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Preclinical impact of bevacizumab on brain and tumor distribution of irinotecan and temozolomide

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Abstract

Glioblastoma (GBM) is the most common primary malignant brain tumour in adults. Prognosis of GBM patients is poor with median overall survival around 15 months. Temozolomide is the chemotherapeutic agent used in the standard of care of newly diagnosed GBM patients relying on radiotherapy with concurrent chemotherapy followed by chemotherapy alone. Irinotecan has shown some efficacy in recurrent malignant gliomas. Bevacizumab has been combined with irinotecan in the treatment of recurrent GBM and with temozolomide in newly diagnosed GBM. As the efficacy of GBM treatments relies on their brain distribution through the blood brain barrier, the aim of the present preclinical work was to study, in in vivo models, the impact of bevacizumab on brain and tumor distribution of temozolomide and irinotecan. Our results show that bevacizumab pre-treatment was associated with a reduced temozolomide brain distribution in tumor-free mice. In tumor bearing mice, bevacizumab increased temozolomide tumor distribution, although not statistically significant. In both tumor-free and tumor-bearing mice, bevacizumab does not modify brain distribution of irinotecan and its metabolite SN-38. Bevacizumab impacts brain distribution of some anti-tumor drugs and potentially their efficacy in GBM. Further studies are warranted to investigate other therapeutic combination.

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Abbreviations

CPT-11:

Irinotecan

SN-38:

7-Ethyl-10-hydroxycamptothecin

TMZ:

Temozolomide

AUC:

Area under the curve

References

  1. Jansen M, de Witt Hamer PC, Witmer AN, Troost D, van Noorden CJF (2004) Current perspectives on antiangiogenesis strategies in the treatment of malignant gliomas. Brain Res Rev 45(3):143–163

    Article  CAS  PubMed  Google Scholar 

  2. Steiner H-H, Karcher S, Mueller MM, Nalbantis E, Kunze S, Herold-Mende C (2004) Autocrine pathways of the vascular endothelial growth factor (VEGF) in glioblastoma multiforme: clinical relevance of radiation-induced increase of VEGF levels. J Neurooncol 66(1):129–138

    Article  PubMed  Google Scholar 

  3. Cordon-Cardo C, O’Brien JP, Casals D, Rittman-Grauer L, Biedler JL, Melamed MR, Bertino JR (1989) Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. PNAS 86(2):695–698

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Jetté L, Murphy GF, Leclerc J-M, BÈliveau R (1995) Interaction of drugs with P-glycoprotein in brain capillaries. Biochem Pharmacol 50(10):1701–1709

    Article  PubMed  Google Scholar 

  5. Schinkel AH, Wagenaar E, Mol CA, van Deemter L (1996) P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J Clin Investig 97(11):2517–2524

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Terasaki T, K-i Hosoya (1999) The blood-brain barrier efflux transporters as a detoxifying system for the brain. Adv Drug Deliv Rev 36(2–3):195–209

    Article  CAS  PubMed  Google Scholar 

  7. Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307(5706):58–62. doi:10.1126/science.1104819

    Article  CAS  PubMed  Google Scholar 

  8. Calatozzolo C, Pollo B, Botturi A, Dinapoli L, Carosi M, Salmaggi A, Maschio M (2012) Multidrug resistance proteins expression in glioma patients with epilepsy. J Neurooncol 110(1):129–135. doi:10.1007/s11060-012-0946-9

    Article  CAS  PubMed  Google Scholar 

  9. Demeule M, Shedid D, Beaulieu E, Del Maestro RF, Moghrabi A, Ghosn PB, Moumdjian R, Berthelet F, Beliveau R (2001) Expression of multidrug-resistance P-glycoprotein (MDR1) in human brain tumors. Int J Cancer 93(1):62–66

    Article  CAS  PubMed  Google Scholar 

  10. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJB, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann Jr, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352(10):987–996. doi:10.1056/NEJMoa043330

    Article  CAS  PubMed  Google Scholar 

  11. Lai A, Tran A, Nghiemphu PL, Pope WB, Solis OE, Selch M, Filka E, Yong WH, Mischel PS, Liau LM, Phuphanich S, Black K, Peak S, Green RM, Spier CE, Kolevska T, Polikoff J, Fehrenbacher L, Elashoff R, Cloughesy T (2010) Phase II study of bevacizumab plus temozolomide during and after radiation therapy for patients with newly diagnosed glioblastoma multiforme. J Clin Oncol. doi:10.1200/jco.2010.30.2729

