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Use of FDA approved methamphetamine to allow adjunctive use of methylnaltrexone to mediate core anti-growth factor signaling effects in glioblastoma

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Abstract

Methylnaltrexone (MNTX) was recently FDA approved to treat opiate induced constipation. It happens to also indirectly reduce Src activity. Src is a 54 kDa tyrosine kinase, crucial in signaling of, and link between, vascular endothelial growth factor (VEGF), and epidermal growth factor (EGF). Glioblastomas use both EGF and VEGF signaling to enhance growth and neo-angiogenesis. Stem cell sub-fractions of glioblastomas are enriched for high VEGF synthesizing cells so this is a particularly valuable adjunctive target during cytotoxic treatment with drugs like temozolomide. MNTX does not cross the blood–brain barrier (BBB). Methamphetamine (MA) temporarily opens the BBB and therefore may allow methylnaltrexone entry into glioblastoma tissue. MA is FDA approved, marketed to treat attention problems in children. MA–MNTX combination should be tested as glioblastoma treatment adjunct. Temozolomide CSF levels are 10–20% of blood levels. Thus MA may also allow greater brain tissue temozolomide levels yet with lower systemic exposure.

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References

  1. Yuan CS (2007) Methylnaltrexone mechanisms of action and effects on opioid bowel dysfunction and other opioid adverse effects. Ann Pharmacother 41(6):984–993. doi:10.1345/aph.1K009

    Article  PubMed  CAS  Google Scholar 

  2. Singleton PA, Lingen MW, Fekete MJ, Garcia JG, Moss J (2006) Methylnaltrexone inhibits opiate and VEGF-induced angiogenesis: role of receptor transactivation. Microvasc Res 72(1–2):3–11. doi:10.1016/j.mvr.2006.04.004

    Article  PubMed  CAS  Google Scholar 

  3. Singleton PA, Garcia JG, Moss J (2008) Synergistic effects of methylnaltrexone with 5-fluorouracil and bevacizumab on inhibition of vascular endothelial growth factor-induced angiogenesis. Mol Cancer Ther 7(6):1669–1679. doi:10.1158/1535-7163.MCT-07-2217

    Article  PubMed  CAS  Google Scholar 

  4. Wong ET, Brem S (2008) Antiangiogenesis treatment for glioblastoma multiforme: challenges and opportunities. J Natl Compr Canc Netw 6(5):515–522

    PubMed  CAS  Google Scholar 

  5. Plate KH, Breier G, Weich HA, Mennel HD, Risau W (1994) Vascular endothelial growth factor and glioma angiogenesis: coordinate induction of VEGF receptors, distribution of VEGF protein and possible in vivo regulatory mechanisms. Int J Cancer 59(4):520–529. doi:10.1002/ijc.2910590415

    Article  PubMed  CAS  Google Scholar 

  6. Charalambous C, Chen TC, Hofman FM (2006) Characteristics of tumor-associated endothelial cells derived from glioblastoma multiforme. Neurosurg Focus 20(4):E22. doi:10.3171/foc.2006.20.4.e22

    Article  PubMed  Google Scholar 

  7. Hong X, Jiang F, Kalkanis SN, Zhang ZG, Zhang XP, DeCarvalho AC, Katakowski M, Bobbitt K, Mikkelsen T, Chopp M (2006) SDF-1 and CXCR4 are up-regulated by VEGF and contribute to glioma cell invasion. Cancer Lett 236(1):39–45. doi:10.1016/j.canlet.2005.05.011

    Article  PubMed  CAS  Google Scholar 

  8. Kast RE (2007) Using blood brain barrier disruption by methamphetamine for drug delivery. J Neurooncol 85(1):109–110. doi:10.1007/s11060-007-9389-0

    Article  PubMed  CAS  Google Scholar 

  9. Stevenson CB, Ehtesham M, McMillan KM, Valadez JG, Edgeworth ML, Price RR, Abel TW, Mapara KY, Thompson RC (2008) CXCR4 expression is elevated in glioblastoma multiforme and correlates with an increase in intensity and extent of peritumoral T2-weighted magnetic resonance imaging signal abnormalities. Neurosurgery 63(3):560–569. doi:10.1227/01.NEU.0000324896.26088.EF

    Article  PubMed  Google Scholar 

  10. Zagzag D, Esencay M, Mendez O, Yee H, Smirnova I, Huang Y, Chiriboga L, Lukyanov E, Liu M, Newcomb EW (2008) Hypoxia- and vascular endothelial growth factor-induced stromal cell-derived factor-1alpha/CXCR4 expression in glioblastomas: one plausible explanation of Scherer’s structures. Am J Pathol 173(2):545–560. doi:10.2353/ajpath.2008.071197

