Cancer Chemotherapy and Pharmacology

, Volume 69, Issue 6, pp 1519–1527

9-Amino acridine pharmacokinetics, brain distribution, and in vitro/in vivo efficacy against malignant glioma

  • Aaron M. Teitelbaum
  • Jose L. Gallardo
  • Jessica Bedi
  • Rajan Giri
  • Adam R. Benoit
  • Michael R. Olin
  • Kate M. Morizio
  • John R. Ohlfest
  • Rory P. Remmel
  • David M. Ferguson
Original Article



The delivery of drugs to the brain is a major obstacle in the design and development of useful treatments for malignant glioma. Previous studies by our laboratory have identified a series of 9-amino acridine compounds that block the catalytic cycle of topoisomerase II resulting in apoptosis and cell death in a variety of cancer cell lines.


This study reports the in vitro and in vivo activity of two promising lead compounds, [{9-[2-(1H-Indol-3-yl)-ethylamino]-acridin-4-yl}-(4-methyl-piperazin-1-yl)-methanone (1) and [9-(1-Benzyl-piperidin-4-ylamino)-acridin-3-yl]-(4-methyl-piperazin-1-yl)-methanone] (2), using an orthotopic glioblastoma mouse model. In addition, the absorption, distribution, and metabolism properties are characterized by determining metabolic stability, MDCK accumulation, Pgp efflux transport, plasma protein binding, and brain distribution in mouse pharmacokinetic studies.


The efficacy results indicate low micromolar ED50 values against glioma cells and a significant increase in the survival of glioma-bearing mice dosed with (2) (p < 0.05). Pharmacokinetic data collected at time intervals following a 60 mg/kg oral dose of acridine 1 and 2 showed both compounds penetrate the blood–brain barrier yielding peak concentrations of 0.25 μM and 0.6 μM, respectively. Peak plasma concentrations were determined to be 2.25 μM (1) and 20.38 μM (2). The results were further compared with data collected using a 15 mg/kg intravenous dose of 2 which yielded a peak concentration in the brain of 1.7 μM at 2.0 h relative to a 2.04 μM peak plasma concentration. The bioavailability was calculated to be 83.8%.


Taken overall, the results suggest compounds in this series may offer new strategies for the design of chemotherapeutics for treating brain cancers with high oral bioavailability and improved efficacy.


Acridine Glioma Anticancer agents Pharmacokinetics In vivo efficacy Topoisomerase 