    Google Scholar 

  12. Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, Carpentier AF, Hoang-Xuan K, Kavan P, Cernea D, Brandes AA, Hilton M, Abrey L, Cloughesy T (2014) Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med 370(8):709–722

    Article  CAS  PubMed  Google Scholar 

  13. Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, Colman H, Chakravarti A, Pugh S, Won M, Jeraj R, Brown PD, Jaeckle KA, Schiff D, Stieber VW, Brachman DG, Werner-Wasik M, Tremont-Lukats IW, Sulman EP, Aldape KD, Curran WJ, Mehta MP (2014) A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med 370(8):699–708

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Kawato Y, Aonuma M, Hirota Y, Kuga H, Sato K (1991) Intracellular roles of SN-38, a metabolite of the camptothecin derivative CPT-11, in the antitumor effect of CPT-11. Cancer Res 51(16):4187–4191

    CAS  PubMed  Google Scholar 

  15. Satoh T, Hosokawa M (1998) The mammalian carboxylesterases: from molecules to functions. Annu Rev Pharmacol Toxicol 38(1):257–288. doi:10.1146/annurev.pharmtox.38.1.257

    Article  CAS  PubMed  Google Scholar 

  16. Iyer L, Ramírez J, Shepard D, Bingham C, Hossfeld D-K, Ratain M, Mayer U (2002) Biliary transport of irinotecan and metabolites in normal and P-glycoprotein-deficient mice. Cancer Chemother Pharmacol 49(4):336–341

    Article  CAS  PubMed  Google Scholar 

  17. Smith NF, Figg WD, Sparreboom A (2006) Pharmacogenetics of irinotecan metabolism and transport: an update. Toxicol In Vitro 20(2):163–175

    Article  CAS  PubMed  Google Scholar 

  18. Blaney SM, Takimoto C, Murry DJ, Kuttesch N, McCully C, Cole DE, Godwin K, Balis FM (1998) Plasma and cerebrospinal fluid pharmacokinetics of 9-aminocamptothecin (9-AC), irinotecan (CPT-11), and SN-38 in nonhuman primates. Cancer Chemother Pharmacol 41(6):464–468. doi:10.1007/s002800050768

    Article  CAS  PubMed  Google Scholar 

  19. Friedman HS, Petros WP, Friedman AH, Schaaf LJ, Kerby T, Lawyer J, Parry M, Houghton PJ, Lovell S, Rasheed K, Cloughsey T, Stewart ES, Colvin OM, Provenzale JM, McLendon RE, Bigner DD, Cokgor I, Haglund M, Rich J, Ashley D, Malczyn J, Elfring GL, Miller LL (1999) Irinotecan therapy in adults with recurrent or progressive malignant glioma. J Clin Oncol 17(5):1516

    CAS  PubMed  Google Scholar 

  20. Prados MD, Lamborn K, Yung WKA, Jaeckle K, Robins HI, Mehta M, Fine HA, Wen PY, Cloughesy T, Chang S, Nicholas MK, Schiff D, Greenberg H, Junck L, Fink K, Hess K, Kuhn J (2006) A phase 2 trial of irinotecan (CPT-11) in patients with recurrent malignant glioma: a North American brain tumor consortium study. Neuro-Oncology 8(2):189–193. doi:10.1215/15228517-2005-010

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Baumann BC, Dorsey JF, Benci JL, Joh DY, Kao GD (2012) Stereotactic intracranial implantation and in vivo bioluminescent imaging of tumor xenografts in a mouse model system of glioblastoma multiforme. J Vis Exp 67:e4089. doi:10.3791/4089

    Google Scholar 

  22. Brehar FM, Ciurea AV, Chivu M, Zarnescu O, Radulescu R, Dragu D (2008) The development of xenograft glioblastoma implants in nude mice brain. J Med Life 1(3):275–286

    CAS  PubMed  Google Scholar 

  23. Szentirmai O, Baker CH, Lin N, Szucs S, Takahashi M, Kiryu S, Kung AL, Mulligan RC, Carter BS (2006) Noninvasive bioluminescence imaging of luciferase expressing intracranial U87 xenografts: correlation with magnetic resonance imaging determined tumor volume and longitudinal use in assessing tumor growth and antiangiogenic treatment effect. Neurosurgery 58(2):365–372

