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Intra-arterial administration improves temozolomide delivery and efficacy in a model of intracerebral metastasis, but has unexpected brain toxicity

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Abstract

We tested the hypothesis that intra-arterial (IA) infusion of temozolomide into the internal carotid artery would safely improve drug delivery to brain and enhance chemotherapy efficacy in a chemosensitive rat brain tumor model. Quantitative autoradiography after 25 µCi 14C-temozolomide was given by oral, intravenous, or IA route of administration, or IA with osmotic blood–brain barrier disruption (BBBD) (n = 5–7 per group) showed that both IA and IA/BBBD administration increased drug delivery in tumor by over threefold compared to normal brain (P < 0.02), and also significantly elevated delivery throughout the infused right hemisphere. Temozolomide (20 mg/kg; ~150 mg/m2) increased median survival when given by oral (25.5 days), intravenous (25.5 days), or IA (33 days) route of administration, compared to 17.5 days in untreated controls (n = 8 per group; overall P < 0.0001). Survival time after IA temozolomide was significantly longer than all other groups (P < 0.01 for all comparisons). BBBD temozolomide was toxic in the efficacy study, but there was no evidence of symptomatic neurotoxicity in rats given IA temozolomide. After these promising animal results, a 49 year old male with glioblastoma multiforme who failed all standard therapy received temozolomide 100 mg/m2 IA. Upon initiation of the second course of IA infusion the patient had increased heart rate, blood pressure, and rash, and the procedure was terminated without sequelae. Follow up IA infusion of temozolomide diluent in normal rats showed damaged cerebrovasculature as determined by dye leakage. These results demonstrate that IA infusion of temozolomide was toxic, with or without BBBD. We conclude that under the current formulation temozolomide is not safe for IA infusion in patients.

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References

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

    Article  PubMed  CAS  Google Scholar 

  2. Gahramanov S, Muldoon LL, Varallyay CG, Li X, Kraemer DF, Fu R, Hamilton BE, Rooney WD, Neuwelt EA (2013) Pseudoprogression of glioblastoma after chemo- and radiation therapy: diagnosis by using dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging with ferumoxytol versus gadoteridol and correlation with survival. Radiology 266:842–852. doi:10.1148/radiol.12111472

    Article  PubMed  PubMed Central  Google Scholar 

  3. Abrey LE, Christodoulou C (2001) Temozolomide for treating brain metastases. Seminars Oncol 28:34–42

    Article  CAS  Google Scholar 

  4. Wang Q, Jiang Z, Qi X, Lu S, Wang S, Leng C, Lu F, Liu HL, Liang S, Shi J (2014) Whole brain radiation therapy followed by intensity-modulated boosting treatment combined with concomitant temozolomide for brain metastases from non-small-cell lung cancer. Clin Transl Oncol 16:1000–1005

    Article  PubMed  Google Scholar 

  5. Portnow J, Badie B, Chen M, Liu A, Blanchard S, Synold TW (2009) The neuropharmacokinetics of temozolomide in patients with resectable brain tumors: potential implications for the current approach to chemoradiation. Clin Cancer Res 15:7092–7098

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  6. Grossman R, Rudek MA, Brastianos H, Zadnik P, Brem H, Tyler B, Blakeley JO (2012) The impact of bevacizumab on temozolomide concentrations in intracranial U87 gliomas. Cancer Chemother Pharmacol 70:129–139

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  7. Muldoon LL, Soussain C, Jahnke K, Johanson C, Siegal T, Smith QR, Hall W, Hynynen K, Senter P, Peereboom DM, Neuwelt EA (2007) Chemotherapy delivery issues in central nervous system malignancy: a reality check. J Clinical Oncol 25:2295–2305

    Article  CAS  Google Scholar 

  8. Azad TD, Pan J, Connolly ID, Remington A, Wilson CM, Grant GA (2015) Therapeutic strategies to improve drug delivery across the blood–brain barrier. Neurosurg Focus 38:E9

    Article  PubMed  PubMed Central  Google Scholar 

  9. Theodotou C, Shah AH, Hayes S, Bregy A, Johnson JN, Aziz-Sultan MA, Komotar RJ (2014) The role of intra-arterial chemotherapy as an adjuvant treatment for glioblastoma. Br J Neurosurg 28:438–446