  1. 1.
    Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114(2):97–109PubMedCrossRefGoogle Scholar
  2. 2.
    CBTRUS (2011) CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2004–2007.
  3. 3.
    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 JG, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352(10):987–996PubMedCrossRefGoogle Scholar
  4. 4.
    Jalali R, Singh P, Menon H, Gujral S (2007) Unexpected case of aplastic anemia in a patient with glioblastoma multiforme treated with Temozolomide. J Neurooncol 85(1):105–107PubMedCrossRefGoogle Scholar
  5. 5.
    George BJ, Eichinger JB, Richard TJ (2009) A rare case of aplastic anemia caused by temozolomide. South Med J 102(9):974–976PubMedCrossRefGoogle Scholar
  6. 6.
    Kopecky J, Priester P, Slovacek L, Petera J, Kopecky O, Macingova Z (2010) Aplastic anemia as a cause of death in a patient with glioblastoma multiforme treated with temozolomide. Strahlenther Onkol 186(8):452–457PubMedCrossRefGoogle Scholar
  7. 7.
    Goldbecker A, Tryc AB, Raab P, Worthmann H, Herrmann J, Weissenborn K (2011) Hepatic encephalopathy after treatment with temozolomide. J Neurooncol 103(1):163–166PubMedCrossRefGoogle Scholar
  8. 8.
    Pothiawala S, Hsu MY, Yang C, Kesari S, Ibrahimi OA (2010) Urticarial hypersensitivity reaction caused by temozolomide. J Drugs Dermatol 9(9):1142–1144PubMedGoogle Scholar
  9. 9.
    Galanis E, Buckner JC (2010) Enzastaurin in the treatment of recurrent glioblastoma: a promise that did not materialize. J Clin Oncol 28(7):1097–1098PubMedCrossRefGoogle Scholar
  10. 10.
    Neyns B, Sadones J, Chaskis C, Dujardin M, Everaert H, Lv S, Duerinck J, Tynninen O, Nupponen N, Michotte A, De Greve J (2011) Phase II study of sunitinib malate in patients with recurrent high-grade glioma. J Neuro Oncol 103(3):491–501CrossRefGoogle Scholar
  11. 11.
    Murray LJ, Bridgewater CH, Levy D (2011) Carboplatin chemotherapy in patients with recurrent high-grade glioma. Clin Oncol 23(1):55–61CrossRefGoogle Scholar
  12. 12.
    Denny WA (2002) Acridine derivatives as chemotherapeutic agents. Curr Med Chem 9(18):1655–1665PubMedGoogle Scholar
  13. 13.
    Belmont P, Bosson J, Godet T, Tiano M (2007) Acridine and acridone derivatives, anticancer properties and synthetic methods: where are we now? Anti Cancer Agents Med Chem 7(2):139–169CrossRefGoogle Scholar
  14. 14.
    Dekker AW, van’t Veer MB, Sizoo W, Haak HL, van der Lelie J, Ossenkoppele G, Huijgens PC, Schouten HC, Sonneveld P, Willemze R, Verdonck LF, van Putten WL, Lowenberg B (1997) Intensive postremission chemotherapy without maintenance therapy in adults with acute lymphoblastic leukemia. Dutch Hemato-Oncology Research Group. J Clin Oncol 15 (2):476–482Google Scholar
  15. 15.
    Mollgard L, Tidefelt U, Sundman-Engberg B, Lofgren C, Lehman S, Paul C (1998) High single dose of mitoxantrone and cytarabine in acute non-lymphocytic leukemia: a pharmacokinetic and clinical study. Ther Drug Monit 20(6):640–645PubMedCrossRefGoogle Scholar
  16. 16.
    Harousseau JL, Cahn JY, Pignon B, Witz F, Milpied N, Delain M, Lioure B, Lamy T, Desablens B, Guilhot F, Caillot D, Abgrall JF, Francois S, Briere J, Guyotat D, Casassus P, Audhuy B, Tellier Z, Hurteloup P, Herve P (1997) Comparison of autologous bone marrow transplantation and intensive chemotherapy as postremission therapy in adult acute myeloid leukemia. The Groupe Ouest Est Leucemies Aigues Myeloblastiques (GOELAM). Blood 90(8):2978–2986PubMedGoogle Scholar
  17. 17.
    Cornford EM, Young D, Paxton JW (1992) Comparison of the blood-brain barrier and liver penetration of acridine antitumor drugs. Cancer Chemother Pharmacol 29(6):439–444PubMedCrossRefGoogle Scholar
  18. 18.
    Evans SM, Young D, Robertson IG, Paxton JW (1992) Intraperitoneal administration of the antitumour agent N-[2-(dimethylamino)ethyl]acridine-4-carboxamide in the mouse: bioavailability, pharmacokinetics and toxicity after a single dose. Cancer Chemother Pharmacol 31(1):32–36PubMedCrossRefGoogle Scholar
  19. 19.
    Caponigro F, Dittrich C, Sorensen JB, Schellens JH, Duffaud F, Paz Ares L, Lacombe D, de Balincourt C, Fumoleau P (2002) Phase II study of XR 5000, an inhibitor of topoisomerases I and II, in advanced colorectal cancer. Eur J Cancer 38(1):70–74PubMedCrossRefGoogle Scholar
  20. 20.