    Article  PubMed  CAS  Google Scholar 

  11. Ostermann S, Csajka C, Buclin T, Leyvraz S, Lejeune F, Decosterd LA, Stupp R (2004) Plasma and cerebrospinal fluid population pharmacokinetics of temozolomide in malignant glioma patients. Clin Cancer Res 10(11):3728–3736. doi:10.1158/1078-0432.CCR-03-0807

    Article  PubMed  CAS  Google Scholar 

  12. Prados MD, Lamborn K, Yung WK, 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, North American Brain Tumor Consortium (2006) A phase 2 trial of irinotecan (CPT-11) in patients with recurrent malignant glioma: a North American brain tumor consortium study. Neuro Oncol 8(2):189–193. doi:10.1215/15228517-2005-010

    Article  PubMed  CAS  Google Scholar 

  13. Puduvalli VK, Giglio P, Groves MD, Hess KR, Gilbert MR, Mahankali S, Jackson EF, Levin VA, Conrad CA, Hsu SH, Colman H, de Groot JF, Ritterhouse MG, Ictech SE, Yung WK (2008) Phase II trial of irinotecan and thalidomide in adults with recurrent glioblastoma multiforme. Neuro Oncol 10(2):216–222. doi:10.1215/15228517-2007-060

    Article  PubMed  CAS  Google Scholar 

  14. 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  PubMed  CAS  Google Scholar 

  15. Reardon DA, Fink KL, Mikkelsen T, Cloughesy TF, O’Neill A, Plotkin S, Glantz M, Ravin P, Raizer JJ, Rich KM, Schiff D, Shapiro WR, Burdette-Radoux S, Dropcho EJ, Wittemer SM, Nippgen J, Picard M, Nabors LB (2008) Randomized phase II study of cilengitide, an integrin-targeting arginine-glycine-aspartic acid peptide, in recurrent glioblastoma multiforme. J Clin Oncol 26(34):5610–5617. doi:10.1200/JCO.2008.16.7510

    Article  PubMed  CAS  Google Scholar 

  16. Benati D, Baldari CT (2008) SRC family kinases as potential therapeutic targets for malignancies and immunological disorders. Curr Med Chem 15(12):1154–1165. doi:10.2174/092986708784310404

    Article  PubMed  CAS  Google Scholar 

  17. Brunton VG, Frame MC (2008) Src and focal adhesion kinase as therapeutic targets in cancer. Curr Opin Pharmacol 8(4):427–432. doi:10.1016/j.coph.2008.06.012

    Article  PubMed  CAS  Google Scholar 

  18. Flynn JR, Wang L, Gillespie DL, Stoddard GJ, Reid JK, Owens J, Ellsworth GB, Salzman KL, Kinney AY, Jensen RL (2008) Hypoxia-regulated protein expression, patient characteristics, and preoperative imaging as predictors of survival in adults with glioblastoma multiforme. Cancer 113(5):1032–1042. doi:10.1002/cncr.23678

    Article  PubMed  Google Scholar 

  19. Yao XH, Ping YF, Chen JH, Xu CP, Chen DL, Zhang R, Wang JM, Bian XW (2008) Glioblastoma stem cells produce vascular endothelial growth factor by activation of a G-protein coupled formylpeptide receptor FPR. J Pathol 215(4):369–376. doi:10.1002/path.2356

    Article  PubMed  CAS  Google Scholar 

  20. Ananthnarayan S, Bahng J, Roring J, Nghiemphu P, Lai A, Cloughesy T, Pope WB (2008) Time course of imaging changes of GBM during extended bevacizumab treatment. J Neurooncol 88(3):339–347. doi:10.1007/s11060-008-9573-x

    Article  PubMed  Google Scholar 

  21. Norden AD, Young GS, Setayesh K, Muzikansky A, Klufas R, Ross GL, Ciampa AS, Ebbeling LG, Levy B, Drappatz J, Kesari S, Wen PY (2008) Bevacizumab for recurrent malignant gliomas: efficacy, toxicity, and patterns of recurrence. Neurology 70(10):779–787. doi:10.1212/01.wnl.0000304121.57857.38

    Article  PubMed  CAS  Google Scholar 

  22. Bergers G, Hanahan D (2008) Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 8(8):592–603. doi:10.1038/nrc2442

    Article  PubMed  CAS  Google Scholar 

  23. Zuniga RM, Torcuator R, Jain R, Anderson J, Doyle T, Ellika S, Schultz L, Mikkelsen T (2009) Efficacy, safety and patterns of response and recurrence in patients with recurrent high-grade gliomas treated with bevacizumab plus irinotecan. J Neurooncol 91(3):329–336. doi:10.1007/s11060-008-9718-y

