Skip to main content

Advertisement

SpringerLink
Log in

Motexafin gadolinium enhances the efficacy of aminolevulinic acid mediated-photodynamic therapy in human glioma spheroids

  • Laboratory Investigation - human/animal tissue
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Photodynamic therapy (PDT) has been investigated as a postoperative treatment in patients with high grade gliomas. The purpose of this in vitro investigation was to determine whether motexafin gadolinium (MGd), a known radiation sensitizer, could potentiate the effects of 5-aminolevulinic acid (ALA)-PDT. Human glioma (ACBT) spheroids (250 μm diameter) were incubated in 5-aminolevulinic acid (ALA) with and without MGd and irradiated with 635 nm light for a total light fluence of 6, 12, or 18 J cm−2 delivered at a fluence rate of 5 mW cm−2. Spheroid growth was monitored for a period of 4 weeks following each treatment. In another set of experiments, 400–500 μm diameter ACBT spheroids were implanted into a gel collagen matrix and subjected to ALA-PDT (fluence: 3 or 6 J cm−2), MGd, or a combination of ALA-PDT and MGd. The migration distance of surviving glioma cells in each treatment group was recorded over a 5-day period. The results showed that MGd interacted with PDT in a synergistic manner resulting in greater cytotoxicity than that achievable with either treatment modality alone. The degree of synergism was shown to increase with increasing light fluence. At the highest light fluence investigated (18 J cm−2), the percentage of spheroids demonstrating growth 4 weeks following exposure to MGd, ALA-PDT, or MGd + ALA-PDT was 100%, 75%, and 15%, respectively. The results of cell migration studies revealed that the combination of PDT and MGd produced a significant inhibitory effect on glioma cell migration: the addition of MGd resulted in an approximately three times reduction in migration distance compared with PDT alone. Overall, the results suggest that MGd can potentiate both the cytotoxic and migration inhibitory effects of ALA-PDT and hence, this combined therapeutic approach has the potential to extend treatment volumes in patients with malignant gliomas.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Stupp R, van den Bent MJ, Hegi ME (2005) Optimal role of temozolomide in the treatment of malignant gliomas. Curr Neurol Neurosci Rep 5:198–206. doi:10.1007/s11910-005-0047-7

    Article  PubMed  CAS  Google Scholar 

  2. Wallner KE, Galicich JH, Krol G, Arbit E, Malkin MG (1989) Patterns of failure following treatments for glioblastoma multiforme and anaplastic astrocytoma. Int J Radiat Oncol Biol Phys 16:1405–1409

    PubMed  CAS  Google Scholar 

  3. Muller PJ, Wilson BC, Lilge LD, Yang V, Hetzel FW, Chen Q et al (2001) Photofrin photodynamic therapy for malignant brain tumors. In: Dougherty TJ (ed) Optical methods for tumor treatment and detection: mechanisms and techniques in photodynamic therapy. Proceedings SPIE, vol 4248, April 2001, SPIE Publishers, Bellingham, WA, pp 34–41

  4. Eljamel MS, Goodman C, Moseley H (2007) ALA and Photofrin® fluorescence-guided resection and repetitive PDT in glioblastoma multiforme: a single centre phase III randomised controlled trial. Lasers Med Sci. doi:10.1007/s10103-007-0494-2

  5. Beck TJ, Kreth FW, Beyer W, Mehrkens JH, Obermeier A, Stepp H et al (2007) Interstitial photodynamic therapy of nonresectable malignant glioma recurrences using 5-aminolevulinic acid induced protoporphyrin IX. Lasers Surg Med 39(5):386–393. doi:10.1002/lsm.20507

    Article  PubMed  Google Scholar 

  6. Dougherty TJ (1993) Photodynamic therapy. Photochem Photobiol 58:895–900. doi:10.1111/j.1751-1097.1993.tb04990.x

    Article  PubMed  CAS  Google Scholar 

  7. Lilge L, Wilson BC (1998) Photodynamic therapy of intracranial tissues: a preclinical comparative study of four different photosensitizers. J Clin Laser Med Surg 16:81–92

    PubMed  CAS  Google Scholar 

  8. Hebeda KM, Saarnak AE, Olivo M, Sterenborg HJ, Wolbers JG (1998) 5-Aminolevulinic acid induced endogenous porphyrin fluorescence in 9L and C6 brain tumours and in the normal rat brain. Acta Neurochir (Wien) 140:503–513. doi:10.1007/s007010050132

    Article  CAS  Google Scholar 

  9. Lilge L, Portnoy M, Wilson BC (2000) Apoptosis induced in vivo by photodynamic therapy in normal brain and intracranial tumor tissue. Br J Cancer 83:1110–1117. doi:10.1054/bjoc.2000.1426

