAAM van Deemter L Smit JJM van der Valk MA Voordouw AC Spits H van Tellingen O Normal viability and altered pharmacokinetics in mice lacking mdr1-type (drug-transporting) P-glycoproteins Proc Natl Acad Sci 94 8 1997 4028 4033 9108099 PMC20562

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Authors
de Gooijer, M. C., de Vries, N. A., Buckle, T., Buil, L. C. M., Beijnen, J. H., Boogerd, W., & van Tellingen, O.
Affiliations
  • The Netherlands Cancer Institute (NL)
  • Utrecht University (NL)
  • Slotervaartziekenhuis (NL)
ORCID
Venue
Neoplasia
Publisher
Elsevier BV
Published
2018-07
Volume
20
Issue
7
Pages
710-720
ISSN
1476-5586 (ISSN-L)
DOI
10.1016/j.neo.2018.05.001
PMC
PMC6030392
OpenAlex
W2805729137
Cited by
136
References
3
Citations by year
2026: 12 · 2025: 23 · 2024: 16 · 2023: 16 · 2022: 27 · 2021: 14 · 2020: 13 · 2019: 11 · 2018: 4
FWCI
3.95
Type
journal article
Language
en
Open access
Licence
Locations
  • Neoplasia (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
Topics
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
Keywords
temozolomide, P-glycoprotein, ABCG2, blood-brain barrier, brain penetration, elacridar, high-grade glioma, pharmacokinetics, antitumor efficacy, multidrug resistance, intracranial tumors
MeSH terms
ATP Binding Cassette Transporter, Subfamily G, Member 2, Temozolomide, Animals, Blood-Brain Barrier, Brain Neoplasms, Cell Line, Dacarbazine, Disease Models, Animal, Humans, Magnetic Resonance Imaging, Male, Neoplasm Proteins, Swine, ATP Binding Cassette Transporter, Subfamily B, Antineoplastic Agents, Alkylating, Mice

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