Glioblastoma multiforme tedavisindeki birincil engel: Kan beyin bariyeri

Emine Yazıcı; Aleyna Gezen; Ece Oylumlu; Gamze Tanrıöver

doi:10.19161/etd.1621826

EN TR

The primary obstacle in glioblastoma multiforme treatment: The blood-brain barrier

Öz

Classified as grade IV astrocytoma by the World Health Organization, Glioblastoma Multiforme (GBM) is the most aggressive and common primary brain tumor of the central nervous system. The current standard treatment for GBM patients in clinical practice involves resection followed by concurrent radiotherapy and chemotherapy. The effectiveness of these approaches in GBM treatment remains limited due to factors such as tumor heterogeneity, glioma stem cells, DNA damage repair mechanisms, and the blood-brain barrier. Temozolomide, due to its lipophilic nature, easily crosses the blood-brain barrier, making it an effective agent in the treatment of gliomas. However, a significant proportion of patients experience recurrence, and due to prolonged exposure to temozolomide, they develop resistance to the treatment. There is currently no alternative therapeutic approach for recurrent GBM patients. Therefore, the investigation of novel agents is of paramount importance to prolong patient survival. The permeability of the blood-brain barrier to therapeutic agents in the treatment of brain tumors exhibits heterogeneity. Consequently, various strategies aimed at modulating this barrier permeability to enhance drug bioavailability should be developed. Overcoming the blood-brain barrier is a critical consideration in targeted therapeutic approaches and must be addressed in the development of effective treatments. This review aims to provide a comprehensive analysis of the relationship between the blood-brain barrier and GBM, presenting the most recent findings and insights on the subject.

Anahtar Kelimeler

Glioblastoma multiforme tedavisindeki birincil engel: Kan beyin bariyeri

Öz

Dünya Sağlık Örgütü tarafından derece 4 astrositom olarak sınıflandırılan Glioblastoma Multiforme (GBM), merkezi sinir sisteminin en agresif ve yaygın görülen primer beyin tümörüdür. Klinikteki GBM hastaları için mevcut tedavi; rezeksiyonun ardından eş zamanlı uygulanan radyoterapi ve kemoterapiyi içermektedir. GBM tedavisindeki bu yaklaşımların etkinliği; tümör heterojenliği, glioma kök hücreleri, DNA hasar onarım mekanizmaları ve kan-beyin bariyeri gibi faktörler nedeniyle yetersiz kalmaktadır. Temozolomid, lipofilik bir ajan olması nedeniyle kan-beyin bariyerini kolaylıkla geçebilmekte ve bu özelliği sayesinde glioma tedavisinde etkili bir ajan olarak kullanılmaktadır. Bununla birlikte, hastaların büyük bir kısmında nüks meydana gelmekte ve bu hastalar temozolomide uzun süre maruz kaldığı için tedaviye direnç geliştirmektedir. Günümüzde, nüks eden GBM hastaları için farklı bir tedavi yaklaşımı söz konusu değildir. Bu yüzden, hasta sağkalımını uzatacak yeni ajanların araştırılması son derece önemlidir. Terapötik ajanların merkezi sinir sistemine iletimi, kan-beyin bariyeri tarafından engellenmekte ve beyindeki hedeflenen bölgelere erişim, GBM için yeni ilaçların geliştirilmesinde en büyük zorluklardan birini oluşturmaktadır. Beyin tümörleri tedavisinde kan-beyin bariyerinin ilaç geçirgenliği heterojen bir yapı sergilemektedir. Sonuç olarak, bu bariyer geçirgenliğinin modüle edilmesi ve ilaç biyoyararlanımını artırmayı hedefleyen çeşitli stratejiler geliştirilmelidir. Kan-beyin bariyerinin aşılması, hedefe yönelik tedavi yaklaşımlarında dikkate alınması gereken önemli bir konudur. Bu derleme, kan-beyin bariyerinin GBM ile ilişkisini inceleyerek, konuya dair güncel bilgileri ayrıntılı bir şekilde sunmayı amaçlamaktadır

