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Comparison of commercial 5-aminolevulinic acid (Gliolan®) and the pharmacy-compounded solution fluorescence in glioblastoma

  • Technical Note - Tumor - Glioma
  • Published:
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Abstract

Background

5-Aminolevulinic acid (5-ALA) has become an important assistant in glioblastoma (GB) surgery. Unfortunately, its price affects its widespread use.

Objective

The aim of this study was to compare commercial 5-ALA with the pharmacy-compounded solution.

Methods

Using first an in vitro experimental approach, different concentrations of the pharmacy-compounded solution and commercial 5-ALA were tested in U87MG, LN229, U373, and T98G commercial glioblastoma cell lines. Fluorescence intensity was compared for each concentration by flow cytometry. Mean fluorescence of culture supernatant and lysate samples were analyzed. In a second phase, both preparations were used for surgical glioblastoma resection and tumor samples were analyzed by confocal microscopy. Mean fluorescence intensity was analyzed for each preparation and compared.

Results

There was a high variability of fluorescence intensity between cell lines, but each cell line showed similar fluorescence for both preparations (compounded preparation and commercial 5-ALA). In the same way, both preparations had similar fluorescence intensity in glioblastoma samples.

Conclusion

Both, compounded and commercial 5-ALA preparations produce equivalent fluorescent responses in human glioblastoma cells. Fluorescence intensity is cell line specific, but fluorescent properties of both preparations are undistinguishable.

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References

  1. Cordova JS, Shu HK, Liang Z et al (2016) Whole-brain spectroscopic MRI biomarkers identify infiltrating margins in glioblastoma patients. Neuro-Oncology 18:1180–1189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, Fantin VR, Jang HG, Jin S, Keenan MC, Marks KM, Prins RM, Ward PS, Yen KE, Liau LM, Rabinowitz JD et al (2010) Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 465:966

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Delgado-López PD, Corrales-García EM (2016) Survival in glioblastoma: a review on the impact of treatment modalities. Clin Transl Oncol 18:1062–1071

    Article  CAS  PubMed  Google Scholar 

  4. Della Puppa A, Ciccarino P, Lombardi G, Rolma G, Cecchin D, Rosetto M (2014) 5-Aminolevulinic acid fluorescence in high grade glioma surgery: surgical outcome, intraoperative findings, and fluorescence patterns. Biomed Res Int 2014:232561

    PubMed  Google Scholar 

  5. Della Puppa A, Gioffrè G, Gardiman MP et al (2014) Intraoperative 5-aminolevulinic acid (ALA)-induced fluorescence of medulloblastoma: phenotypic variability and CD133(+) expression according to different fluorescence patterns. Neurol Sci 35:99–102

    Article  PubMed  Google Scholar 

  6. Díez Valle R, Tejada Solis S, Idoate Gastearena MA, García de Eulate R, Domínguez Echávarri P, Aristu Mendiroz J (2011) Surgery guided by 5-aminolevulinic fluorescence in glioblastoma: volumetric analysis of extent of resection in single-center experience. Neurooncol 102:105–113

    Article  CAS  Google Scholar 

  7. Diez-Valle R, Tejeda-Solis S (2015) To what extent will 5-aminolevulinic acid change the face of malignant glioma surgery? CNS Oncol 4:265–272

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Hefti M, Albert I, Luginbuehl V (2012) Phenytoin reduces 5-aminolevulinic acid-induced protoporphyrin IX accumulation in malignant glioma cells. J Neuro-Oncol 108:443–450

    Article  CAS  Google Scholar 

  9. Ishihara R, Katayama Y, Watanabe T, Yoshino A, Fukushima T, Sakatani K (2007) Quantitative spectroscopic analysis of 5-aminolevulinic acid-induced protoporphyrin IX fluorescence intensity in diffusely infiltrating astrocytomas. Neurol Med Chir 47:53–57