    Article  PubMed  CAS  Google Scholar 

  10. Obwegeser A, Jakober R, Kostron H (1998) Uptake and kinetics of 14C-labelled meta-tetrahydroxylchlorin and 5-aminolevulinic acid in the C6 rat glioma model. Br J Cancer 78:733–738

    PubMed  CAS  Google Scholar 

  11. Stummer W, Stocker S, Novotny A, Heimann A, Sauer O, Kempski O et al (1998) In vitro and in vivo porphyrin accumulation by C6 glioma cells after exposure to 5-aminolevulinic acid. J Photochem Photobiol B Biol 45:160–169. doi:10.1016/S1011-1344(98)00176-6

    Article  CAS  Google Scholar 

  12. Stummer W, Stocker S, Wagner S, Stepp H, Fritsch C, Goetz C et al (1998) Intraoperative detection of malignant gliomas by 5-aminolevulinic acid induced porphyrin fluorescence. Neurosurgery 42:518–526. doi:10.1097/00006123-199803000-00017

    Article  PubMed  CAS  Google Scholar 

  13. Terr L, Weiner LP (1983) An autoradiographic study of 5-aminolevulinic acid uptake by mouse brain. Exp Neurol 79:564–568. doi:10.1016/0014-4886(83)90234-0

    Article  PubMed  CAS  Google Scholar 

  14. Stummer W, Novotny A, Stepp H, Goetz C, Bise K, Reulen HJ (2000) Fluorescence-guided resection of glioblastoma multiforme by using 5-aminolevulinic acid-induced porphyrins: a prospective study in 52 consecutive patients. J Neurosurg 93:1003–1013

    Article  PubMed  CAS  Google Scholar 

  15. Angell-Petersen E, Hirschberg H, Madsen SJ (2007) Determination of fluence rate and temperature distributions in the rat brain; implications for photodynamic therapy. J Biomed Opt 12(1):014003-1–014003-9

    Article  Google Scholar 

  16. Sessler JL, Burrell AK (1992) Expanded porphyrins. Top Curr Chem 161:177–273

    CAS  Google Scholar 

  17. Magda D, Miller RA (2006) Motexafin gadolinium: a novel redox active drug for cancer therapy. Semin Cancer Biol 16(6):466–476. doi:10.1016/j.semcancer.2006.09.002

    Article  PubMed  CAS  Google Scholar 

  18. Evens AM (2004) Motexafin gadolinium: a redox-active tumor selective agent for the treatment of cancer. Curr Opin Oncol 16(6):576–580. doi:10.1097/01.cco.0000142073.29850.98

    Article  PubMed  CAS  Google Scholar 

  19. Madsen SJ, Sun C-H, Tromberg BJ, Wallace VP, Hirschberg H (2000) Photodynamic therapy of human glioma spheroids using 5-aminolevulinic acid. Photochem Photobiol 72(1):128–134. doi:10.1562/0031-8655(2000)072<0128:PTOHGS>2.0.CO;2

    Article  PubMed  CAS  Google Scholar 

  20. Sutherland RM, Carlsson J, Durand RE, Yuhas J (1981) Spheroids in cancer research. Cancer Res 41:2980–2994

    Google Scholar 

  21. Drewinko B, Loo TL, Brown B, Gottlieb JA, Freireich EJ (1976) Combination therapy in vitro with adriamycin: observation of additive, antagonistic, and synergistic effects when used in two-drug combinations on cultured human lymphoma cells. Cancer Biochem Biophys 1:187–195

    PubMed  CAS  Google Scholar 

  22. Hirschberg H, Sun C-H, Krasieva T, Madsen SJ (2006) Effects of ALA-mediated photodynamic therapy on the invasiveness of human glioma cells. Lasers Surg Med 38:939–945. doi:10.1002/lsm.20445

    Article  PubMed  Google Scholar 

  23. Mathews MS, Sun C–H, Madsen SJ, Hirschberg H (2007) Comparing the effects of repetitive and chronic PDT in human glioma spheroids. In: Kollias N, Choi B, Zeng H et al (eds) Photonic therapeutics and diagnostics III. Proceedings SPIE, vol 6424, SPIE Publishers, Bellingham, WA, pp D1–D9

  24. Madsen SJ, Sun C-H, Tromberg BJ, Hirschberg H (2003) Repetitive 5-aminolevulinic acid-mediated photodynamic therapy on human glioma spheroids. J Neurooncol 62(3):243–250. doi:10.1023/A:1023362011705