    Article  PubMed  Google Scholar 

  24. Goldwirt L, Zahr N, Farinotti R, Fernandez C (2013) Development of a new UPLC-MSMS method for the determination of temozolomide in mice: application to plasma pharmacokinetics and brain distribution study. Biomed Chromatogr 27(7):889–893. doi:10.1002/bmc.2877

    Article  CAS  PubMed  Google Scholar 

  25. Goldwirt L, Lemaitre F, Zahr N, Farinotti R, Fernandez C (2012) A new UPLC-MS/MS method for the determination of irinotecan and 7-ethyl-10-hydroxycamptothecin (SN-38) in mice: application to plasma and brain pharmacokinetics. J Pharm Biomed Anal 66:325–333. doi:10.1016/j.jpba.2012.04.003

    Article  CAS  PubMed  Google Scholar 

  26. Bailer AJ (1988) Testing for the equality of area under the curves when using destructive measurement techniques. J Pharmacokinet Biopharm 16(3):303–309. doi:10.1007/bf01062139

    Article  CAS  PubMed  Google Scholar 

  27. Maity A, Pore N, Lee J, Solomon D, Rourke DM (2000) Epidermal growth factor receptor transcriptionally up-regulates vascular endothelial growth factor expression in human glioblastoma cells via a pathway involving phosphatidylinositol 3-kinase and distinct from that induced by hypoxia. Cancer Res 60(20):5879–5886

    CAS  PubMed  Google Scholar 

  28. Oka N, Soeda A, Inagaki A, Onodera M, Maruyama H, Hara A, Kunisada T, Mori H, Iwama T (2007) VEGF promotes tumorigenesis and angiogenesis of human glioblastoma stem cells. Biochem Biophys Res Commun 360(3):553–559

    Article  CAS  PubMed  Google Scholar 

  29. Chan ASY, Leung SY, Wong MP, Yuen ST, Cheung N, Fan YW, Chung LP (1998) Expression of vascular endothelial growth factor and its receptors in the anaplastic progression of astrocytoma, oligodendroglioma, and ependymoma. Am J Surg Pathol 22(7):816–826

    Article  CAS  PubMed  Google Scholar 

  30. Leon SP, Folkerth RD, Black PM (1996) Microvessel density is a prognostic indicator for patients with astroglial brain tumors. Cancer 77(2):362–372

    Article  CAS  PubMed  Google Scholar 

  31. Weindel K, Moringlane JR, Marm D, Weich HA (1994) Detection and quantification of vascular endothelial growth factor/vascular permeability factor in brain tumor tissue and cyst fluid: the key to angiogenesis? Neurosurgery 35(3):439–449

    Article  CAS  PubMed  Google Scholar 

  32. Kim KJ, Li B, Winer J, Armanini M, Gillett N, Phillips HS, Ferrara N (1993) Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 362(6423):841–844

    Article  CAS  PubMed  Google Scholar 

  33. von Baumgarten L, Brucker D, Tirniceru A, Kienast Y, Grau S, Burgold S, Herms J, Winkler F (2011) Bevacizumab has differential and dose-dependent effects on glioma blood vessels and tumor cells. Clin Cancer Res 17(19):6192–6205. doi:10.1158/1078-0432.ccr-10-1868

    Article  Google Scholar 

  34. Mathieu V, De Neve N, Le Mercier M, Dewelle J, Gaussin JF, Dehoux M, Kiss R, Lefranc F (2008) Combining bevacizumab with temozolomide increases the antitumor efficacy of temozolomide in a human glioblastoma orthotopic xenograft model. Neoplasia 10(12):1383–1392

    PubMed Central  CAS  PubMed  Google Scholar 

  35. Gerber H-P, Ferrara N (2005) Pharmacology and pharmacodynamics of bevacizumab as monotherapy or in combination with cytotoxic therapy in preclinical studies. Cancer Res 65(3):671–680

    CAS  PubMed  Google Scholar 

  36. Claes A, Wesseling P, Jeuken J, Maass C, Heerschap A, Leenders WPJ (2008) Antiangiogenic compounds interfere with chemotherapy of brain tumors due to vessel normalization. Mol Cancer Ther 7(1):71–78. doi:10.1158/1535-7163.mct-07-0552

    Article  CAS  PubMed  Google Scholar 

  37. Winkler F, Kozin SV, Tong RT, Chae SS, Booth MF, Garkavtsev I, Xu L, Hicklin DJ, Fukumura D, di Tomaso E, Munn LL, Jain RK (2004) Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 6:553–563