    Article  Google Scholar 

  10. Ishikawa T, Kajimoto Y, Inoue Y, Ikegami Y, Kuroiwa T (2015) Critical role of ABCG2 in ALA-photodynamic diagnosis and therapy of human brain tumor. Adv Cancer Res 125:197–216

    Article  CAS  PubMed  Google Scholar 

  11. Juzeniene A, Kaliszewski M, Bugaj A, Moan J (2009) Clearance of protoporphyrin IX induced by 5-aminolevulinic acid from WiDr human colon carcinoma cells. Proc of SPIE 7380

  12. Kamp MA, Krause Molle Z, Munoz-Bendix C et al (2018) Various shades of red—a systematic analysis of qualitative estimation of ALA-derived fluorescence in neurosurgery. Neurosurg Rev 41:3–18

    Article  PubMed  Google Scholar 

  13. Kim JE, Cho HR, Xu WJ et al (2015) Mechanism for enhanced 5-aminolevulinic acid fluorescence in isocitrate dehydrogenase 1 mutant malignant gliomas. Oncotarget 6:20266–20277

    PubMed  PubMed Central  Google Scholar 

  14. Lacroix M, Albi-Said D, Fourney DR et al (2001) A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival. J Neurosurg 95:190–198

    Article  CAS  PubMed  Google Scholar 

  15. Lawrence JE, Steele CJ, Rovin RA, Beltron RJ, Rj W (2016) Dexamethasone alone and in combination with desipramine, phenytoin, valproic acid or levetiracetam interferes with5-ALA-mediated PpIX production and cellular retention in glioblastoma cells. J Neuro-Oncol 127:15–21

    Article  CAS  Google Scholar 

  16. Louis DN, Perry A, Reifenberger G et al (2016) The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol 131:803

    Article  PubMed  Google Scholar 

  17. Makary MA, Daniel M (2016) Medical error—the third leading cause of death in the US. BMJ 353:i2139

    Article  PubMed  Google Scholar 

  18. Moan J, Bech O, Gaullier JM, Stokke T, Steen HB, Ma LW et al (1998) Protoporphyrin IX accumulation in cells treated with 5-aminolevulinic acid: dependence on cell density, cell size, and cell cycle. Int J Cancer 75:134–139

    Article  CAS  PubMed  Google Scholar 

  19. Moiyadi AV, Sridhar E (2015) 5-Aminolevulinic acid-induced fluorescence unmasks biological intratumoral heterogeneity within histologically homogeneous areas of malignant gliomas. Acta Neurochir 157:617–619

    Article  PubMed  Google Scholar 

  20. Moiyadi AV, Stummer W (2015) α-Aminolevulinic acid-induced fluorescence-guided resection of brain tumors. Neurol India 63:155–165

    Article  PubMed  Google Scholar 

  21. Moon JH, Kim SH, Shim JK et al (2016) Histopathological implications of ventricle wall 5-aminolevulinic acid-induced fluorescence in the absence of tumor involvement on magnetic resonance images. Oncol Rep 36:837–844

    Article  CAS  PubMed  Google Scholar 

  22. Neidert MC, Hostettler IC, Burkhardt JK et al (2016) The influence of intraoperative resection control modalities on survival following gross total resection of glioblastoma. Neurosurg Rev 39:401–409

    Article  PubMed  Google Scholar 

  23. Piccirillo SG, Dietz S, Madhu B, Griffiths J, Price SJ, Collins VP et al (2012) Fluorescence-guided surgical sampling of glioblastoma identifies phenotypically distinct tumour-initiating cell populations in the tumour mass and margin. Br J Cancer 24:462–468

    Article  CAS  Google Scholar 

  24. Pogue BW, Gibbs-Strauss S, Valdés PA, Samkoe K, Roberts DW, Paulsen KD (2010) Review of neurosurgical fluorescence imaging methodologies. IEEE J Sel Top Quantum Electron 16:493–505