    Article  PubMed  CAS  Google Scholar 

  24. Maharaj AS, Saint-Geniez M, Maldonado AE, D’Amore PA (2006) Vascular endothelial growth factor localization in the adult. Am J Pathol 168(2):639–648. doi:10.2353/ajpath.2006.050834

    Article  PubMed  CAS  Google Scholar 

  25. Chen S, Kasama Y, Lee JS, Jim B, Marin M, Ziyadeh FN (2004) Podocyte-derived vascular endothelial growth factor mediates the stimulation of alpha3(IV) collagen production by transforming growth factor-beta1 in mouse podocytes. Diabetes 53(11):2939–2949. doi:10.2337/diabetes.53.11.2939

    Article  PubMed  CAS  Google Scholar 

  26. Knizetova P, Ehrmann J, Hlobilkova A, Vancova I, Kalita O, Kolar Z, Bartek J (2008) Autocrine regulation of glioblastoma cell cycle progression, viability and radioresistance through the VEGF-VEGFR2 (KDR) interplay. Cell Cycle 7(16):2553–2561

    PubMed  CAS  Google Scholar 

  27. Huang J, Chen K, Gong W, Zhou Y, Le Y, Bian X, Wang JM (2008) Receptor “hijacking” by malignant glioma cells: a tactic for tumor progression. Cancer Lett 267(2):254–261. doi:10.1016/j.canlet.2008.03.014

    Article  PubMed  CAS  Google Scholar 

  28. Huang J, Hu J, Bian X, Chen K, Gong W, Dunlop NM, Howard OM, Wang JM (2007) Transactivation of the epidermal growth factor receptor by formylpeptide receptor exacerbates the malignant behavior of human glioblastoma cells. Cancer Res 67(12):5906–5913. doi:10.1158/0008-5472.CAN-07-0691

    Article  PubMed  CAS  Google Scholar 

  29. Goldman CK, Kim J, Wong WL, King V, Brock T, Gillespie GY (1993) Epidermal growth factor stimulates vascular endothelial growth factor production by human malignant glioma cells: a model of glioblastoma multiforme pathophysiology. Mol Biol Cell 4(1):121–133

    PubMed  CAS  Google Scholar 

  30. Fisher T, Galanti G, Lavie G, Jacob-Hirsch J, Kventsel I, Zeligson S, Winkler R, Simon AJ, Amariglio N, Rechavi G, Toren A (2007) Mechanisms operative in the antitumor activity of temozolomide in glioblastoma multiforme. Cancer J 13(5):335–344. doi:10.1097/PPO.0b013e318157053f

    Article  PubMed  CAS  Google Scholar 

  31. Steiner HH, 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(1–2):129–138. doi:10.1023/B:NEON.0000013495.08168.8f

    Article  PubMed  Google Scholar 

  32. Lund EL, Høg A, Olsen MW, Hansen LT, Engelholm SA, Kristjansen PE (2004) Differential regulation of VEGF, HIF1-alpha and angiopoietin-1, -2 and -4 by hypoxia and ionizing radiation in human glioblastoma. Int J Cancer 108(6):833–838. doi:10.1002/ijc.11662

    Article  PubMed  CAS  Google Scholar 

  33. Hovinga KE, Stalpers LJ, van Bree C, Donker M, Verhoeff JJ, Rodermond HM, Bosch DA, van Furth WR (2005) Radiation-enhanced vascular endothelial growth factor (VEGF) secretion in glioblastoma multiforme cell lines—a clue to radioresistance? J Neurooncol 74(2):99–103. doi:10.1007/s11060-004-4204-7

    Article  PubMed  CAS  Google Scholar 

  34. Du J, Bernasconi P, Clauser KR, Mani DR, Finn SP, Beroukhim R, Burns M, Julian B, Peng XP, Hieronymus H, Maglathlin RL, Lewis TA, Liau LM, Nghiemphu P, Mellinghoff IK, Louis DN, Loda M, Carr SA, Kung AL, Golub TR (2009) Bead-based profiling of tyrosine kinase phosphorylation identifies Src as a potential target for glioblastoma therapy. Nat Biotechnol 27(1):77–83. doi:10.1038/nbt.1513

    Article  PubMed  CAS  Google Scholar 

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  1. University of Vermont, 2 Church Street, Burlington, VT, 05401, USA

    R. E. Kast

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Kast, R.E. Use of FDA approved methamphetamine to allow adjunctive use of methylnaltrexone to mediate core anti-growth factor signaling effects in glioblastoma. J Neurooncol 94, 163–167 (2009). https://doi.org/10.1007/s11060-009-9863-y

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  • DOI: https://doi.org/10.1007/s11060-009-9863-y

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