    Article  PubMed  Google Scholar 

  25. Giese A, Loo MA, Tran N, Haskett D, Coons SW, Berens ME (1996) Dichotomy of astrocytoma migration and proliferation. Int J Cancer 67:275–282. doi:10.1002/(SICI)1097-0215(19960717)67:2<275::AID-IJC20>3.0.CO;2-9

    Article  PubMed  CAS  Google Scholar 

  26. Giese A, Loo MA, Rief MD, Tran N, Berens ME (1995) Substrates for astrocytoma invasion. Neurosurgery 37:294–302. doi:10.1097/00006123-199508000-00015

    Article  PubMed  CAS  Google Scholar 

  27. Binder DK, Berger MS (2002) Proteases and the biology of glioma invasion. J Neurooncol 56:149–158. doi:10.1023/A:1014566604005

    Article  PubMed  Google Scholar 

  28. Rao JS (2000) Molecular mechanisms of glioma invasiveness: the role of proteases. Nat Rev Cancer 3(7):489–501. doi:10.1038/nrc1121

    Article  CAS  Google Scholar 

  29. Uhm JH, Dooley NP, Villemure JG, Yong VW (1997) Mechanisms of glioma invasion: role of matrix-metalloproteinases. Can J Neurol Sci 24:3–15

    PubMed  CAS  Google Scholar 

  30. Koul D, Parthasarathy R, Shen R, Davies MA, Jasser SA, Chintala SK et al (2001) Suppression of matrix metalloproteinase-2 gene expression and invasion in human glioma cells by MMAC/PTEN. Oncogene 20:6669–6678. doi:10.1038/sj.onc.1204799

    Article  PubMed  CAS  Google Scholar 

  31. Maidment SL (1997) The cytoskeleton and brain tumour cell migration. Anticancer Res 17:4145–4149

    PubMed  CAS  Google Scholar 

  32. Chicoine MR, Silbergeld DL (1995) Assessment of brain tumor cell motility in vivo and in vitro. J Neurosurg 82:615–622

    PubMed  CAS  Google Scholar 

  33. Muller PJ, Wilson BC (1986) An update on the penetration depth of 630 nm light in normal and malignant human brain tissue in vivo. Phys Med Biol 31:1295–1297. doi:10.1088/0031-9155/31/11/012

    Article  PubMed  CAS  Google Scholar 

  34. Wilson BC, Jeeves WP, Lowe DM (1985) In vivo and post mortem measurements of the attenuation spectra of light in mammalian tissues. Photochem Photobiol 42:153–162. doi:10.1111/j.1751-1097.1985.tb01554.x

    Article  PubMed  CAS  Google Scholar 

  35. Doiron DR, Svaasand LO, Profio AE (1983) Light dosimetry in tissue applications to photoradiation therapy. In: Kessel D, Dougherty TJ (eds) Porphyrin photosensitization. Plenum Press, New York, pp 63–75

    Google Scholar 

  36. Powers SK, Brown JT (1986) Light dosimetry in brain tissue: an in vivo model applicable to photodynamic therapy. Lasers Surg Med 6:318–322. doi:10.1002/lsm.1900060305

    Article  PubMed  CAS  Google Scholar 

  37. Chen Q, Chopp M, Madigan L, Dereski MO, Hetzel FW (1996) Damage threshold of normal rat brain in photodynamic therapy. Photochem Photobiol 64:163–167. doi:10.1111/j.1751-1097.1996.tb02437.x

    Article  PubMed  CAS  Google Scholar 

  38. Madsen SJ, Sun C-H, Tromberg BJ, Hirschberg H (2001) Development of a novel indwelling balloon applicator for optimizing light delivery in photodynamic therapy. Lasers Surg Med 29:406–412. doi:10.1002/lsm.10005

    Article  PubMed  CAS  Google Scholar 

  39. Bisland SK, Lilge L, Lin A, Rusnow R, Wilson BC (2004) Metronomic photodynamic therapy as a new paradigm for photodynamic therapy: rationale and preclinical evaluation of technical feasibility for treating malignant brain tumors. Photochem Photobiol 80:22–30. doi:10.1562/2004-03-05-RA-100.1

    Article  PubMed  CAS  Google Scholar 

  40. Sessler JL, Miller RA (2000) Texaphyrins: new drugs with diverse clinical applications in radiation and photodynamic therapy. Biochem Pharmacol 59:733–739. doi:10.1016/S0006-2952(99)00314-7

    Article  PubMed  CAS  Google Scholar 

  41. Khuntia D, Mehta M (2004) Motexafin gadolinium: a clinical review of a novel radioenhancer for brain tumors. Expert Rev Anticancer Ther 4:981–989. doi:10.1586/14737140.4.6.981