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Rampazzo E, Della Puppa A, Frasson C, Battilana G, Bianco S, Scienza R et al (2014) Phenotypic and functional characterization of glioblastoma cancer stem cells identified through 5-aminolevulinic acid-assisted surgery. J Neuro-Oncol 116:505–513

    Article  CAS  Google Scholar 

  26. Roberts DW, Valdes PA, Harris BT et al (2011) Coregistered fluorescence-enhanced tumor resection of malignant glioma: relationships between δ-aminolevulinic acid-induced protoporphyrin IX fluorescence, magnetic resonance imaging enhancement, and neuropathological parameters. Clinical article. J Neurosurg 114:595–603

    Article  PubMed  Google Scholar 

  27. Sachar M, Anderson KE, Ma X (2015) Protoporphyrin IX: the good, the bad, and the ugly. J Pharmacol Exp Ther 356:267–275

    Article  CAS  PubMed  Google Scholar 

  28. Sanai N, Polley MY, McDermott MW, Parsa AT, Berger MS (2011) An extent of resection threshold for newly diagnosed gliobastomas. J Neurosurg 115:3–8

    Article  PubMed  Google Scholar 

  29. Schebesch KM, Brawanski A, Hohenberger C, Höhne J (2016) Fluorescein sodium-guided surgery of malignant brain tumors: history, current concepts, and future projects. Turk Neurosurg 26:185–194

    PubMed  Google Scholar 

  30. Schucht P, Beck J, Abu-Isa J et al (2012) Gross total resection rates in contemporary glioblastoma surgery: results of an institutional protocol combining 5-aminolevulinic acid intraoperative fluorescence imaging and brain mapping. Neurosurgery 71:927–936

    Article  PubMed  Google Scholar 

  31. Schwake M, Stummer W, Suero-Molina EJ, Wölfer J (2015) Simultaneous fluorescein sodium and 5-ALA in fluorescence-guided glioma surgery. Acta Neurochir 157:887–879

    Article  Google Scholar 

  32. Senders JT, Muskens IS, Schnoor R, Karhade AV, Cote DJ, Smith TR, Broekman MLD (2017) Agents for fluorescence-guided glioma surgery: a systematic review of preclinical and clinical results. Acta Neurochir 159:151–167

    Article  PubMed  Google Scholar 

  33. Slof J, Díez Valle R, Galván J (2015) Cost-effectiveness of 5-aminolevulinic acid-induced fluorescence in malignant gliomasurgery [Spanish]. Neurología 30:163–168

    Article  CAS  PubMed  Google Scholar 

  34. Stummer W, Meinel PU, Wiestler OD, Zanella F, Reulen HJ (2006) Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomized controlled multicentre phase III trial. Lancet Oncol 7:392–401

    Article  CAS  PubMed  Google Scholar 

  35. Stummer W, Stepp H, Möller G, Ehrhardt A, Leonhard M, Reulen HJ (1998) Technical principles for protoporphyrin-IX-fluorescence guided microsurgical resection of malignant glioma tissue. Acta Neurochir 140:995–1000

    Article  CAS  PubMed  Google Scholar 

  36. Stummer W, Tonn JC, Goetz C, Ullrich W, Stepp H, Bink A et al (2015) 5-Aminolevulinic acid-derived tumor fluorescence: the diagnostic accuracy of visible fluorescence qualities as corroborated by spectrometry and histology and postoperative imaging. Neurosurgery 74:310–309

    Article  Google Scholar 

  37. Stupp R, Hegi ME, Mason WP et al (2009) Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomized phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 10:459–466

    Article  CAS  PubMed  Google Scholar 

  38. Suzuki T, Wada S, Eguchi H et al (2013) Cadherin 13 overexpression as an important factor related to the absence of tumor fluorescence in 5-aminolevulinic acid-guided resection of glioma. J Neurosurg 119:1331–1339