    Dittrich C, Coudert B, Paz-Ares L, Caponigro F, Salzberg M, Gamucci T, Paoletti X, Hermans C, Lacombe D, Fumoleau P (2003) Phase II study of XR 5000 (DACA), an inhibitor of topoisomerase I and II, administered as a 120-h infusion in patients with non-small cell lung cancer. Eur J Cancer 39(3):330–334PubMedCrossRefGoogle Scholar
  21. 21.
    Dittrich C, Dieras V, Kerbrat P, Punt C, Sorio R, Caponigro F, Paoletti X, de Balincourt C, Lacombe D, Fumoleau P (2003) Phase II study of XR5000 (DACA), an inhibitor of topoisomerase I and II, administered as a 120-h infusion in patients with advanced ovarian cancer. Invest New Drugs 21(3):347–352PubMedCrossRefGoogle Scholar
  22. 22.
    Twelves C, Campone M, Coudert B, Van den Bent M, de Jonge M, Dittrich C, Rampling R, Sorio R, Lacombe D, de Balincourt C, Fumoleau P (2002) Phase II study of XR5000 (DACA) administered as a 120-h infusion in patients with recurrent glioblastoma multiforme. Ann Oncol 13(5):777–780PubMedCrossRefGoogle Scholar
  23. 23.
    Adjei AA, Budihardjo II, Rowinsky EK, Kottke TJ, Svingen PA, Buckwalter CA, Grochow LB, Donehower RC, Kaufmann SH (1997) Cytotoxic synergy between pyrazoloacridine (NSC 366140) and cisplatin in vitro: inhibition of platinum-DNA adduct removal. Clin Cancer Res 3(5):761–770PubMedGoogle Scholar
  24. 24.
    Galanis E, Buckner JC, Maurer MJ, Reid JM, Kuffel MJ, Ames MM, Scheithauer BW, Hammack JE, Pipoly G, Kuross SA (2005) Phase I/II trial of pyrazoloacridine and carboplatin in patients with recurrent glioma: a North Central Cancer Treatment Group trial. Invest New Drugs 23(5):495–503PubMedCrossRefGoogle Scholar
  25. 25.
    Goodell JR, Madhok AA, Hiasa H, Ferguson DM (2006) Synthesis and evaluation of acridine- and acridone-based anti-herpes agents with topoisomerase activity. Bioorg Med Chem 14(16):5467–5480PubMedCrossRefGoogle Scholar
  26. 26.
    Goodell JR, Ougolkov AV, Hiasa H, Kaur H, Remmel R, Billadeau DD, Ferguson DM (2008) Acridine-based agents with topoisomerase II activity inhibit pancreatic cancer cell proliferation and induce apoptosis. J Med Chem 51(2):179–182PubMedCrossRefGoogle Scholar
  27. 27.
    Oppegard LM, Ougolkov AV, Luchini DN, Schoon RA, Goodell JR, Kaur H, Billadeau DD, Ferguson DM, Hiasa H (2009) Novel acridine-based compounds that exhibit an anti-pancreatic cancer activity are catalytic inhibitors of human topoisomerase II. Eur J Pharmacol 602(2–3):223–229PubMedCrossRefGoogle Scholar
  28. 28.
    Wiesner SM, Freese A, Ohlfest JR (2005) Emerging concepts in glioma biology: implications for clinical protocols and rational treatment strategies. Neurosurg Focus 19(4):E3PubMedCrossRefGoogle Scholar
  29. 29.
    Olin MR, Andersen BM, Zellmer DM, Grogan PT, Popescu FE, Xiong Z, Forster CL, Seiler C, SantaCruz KS, Chen W, Blazar BR, Ohlfest JR (2010) Superior efficacy of tumor cell vaccines grown in physiologic oxygen. Clin Cancer Res 16 (19):4800–4808Google Scholar
  30. 30.
    Galvez-Peralta M, Hackbarth JS, Flatten KS, Kaufmann SH, Hiasa H, Xing C, Ferguson DM (2009) On the role of topoisomerase I in mediating the cytotoxicity of 9-aminoacridine-based anticancer agents. Bioorg Med Chem Lett 19(15):4459–4462PubMedCrossRefGoogle Scholar
  31. 31.
    Loscher W, Potschka H (2005) Role of drug efflux transporters in the brain for drug disposition and treatment of brain diseases. Prog Neurobiol 76(1):22–76PubMedCrossRefGoogle Scholar
  32. 32.
    Shu Y, Bello CL, Mangravite LM, Feng B, Giacomini KM (2001) Functional characteristics and steroid hormone-mediated regulation of an organic cation transporter in Madin-Darby canine kidney cells. J Pharmacol Exp Ther 299(1):392–398PubMedGoogle Scholar
  33. 33.
    Lin CJ, Tai Y, Huang MT, Tsai YF, Hsu HJ, Tzen KY, Liou HH (2010) Cellular localization of the organic cation transporters, OCT1 and OCT2, in brain microvessel endothelial cells and its implication for MPTP transport across the blood-brain barrier and MPTP-induced dopaminergic toxicity in rodents. J Neurochem 114(3):717–727PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Aaron M. Teitelbaum
    • 1
  • Jose L. Gallardo
    • 2
  • Jessica Bedi
    • 2
  • Rajan Giri
    • 1
  • Adam R. Benoit
    • 1
  • Michael R. Olin
    • 2
  • Kate M. Morizio
    • 1
  • John R. Ohlfest
    • 2
  • Rory P. Remmel
    • 1
  • David M. Ferguson
    • 1
    • 3
  1. 1.Department of Medicinal ChemistryUniversity of MinnesotaMinneapolisUSA
  2. 2.Department of Pediatrics and Neurosurgery, Brain Barriers Research CenterUniversity of MinnesotaMinneapolisUSA
  3. 3.Center for Drug DesignUniversity of MinnesotaMinneapolisUSA

Personalised recommendations