    CAS  PubMed  Google Scholar 

  38. EMEA (2005) Bevacizumab European public assessment report—Scientific Discussion

  39. Goldwirt L, Beccaria K, Carpentier A, Farinotti R, Fernandez C (2014) Irinotecan and temozolomide brain distribution: a focus on ABCB1. Cancer Chemother Pharmacol 74(1):185–193

    Article  CAS  PubMed  Google Scholar 

  40. Kemper EM, Leenders W, Küsters B, Lyons S, Buckle T, Heerschap A, Boogerd W, Beijnen JH, van Tellingen O (2006) Development of luciferase tagged brain tumour models in mice for chemotherapy intervention studies. Eur J Cancer 42(18):3294–3303. doi:10.1016/j.ejca.2006.07.013

    Article  CAS  PubMed  Google Scholar 

  41. Matsumoto T, Tani E, Kaba K, Shindo H, Miyaji K (1991) Expression of P-glycoprotein in human glioma cell lines and surgical glioma specimens. J Neurosurg 74(3):460–466. doi:10.3171/jns.1991.74.3.0460

    Article  CAS  PubMed  Google Scholar 

  42. Schaich M, Kestel L, Pfirrmann M, Robel K, Illmer T, Kramer M, Dill C, Ehninger G, Schackert G, Krex D (2009) A MDR1 (ABCB1) gene single nucleotide polymorphism predicts outcome of temozolomide treatment in glioblastoma patients. Ann Oncol 20(1):175–181. doi:10.1093/annonc/mdn548

    Article  CAS  PubMed  Google Scholar 

  43. Siemann DW (2011) The unique characteristics of tumor vasculature and preclinical evidence for its selective disruption by tumor-vascular disrupting agents. Cancer Treat Rev 37(1):63–74. doi:10.1016/j.ctrv.2010.05.001

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Ellingson BM, Cloughesy TF, Lai A, Nghiemphu PL, Lalezari S, Zaw T, Motevalibashinaeini K, Mischel PS, Pope WB (2012) Quantification of edema reduction using differential quantitative T2 (DQT2) relaxometry mapping in recurrent glioblastoma treated with bevacizumab. J Neurooncol 106(1):111–119. doi:10.1007/s11060-011-0638-x

    Article  CAS  PubMed  Google Scholar 

  45. Chamberlain MC (2011) Bevacizumab for the treatment of recurrent glioblastoma. Clin Med Insights Oncol 5:117–129. doi:10.4137/CMO.S7232

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Lin F, Marchetti S, Pluim D, Iusuf D, Mazzanti R, Schellens JHM, Beijnen JH, van Tellingen O (2013) Abcc4 together with Abcb1 and Abcg2 form a robust cooperative drug efflux system that restricts the brain entry of camptothecin analogues. Clin Cancer Res 19(8):2084–2095. doi:10.1158/1078-0432.ccr-12-3105

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors thank Stella Ghouti for grammatical English corrections and Georges Khazen for statistical expertise.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Clinical Pharmacy Department - EA 4123, College of Pharmacy, Paris Sud University, 5 rue Jean Baptiste Clement, 92296, Châtenay Malabry, France

    Lauriane Goldwirt, Robert Farinotti & Christine Fernandez

  2. Department of Neurosurgery, Pitie-Salpetriere Hospital, AP-HP, 75013, Paris, France

    Kevin Beccaria & Alexandre Carpentier

  3. Pharmacy Department, Saint Antoine Hospital, AP-HP, 75012, Paris, France

    Christine Fernandez

  4. Sorbonne Universités, UPMC Univ Paris 06, Inserm, CNRS, UM 75, U 1127, UMR 7225, ICM, 75013, Paris, France

    Ahmed Idbaih, Charlotte Schmitt, Camille Levasseur & Marianne Labussiere

  5. Department of Neurooncology, Pitie-Salpetriere Hospital, AP-HP, 75013, Paris, France

    Ahmed Idbaih

  6. Department of Pharmaceutical Sciences, School of Pharmacy, Lebanese American University, Byblos, Lebanon

    Aline Milane

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  1. Lauriane Goldwirt
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  2. Kevin Beccaria
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Correspondence to Lauriane Goldwirt.

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Goldwirt, L., Beccaria, K., Carpentier, A. et al. Preclinical impact of bevacizumab on brain and tumor distribution of irinotecan and temozolomide. J Neurooncol 122, 273–281 (2015). https://doi.org/10.1007/s11060-015-1717-1

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