Anahtar Kelimeler

Kaynakça

Pandey V, Ranjan N, Narne P, Babu PP. Roscovitine effectively enhances antitumor activity of temozolomide in vitro and in vivo mediated by increased autophagy and Caspase-3 dependent apoptosis. Sci Rep. 2019;9(1):5012.
Shergalis A, Bankhead A, Luesakul U, Muangsin N, Neamati N. Current challenges and opportunities in treating glioblastomas. Pharmacol Rev. 2018;70(3):412-45.
Bush NAO, Chang SM, Berger MS. Current and future strategies for treatment of glioma. Vol. 40, Neurosurgical Review. 2017;1–14.
Ohgaki H, Kleihues P. The definition of primary and secondary glioblastoma. Vol. 19, Clinical Cancer Research. 2013;Feb 15;19(4):764-72.
Ohgaki H, Dessen P, Jourde B, Horstmann S, Nishikawa T, Di Patre PL, et al. Genetic pathways to glioblastoma: A population-based study. Cancer Res. 2004;64(19):6892-9.
Khabibov M, Garifullin A, Boumber Y, Khaddour K, Fernandez M, Khamitov F, et al. Signaling pathways and therapeutic approaches in glioblastoma multiforme (Review). Int J Oncol. 2022;60(6):69.
Kim M, Ladomersky E, Mozny A, Kocherginsky M, O’shea K, Reinstein ZZ, et al. Glioblastoma as an age-related neurological disorder in adults. Neurooncol Adv. 2021;3(1):vdab125.
Wu W, Klockow JL, Zhang M, Lafortune F, Chang E, Jin L, et al. Glioblastoma multiforme (GBM): An overview of current therapies and mechanisms of resistance. Vol. 171, Pharmacological Research. 2021.