    Article  PubMed  CAS  Google Scholar 

  42. Carde P, Timmerman R, Mehta MP, Koprowski CD, Ford J, Tishler RB et al (2001) Multicenter phase IB/II trial of the radiation enhancer motexafin gadolinium in patients with brain metastases. J Clin Oncol 19:2074–2083

    PubMed  CAS  Google Scholar 

  43. Hirschberg H, Wu GN, Madsen SJ (2007) Evaluation of motexafin gadolinium (MGd) as a contrast agent for intraoperative MRI. Minim Invasive Neurosurg 50:1–6. doi:10.1055/s-2007-993158

    Article  Google Scholar 

  44. Donnelly ET, Liu YF, Fatunmbi YO, Lee I, Magda D, Rockwell S (2004) Effects of texaphyrins on the oxygenation of EMT6 mouse mammary tumors. Int J Radiat Oncol Biol Phys 58(5):1570–1576. doi:10.1016/j.ijrobp.2003.12.017

    Article  PubMed  CAS  Google Scholar 

  45. Wu GN, Ford JM, Alger JR (2006) MRI measurement of the uptake and retention of motexafin gadolinium in glioblastoma multiforme and uninvolved normal human brain. J Neurooncol 77:95–103. doi:10.1007/s11060-005-9101-1

    Article  PubMed  CAS  Google Scholar 

  46. Hirschberg H, Sørensen DR, Angell-Petersen E, Peng Q, Tromberg B, Sun CH et al (2006) Repetitive photodynamic therapy of malignant brain tumors. J Environ Pathol Toxicol Oncol 25(1–2):261–280

    PubMed  CAS  Google Scholar 

  47. Viala J, Vanel D, Meingan P, Lartigau E, Carde P, Renschler MF (1999) Phases IB and II multidose trial of gadolinium texaphyrin, a radiation sensitizer detectable at MR imaging: preliminary results in brain metastases. Radiology 212:755–759

    PubMed  CAS  Google Scholar 

  48. Mehta MP, Shapiro WR, Glantz MJ, Patchell RA, Weitzner MA, Meyers CA et al (2002) Lead-in phase to randomized trial of motexafin gadolinium and whole-brain radiation for patients with brain metastases: centralized assessment of magnetic resonance imaging, neurocognitive, and neurologic end points. J Clin Oncol 20:3445–3453. doi:10.1200/JCO.2002.07.500

    Article  PubMed  CAS  Google Scholar 

  49. Mehta MP, Rodrigus P, Terhaard CH, Rao A, Suh J, Roa W et al (2003) Survival and neurologic outcomes in a randomized trial of motexafin gadolinium and whole-brain radiation therapy in brain metastases. J Clin Oncol 21(13):2529–2536. doi:10.1200/JCO.2003.12.122

    Article  PubMed  CAS  Google Scholar 

  50. Meyers CA, Smith JA, Bezjak A, Mehta MP, Liebmann J, Illidge T et al (2004) Neurocognitive function and progression in patients with brain metastases treated with whole-brain radiation and motexafin gadolinium: results of a randomized phase III trial. J Clin Oncol 22(1):157–165. doi:10.1200/JCO.2004.05.128

    Article  PubMed  CAS  Google Scholar 

  51. Rosenthal DI, Nurenberg P, Becerra CR, Frenkel EP, Carbone DP, Lum BL et al (1999) A phase I single dose trial of gadolinium texaphyrin (Gd-Tex), a tumor selective radiation sensitizer detectable by magnetic resonance imaging. Clin Cancer Res 5:739–745

    PubMed  CAS  Google Scholar 

  52. Miller RA, Woodburn K, Fan Q, Renschler MF, Sessler JL, Koutcher JA (1999) In vivo animal studies with gadolinium (III) texaphyrin as a radiation enhancer. Int J Radiat Oncol Biol Phys 45(4):981–989. doi:10.1016/S0360-3016(99)00274-6

    PubMed  CAS  Google Scholar 

  53. De Stasio G, Rajesh D, Ford JM, Daniels MJ, Erhardt RJ, Frazer BH et al (2006) Motexafin-gadolinium taken up in vitro by at least 90% of glioblastoma cell nuclei. Clin Cancer Res 12(1):206–213. doi:10.1158/1078-0432.CCR-05-0743

    Article  PubMed  CAS  Google Scholar 

  54. Woodburn KW (2001) Intracellular localization of the radiation enhancer motexafin gadolinium using interferometric Fourier fluorescence microscopy. J Pharmacol Exp Ther 297:888–894