    Article  PubMed  Google Scholar 

  10. Doolittle ND, Miner ME, Hall WA, Siegal T, Hanson EJ, Osztie E, McAllister LD, Bubalo JS, Kraemer DF, Fortin D, Nixon R, Muldoon LL, Neuwelt EA (2000) Safety and efficacy of a multi-center study using intraarterial chemotherapy in conjunction with osmotic opening of the blood–brain barrier for the treatment of malignant brain tumors. Cancer 88:637–647

    Article  PubMed  CAS  Google Scholar 

  11. Doolittle ND, Muldoon LL, Culp AY, Neuwelt EA (2014) Delivery of chemotherapeutics across the blood–brain barrier: challenges and advances. Adv Pharmacol 71:203–243. doi:10.1016/bs.apha.2014.06.002

    Article  PubMed  CAS  Google Scholar 

  12. Angelov L, Doolittle ND, Kraemer DF, Siegal T, Barnett GH, Peereboom DM, Stevens G, McGergor J, Jahnke K, Lacy CA, Hedrick NA, Shalom E, Ference S, Bell S, Sorenson L, Tyson RM, Haluska M, Neuwelt EA (2009) Blood–brain barrier disruption and intra-arterial methotrexate-based therapy for newly diagnosed primary CNS lymphoma: a multi-institutional experience. J Clinical Oncol 27:3503–3509

    Article  CAS  Google Scholar 

  13. Neuwelt EA, Pagel MA, Kraemer DF, Peterson DR, Muldoon LL (2004) Bone marrow chemoprotection without compromise of chemotherapy efficacy in a rat brain tumor model. J Pharmacol Exp Ther 309:594–599

    Article  PubMed  CAS  Google Scholar 

  14. Silbergeld DL, Chicoine MR (1997) Isolation and characterization of human malignant glioma cells from histologically normal brain. J Neurosurg Pediatr 86:525–531

    Article  CAS  Google Scholar 

  15. Imbesi F, Marchioni E, Benericetti E, Zappoli F, Galli A, Corato M, Ceroni M (2006) A randomized phase III study: comparison between intravenous and intraarterial ACNU administration in newly diagnosed primary glioblastomas. Anticancer Res 26:553–558

    PubMed  CAS  Google Scholar 

  16. Zhou Q, Gallo JM (2009) Differential effect of sunitinib on the distribution of temozolomide in an orthotopic glioma model. Neuro Oncol 11:301–310

    Article  PubMed  PubMed Central  Google Scholar 

  17. Doolittle ND, Korfel A, Lubow MA, Schorb E, Schlegel U, Rogowski S, Fu R, Dosa E, Illerhaus G, Kraemer DF, Muldoon LL, Calabrese P, Hedrick NA, Tyson RM, Jahnke K, Maron LM, Butler RW, Neuwelt EA (2013) Long-term cognitive function, neuroimaging, and quality of life in primary CNS lymphoma. Neurology 81:84–92. doi:10.1212/WNL.0b013e318297eeba

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  18. Fortin D, Morin PA, Belzile F, Mathieu D, Paré FM (2014) Intra-arterial carboplatin as a salvage strategy in the treatment of recurrent glioblastoma multiforme. J Neurooncol 119:397–403

    Article  PubMed  CAS  Google Scholar 

  19. 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 10:1383–1392

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  20. Pishko GL, Muldoon LL, Pagel MA, Schwartz DL, Neuwelt EA (2015) Vascular endothelial growth factor blockade alters magnetic resonance imaging biomarkers of vascular function and decreases barrier permeability in a rat model of lung cancer brain metastasis. Fluids Barriers CNS 12:5. doi:10.1186/2045-8118-12-5

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  21. Liu HL, Huang CY, Chen JY, Wang HY, Chen PY, Wei KC (2014) Pharmacodynamic and therapeutic investigation of focused ultrasound-induced blood–brain barrier opening for enhanced temozolomide delivery in glioma treatment. PLoS ONE 9:e114311

    Article  PubMed  PubMed Central  Google Scholar 

  22. Fan CH, Ting CY, Chang YC, Wei KC, Liu HL, Yeh CK (2015) Drug-loaded bubbles with matched focused ultrasound excitation for concurrent blood–brain barrier opening and brain-tumor drug delivery. Acta Biomater 15:89–101