Hanif F, Muzaffar K, Perveen K, Malhi SM, Simjee SU. Glioblastoma multiforme: A review of its epidemiology and pathogenesis through clinical presentation and treatment. Vol. 18, Asian Pacific Journal of Cancer Prevention. 2017;3-9.
Grochans S, Cybulska AM, Simińska D, Korbecki J, Kojder K, Chlubek D, et al. Epidemiology of Glioblastoma Multiforme–Literature Review. Vol. 14, Cancers. 2022;2412.
Yue Q, Wang Z, Shen Y, Lan Y, Zhong X, Luo X, et al. Histone H3K9 Lactylation Confers Temozolomide Resistance in Glioblastoma via LUC7L2-Mediated MLH1 Intron Retention. Advanced Science. 2024;11(19):e2309290.
Gupta T, Sahoo RK, Singh H, Katke S, Chaurasiya A, Gupta U. Lipid-Based Nanocarriers in the Treatment of Glioblastoma Multiforme (GBM): Challenges and Opportunities. Vol. 24, AAPS PharmSciTech. 2023:102.
Guevara B, Cullison K, Maziero D, Azzam GA, De La Fuente MI, Brown K, et al. Simulated Adaptive Radiotherapy for Shrinking Glioblastoma Resection Cavities on a Hybrid MRI–Linear Accelerator. Cancers (Basel). 2023;15(5):1555.
Navarria P, Minniti G, Clerici E, Tomatis S, Pinzi V, Ciammella P, et al. Re-irradiation for recurrent glioma: outcome evaluation, toxicity and prognostic factors assessment. A multicenter study of the Radiation Oncology Italian Association (AIRO). J Neurooncol. 2019;142(1):59-67.
Jnaidi R, Almeida AJ, Gonçalves LM. Solid lipid nanoparticles and nanostructured lipid carriers as smart drug delivery systems in the treatment of glioblastoma multiforme. Vol. 12, Pharmaceutics. 2020;860.
Zhao Y, Gan L, Ren L, Lin Y, Ma C, Lin X. Factors influencing the blood-brain barrier permeability. Brain Res. 2022;1788.
Angom RS, Nakka NMR, Bhattacharya S. Advances in Glioblastoma Therapy: An Update on Current Approaches. Vol. 13, Brain Sciences. 2023;1536.
Czarnywojtek A, Borowska M, Dyrka K, Van Gool S, Sawicka-Gutaj N, Moskal J, et al. Glioblastoma Multiforme: The Latest Diagnostics and Treatment Techniques. Vol. 108, Pharmacology. 2023;423-31.
Tomar MS, Kumar A, Srivastava C, Shrivastava A. Elucidating the mechanisms of Temozolomide resistance in gliomas and the strategies to overcome the resistance. Vol. 1876, Biochimica et Biophysica Acta - Reviews on Cancer. 2021;188616.
Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJB, et al. Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma. New England Journal of Medicine. 2005;352(10):987-96.
Minniti G, Niyazi M, Alongi F, Navarria P, Belka C. Current status and recent advances in reirradiation of glioblastoma. Vol. 16, Radiation Oncology. 2021:36.
Wick W, Gorlia T, Bendszus M, Taphoorn M, Sahm F, Harting I, et al. Lomustine and Bevacizumab in Progressive Glioblastoma. New England Journal of Medicine. 2017;377(20):1954-63.
Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, et al. Bevacizumab plus Radiotherapy–Temozolomide for Newly Diagnosed Glioblastoma. New England Journal of Medicine. 2014;370(8):709-22.
Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, et al. A Randomized Trial of Bevacizumab for Newly Diagnosed Glioblastoma. New England Journal of Medicine. 2014;370(8):699-708.
Mehta M, Wen P, Nishikawa R, Reardon D, Peters K. Critical review of the addition of tumor treating fields (TTFields) to the existing standard of care for newly diagnosed glioblastoma patients. Vol. 111, Critical Reviews in Oncology/Hematology. 2017;60-65.
Dymova MA, Kuligina E V., Richter VA. Molecular mechanisms of drug resistance in glioblastoma. Vol. 22, International Journal of Molecular Sciences. 2021;6385.
Fong H, Zhou B, Feng H, Luo C, Bai B, Zhang J, et al. Recapitulation of Structure–Function–Regulation of Blood–Brain Barrier under (Patho)Physiological Conditions. Vol. 13, Cells. 2024;260.
Wong AD, Ye M, Levy AF, Rothstein JD, Bergles DE, Searson PC. The blood-brain barrier: An engineering perspective. Frontiers in Neuroengineering. 2013;6-7.
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. Vol. 19, Drug Resistance Updates. 2015;1-12.
Wu D, Chen Q, Chen X, Han F, Chen Z, Wang Y. The blood–brain barrier: structure, regulation, and drug delivery. Vol. 8, Signal Transduction and Targeted Therapy. 2023;217.
Alahmari A. Blood-Brain Barrier Overview: Structural and Functional Correlation. Vol. 2021, Neural Plasticity. 2021.
Ahmed MH, Canney M, Carpentier A, Idbaih A. Overcoming the blood brain barrier in glioblastoma: Status and future perspective. Vol. 179, Revue Neurologique. 2023;430-36.
Rong L, Li N, Zhang Z. Emerging therapies for glioblastoma: current state and future directions. Vol. 41, Journal of Experimental and Clinical Cancer Research. 2022:142.
Mosteiro A, Pedrosa L, Ferrés A, Diao D, Sierra À, González JJ. The Vascular Microenvironment in Glioblastoma: A Comprehensive Review. Vol. 10, Biomedicines. 2022:1285.
Arvanitis CD, Ferraro GB, Jain RK. The blood–brain barrier and blood–tumour barrier in brain tumours and metastases. Vol. 20, Nature Reviews Cancer. 2020:26-41.
Noorani I, de la Rosa J. Breaking barriers for glioblastoma with a path to enhanced drug delivery. Vol. 14, Nature Communications. 2023;5909. Ghosh C, Puvenna V, Gonzalez-Martinez J, Janigro D, Marchi N. Blood-Brain Barrier P450 Enzymes and Multidrug Transporters in Drug Resistance: A Synergistic Role in Neurological Diseases. Curr Drug Metab. 2011;12(8):742-49.
Li Y, Liu L, Li J, Xie L, Wang GJ, Liu XD. Transport of gatifloxacin involves Na+/Ca2+ exchange and excludes P-glycoprotein and multidrug resistance associated-proteins in primary cultured rat brain endothelial cells. Eur J Pharmacol. 2009;616(1–3):68-72.
Mineiro R, Albuquerque T, Neves AR, Santos CRA, Costa D, Quintela T. The Role of Biological Rhythms in New Drug Formulations to Cross the Brain Barriers. Vol. 24, International Journal of Molecular Sciences. 2023;12541.
Sonabend AM, Gould A, Amidei C, Ward R, Schmidt KA, Zhang DY, et al. Repeated blood–brain barrier opening with an implantable ultrasound device for delivery of albumin-bound paclitaxel in patients with recurrent glioblastoma: a phase 1 trial. Lancet Oncol. 2023;24(5):509-22.
Pitz MW, Desai A, Grossman SA, Blakeley JO. Tissue concentration of systemically administered antineoplastic agents in human brain tumors. Vol. 104, Journal of Neuro-Oncology. 2011;629-38.
Jacobs VL, Valdes PA, Hickey WF, de Leo JA. Current review of in vivo GBM rodent models: Emphasis on the CNS-1 tumour model. Vol. 3, ASN Neuro. 2011;e00063.
Liebner S, Dijkhuizen RM, Reiss Y, Plate KH, Agalliu D, Constantin G. Functional morphology of the blood–brain barrier in health and disease. Vol. 135, Acta Neuropathologica. 2018;311-36.
Yang FY, Wong TT, Teng MC, Liu RS, Lu M, Liang HF, et al. Focused ultrasound and interleukin-4 receptor-targeted liposomal doxorubicin for enhanced targeted drug delivery and antitumor effect in glioblastoma multiforme. Journal of Controlled Release. 2012;160(3):652-58.
Leten C, Struys T, Dresselaers T, Himmelreich U. In vivo and ex vivo assessment of the blood brain barrier integrity in different glioblastoma animal models. J Neurooncol. 2014;119(2):297-306.
Nduom EK, Yang C, Merrill MJ, Zhuang Z, Lonser RR. Characterization of the blood-brain barrier of metastatic and primary malignant neoplasms. J Neurosurg. 2013;119(2):427-33.
Robey RW, Pluchino KM, Hall MD, Fojo AT, Bates SE, Gottesman MM. Revisiting the role of ABC transporters in multidrug-resistant cancer. Vol. 18, Nature Reviews Cancer. 2018;452-464.
Aghajani M, Jalilzadeh N, Aghebati-Maleki A, Yari A, Tabnak P, Mardi A, et al. Current approaches in glioblastoma multiforme immunotherapy. Vol. 26, Clinical and Translational Oncology. 2024;1584-1612.
Dréan A, Goldwirt L, Verreault M, Canney M, Schmitt C, Guehennec J, et al. Blood-brain barrier, cytotoxic chemotherapies and glioblastoma. Vol. 16, Expert Review of Neurotherapeutics. 2016;1285-1300.