    Article  CAS  PubMed  Google Scholar 

  39. Tamura A, Onishi Y, An R, Hoshiba S, Wakabayashi K, Hoshijima K et al (2007) In vitro evaluation of photosensitivity risk related to genetic polymorphisms of human ABC transporter ABCG2 and inhibition by drugs. Drug Metab Pharmacokinetic 22:428–440

    Article  CAS  Google Scholar 

  40. Teng L, Nakada M, Sg Z et al (2011) Silencing of ferrochelatase enhances 5-aminolevulinic acid-based fluorescence and photodynamic therapy efficacy. Br J Cancer 104:798–807

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Valdes PA, Bekelis K, Harris BT et al (2014) 5-Aminolevulinic acid-induced protoporphyrin IX fluorescence in meningioma: qualitative and quantitative measurements in vivo. Neurosurgery 10:74–82

    PubMed  Google Scholar 

  42. Valdes PA, Jacobs V, Harris BT et al (2015) Quantitive fluorescence using 5-aminolevulinic acid-induced protoporphyrin IX biomarker as a surgical adjunct in low-grade glioma surgery. J Neurosurg 123:771–780

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Valdes PA, Kim A, Brantsch M et al (2011) δ-Aminolevulinic acid-induced protoporphyrin IX concentration correlates with histopathologic markers of malignancy inhuman gliomas: the need for quantitative fluorescence-guided resection to identify regions of increasing malignancy. Neuro-Oncology 13:846–856

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Widhalm G, Wolfsberger S, Minchev G, Woehrer A, Krssak M, Czech T et al (2010) 5-Aminolevulinic acid is a promising marker for detection of anaplastic foci in diffusely infiltrating gliomas with nonsignificant contrast enhancement. Cancer 116:1545–1552

    Article  CAS  PubMed  Google Scholar 

  45. Zhao SG, Chen XF, Wang LG et al (2013) Increased expression of ABCB6 enhances protoporphyrin IX accumulation and photodynamic effect in human glioma. Ann Surg Oncol 20:4379–4388

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Neurosurgical Department, Son Espases University Hospital, 79, carretera de Valldemossa, 07120, Majorca, Spain

    Santiago Garfias Arjona, Mónica Lara Almunia, Javier Ángel Ibáñez Domínguez & Marta Brell Doval

  2. Pharmacology Department, Son Espases University Hospital, Majorca, Spain

    Olga Delgado Sánchez

  3. Cancer Cell Biology Laboratory, Institut Universitari d’Investigació en Ciències de la Salut (IUNICS), Universitat de les Illes Balears and Institut d’Investigació Sanitària Illes Balears (IdISBa), Majorca, Spain

    Priam Villalonga

  4. Departament of Fundamental Biology, Universitat de les Illes Balears, Majorca, Spain

    Priam Villalonga

  5. Departament of Chemistry, Universitat de les Illes Balears, Majorca, Spain

    Ruth Villalonga-Planells

  6. Research Department, Son Espases University Hospital, Majorca, Spain

    Javier Pierola Lopetegui, Joan Bestard Escalas & Albert Maimó Barceló

  7. Institut d’Investigació Sanitària Illes Balears (IdISBa), Majorca, Spain

    Priam Villalonga, Javier Pierola Lopetegui, Joan Bestard Escalas & Albert Maimó Barceló

Authors
  1. Santiago Garfias Arjona
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  2. Mónica Lara Almunia
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Correspondence to Santiago Garfias Arjona.

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Garfias Arjona, S., Lara Almunia, M., Ibáñez Domínguez, J.Á. et al. Comparison of commercial 5-aminolevulinic acid (Gliolan®) and the pharmacy-compounded solution fluorescence in glioblastoma. Acta Neurochir 161, 1733–1741 (2019). https://doi.org/10.1007/s00701-019-03930-4

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  • DOI: https://doi.org/10.1007/s00701-019-03930-4

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