    Article  PubMed  CAS  Google Scholar 

  23. Bernal GM, LaRiviere MJ, Mansour N, Pytel P, Cahill KE, Voce DJ, Kang S, Spretz R, Welp U, Noriega SE, Nunez L, Larsen G, Weichselbaum RR, Yamini B (2014) Convection-enhanced delivery and in vivo imaging of polymeric nanoparticles for the treatment of malignant glioma. Nanomedicine 10:149–157

    Article  PubMed  CAS  Google Scholar 

  24. Joshi S, Singh-Moon RP, Wang M, Chaudhuri DB, Holcomb M, Straubinger NL, Bruce JN, Bigio IJ, Straubinger RM (2014) Transient cerebral hypoperfusion assisted intraarterial cationic liposome delivery to brain tissue. J Neurooncol 118:73–82

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  25. Kunwar S, Chang S, Westphal M, Vogelbaum M, Sampson J, Barnett G, Shaffrey M, Ram Z, Piepmeier J, Prados M, Croteau D, Pedain C, Leland P, Husain SR, Joshi BH, Puri RK (2010) Phase III randomized trial of CED of IL13-PE38QQR vs Gliadel wafers for recurrent glioblastoma. Neuro Oncol 12:871–881

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  26. Newton HB (2012) Neurological complications of chemotherapy to the central nervous system. Handb Clin Neurol 105:903–916

    Article  PubMed  Google Scholar 

  27. Soffietti R, Trevisan E, Rudà R (2014) Neurologic complications of chemotherapy and other newer and experimental approaches. Handb Clin Neurol 121:1199–1218

    Article  PubMed  Google Scholar 

  28. Lin F, de Gooijer MC, Roig EM, Buil LC, Christnerm SM, Beumer JH, Würdinger T, Beijnen JH, van Tellingen O (2014) ABCB1, ABCG2, and PTEN determine the response of glioblastoma to temozolomide and ABT-888 therapy. Clin Cancer Res 20:2703–2713

    Article  PubMed  CAS  Google Scholar 

  29. Candolfi M, Yagiz K, Wibowo M, Ahlzadeh GE, Puntel M, Ghiasi H, Kamran N, Paran C, Lowenstein PR, Castro MG (2014) Temozolomide does not impair gene therapy-mediated antitumor immunity in syngeneic brain tumor models. Clin Cancer Res 20:1555–1565

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  30. Shin BJ, Burkhardt JK, Riina HA, Boockvar JA (2012) Superselective intra-arterial cerebral infusion of novel agents after blood–brain disruption for the treatment of recurrent glioblastoma multiforme: a technical case series. Neurosurg Clin N Am 23:323–329

    Article  PubMed  Google Scholar 

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Funding

This work was supported by a Veterans Administration Merit Review grant; the National Institutes of Health National Cancer Institute grant CA137488; National Institute of Neurological Diseases and Stroke grant NS44687; and the Walter S. and Lucienne Driskill Foundation, all to Edward A. Neuwelt.

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Authors and Affiliations

  1. Department of Neurology, Oregon Health & Sciences University, L603; 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA

    Leslie L. Muldoon, Joao Prola Netto & Edward A. Neuwelt

  2. Department of Cell, Developmental and Cancer Biology, Oregon Health & Sciences University, Portland, OR, 97239, USA

    Leslie L. Muldoon

  3. Department of Neurosurgery, Oregon Health & Sciences University, Portland, OR, 97239, USA

    Edward A. Neuwelt

  4. Veterans Administration Medical Center, Portland, OR, 97239, USA

    Michael A. Pagel & Edward A. Neuwelt

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  1. Leslie L. Muldoon
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  2. Michael A. Pagel
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  4. Edward A. Neuwelt
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Correspondence to Edward A. Neuwelt.

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Muldoon, L.L., Pagel, M.A., Netto, J.P. et al. Intra-arterial administration improves temozolomide delivery and efficacy in a model of intracerebral metastasis, but has unexpected brain toxicity. J Neurooncol 126, 447–454 (2016). https://doi.org/10.1007/s11060-015-2000-1

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  • DOI: https://doi.org/10.1007/s11060-015-2000-1

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