Ayrıntılar

Birincil Dil

Türkçe

Konular

Beyin ve Sinir Cerrahisi (Nöroşirurji), Kanser Hücre Biyolojisi

Bölüm

Derleme

Yazarlar

Emine Yazıcı ^*
0009-0009-7320-5764
Türkiye

Aleyna Gezen
0009-0001-2753-274X
Türkiye

Ece Oylumlu
0000-0003-4234-9086
Türkiye

Gamze Tanrıöver
0000-0002-8002-5544
Türkiye

Yayımlanma Tarihi

12 Mart 2025

Gönderilme Tarihi

16 Ocak 2025

Kabul Tarihi

31 Ocak 2025

Yayımlandığı Sayı

Yıl 2025 Cilt: 64 Sayı: 1

DOI

https://doi.org/10.19161/etd.1621826

IZ

https://izlik.org/JA95FB89DF

Kaynak Göster

RIS / Bibtex

APA

Yazıcı, E., Gezen, A., Oylumlu, E., & Tanrıöver, G. (2025). Glioblastoma multiforme tedavisindeki birincil engel: Kan beyin bariyeri. Ege Tıp Dergisi, 64(1), 184-192. https://doi.org/10.19161/etd.1621826

AMA

1.Yazıcı E, Gezen A, Oylumlu E, Tanrıöver G. Glioblastoma multiforme tedavisindeki birincil engel: Kan beyin bariyeri. ETD. 2025;64(1):184-192. doi:10.19161/etd.1621826

Chicago

Yazıcı, Emine, Aleyna Gezen, Ece Oylumlu, ve Gamze Tanrıöver. 2025. “Glioblastoma multiforme tedavisindeki birincil engel: Kan beyin bariyeri”. Ege Tıp Dergisi 64 (1): 184-92. https://doi.org/10.19161/etd.1621826.

EndNote

Yazıcı E, Gezen A, Oylumlu E, Tanrıöver G (01 Mart 2025) Glioblastoma multiforme tedavisindeki birincil engel: Kan beyin bariyeri. Ege Tıp Dergisi 64 1 184–192.

IEEE

[1]E. Yazıcı, A. Gezen, E. Oylumlu, ve G. Tanrıöver, “Glioblastoma multiforme tedavisindeki birincil engel: Kan beyin bariyeri”, ETD, c. 64, sy 1, ss. 184–192, Mar. 2025, doi: 10.19161/etd.1621826.

ISNAD

Yazıcı, Emine - Gezen, Aleyna - Oylumlu, Ece - Tanrıöver, Gamze. “Glioblastoma multiforme tedavisindeki birincil engel: Kan beyin bariyeri”. Ege Tıp Dergisi 64/1 (01 Mart 2025): 184-192. https://doi.org/10.19161/etd.1621826.

JAMA

1.Yazıcı E, Gezen A, Oylumlu E, Tanrıöver G. Glioblastoma multiforme tedavisindeki birincil engel: Kan beyin bariyeri. ETD. 2025;64:184–192.

MLA

Yazıcı, Emine, vd. “Glioblastoma multiforme tedavisindeki birincil engel: Kan beyin bariyeri”. Ege Tıp Dergisi, c. 64, sy 1, Mart 2025, ss. 184-92, doi:10.19161/etd.1621826.

Vancouver

1.Emine Yazıcı, Aleyna Gezen, Ece Oylumlu, Gamze Tanrıöver. Glioblastoma multiforme tedavisindeki birincil engel: Kan beyin bariyeri. ETD. 01 Mart 2025;64(1):184-92. doi:10.19161/etd.1621826