    PubMed  CAS  Google Scholar 

  55. Hirschberg H, Mathews MS, Angell-Petersen E, Spetalen S, Madsen SJ (2007) Increased brain edema following 5-aminolevulinic acid administration mediated photodynamic therapy in normal and tumor-bearing rats. In: Kollias N, Choi B, Zeng H et al (eds) Photonic therapeutics and diagnostics III. Proceedings SPIE, vol 6424, SPIE Publishers, Bellingham, WA, pp B1–B8

  56. Hirschberg H, Zhang M, Chighvinadze D, Peng Q, Madsen SJ (2008) Targeted opening of the blood brain barrier by ALA mediated PDT. In: Kollias N, Choi B, Zeng H et al (eds) Photonic therapeutics and diagnostics IV. Proceedings SPIE, vol 6842, SPIE Publishers, Bellingham, WA, pp O1–O11

  57. Madsen SJ, Angell-Petersen E, Spitalen S, Carper SW, Ziegler S, Hirschberg H (2006) Photodynamic therapy of newly implanted glioma cells in the rat brain. Lasers Surg Med 38:540–548. doi:10.1002/lsm.20274

    Article  PubMed  Google Scholar 

  58. Madsen SJ, Kharkhuu K, Hirschberg H (2007) Utility of the F98 rat glioma model for photodynamic therapy. J Environ Pathol Toxicol Oncol 26(2):149–155

    PubMed  CAS  Google Scholar 

  59. Madsen SJ, Sun C-H, Tromberg BJ, Yeh AT, Sanchez R, Hirschberg H (2002) Effects of combined photodynamic therapy and ionizing radiation on human glioma spheroids. Photochem Photobiol 76:411–416. doi:10.1562/0031-8655(2002)076<0411:EOCPTA>2.0.CO;2

    Article  PubMed  CAS  Google Scholar 

  60. Hirschberg H, Sun C-H, Yeh AT, Tromberg BJ, Madsen SJ (2004) Enhanced effects of concurrent 5-aminolevulinic acid-mediated photodynamic therapy by hyperthermia on human glioma spheroids. J Neurooncol 70:289–299. doi:10.1007/s11060-004-9161-7

    Article  PubMed  Google Scholar 

  61. Iinuma S, Farshi SS, Ortel B, Hasan T (1994) A mechanistic study of cellular photodestruction with 5-aminolevulinic acid-induced porphyrin. Br J Cancer 70:21–28

    PubMed  CAS  Google Scholar 

  62. Verma A, Facchina SL, Hirsch DJ, Song S-Y, Dillahey LF, Williams JR et al (1998) Photodynamic tumor therapy: mitochondrial benzodiazepine receptors as a therapeutic target. Mol Med 4:40–48

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Steen Madsen is grateful for the support of the UNLV Office of Research. Portions of this work were made possible, in part, through access to the Laser Microbeam and Medical Program (LAMMP) and the Chao Cancer Center Optical Biology Shared Resource at the University of California, Irvine. These facilities are supported by the National Institutes of Health under grants RR-01192 and CA-62203, respectively. In addition, Beckman Laser Institute programmatic support was provided by the Department of Energy (DOE #DE-FG03-91ER61227), and the Office of Naval Research (ONR #N00014-91-C-0134).

Author information

Authors and Affiliations

  1. Department of Health Physics, University of Nevada, 4505 Maryland Pkwy, PO Box 453037, Las Vegas, NV, 89154-3037, USA

    Steen J. Madsen, Van Vo & Henry Hirschberg

  2. Beckman Laser Institute and Medical Clinic, University of California, Irvine, 92612, USA

    Marlon S. Mathews, Chung-Ho Sun, Rogelio Sanchez & Henry Hirschberg

  3. Department of Neurological Surgery, University of California, Irvine Medical Center, Orange, CA, 92868, USA

    Marlon S. Mathews

  4. Department of Surgical Oncology, The Norwegian Radium Hospital, Oslo, 0310, Norway

    Even Angell-Petersen

Authors
  1. Steen J. Madsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marlon S. Mathews
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Even Angell-Petersen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chung-Ho Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Van Vo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rogelio Sanchez
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Henry Hirschberg
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Steen J. Madsen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Madsen, S.J., Mathews, M.S., Angell-Petersen, E. et al. Motexafin gadolinium enhances the efficacy of aminolevulinic acid mediated-photodynamic therapy in human glioma spheroids. J Neurooncol 91, 141–149 (2009). https://doi.org/10.1007/s11060-008-9692-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-008-9692-4

Keywords

Search

Navigation