nach oben

Erschienen in:

01.06.2012 | Original Article

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

verfasst von: 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

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 6/2012

Einloggen, um Zugang zu erhalten

Abstract

Purpose

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.

Methods

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.

Results

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%.

Conclusion

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.

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):97–109PubMedCrossRef

CBTRUS (2011) CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2004–2007. http://www.cbtrus.org/2011-NPCR-SEER/WEB-0407-Report-3-3-2011.pdf

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):987–996PubMedCrossRef

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):105–107PubMedCrossRef

George BJ, Eichinger JB, Richard TJ (2009) A rare case of aplastic anemia caused by temozolomide. South Med J 102(9):974–976PubMedCrossRef

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):452–457PubMedCrossRef

Goldbecker A, Tryc AB, Raab P, Worthmann H, Herrmann J, Weissenborn K (2011) Hepatic encephalopathy after treatment with temozolomide. J Neurooncol 103(1):163–166PubMedCrossRef

Pothiawala S, Hsu MY, Yang C, Kesari S, Ibrahimi OA (2010) Urticarial hypersensitivity reaction caused by temozolomide. J Drugs Dermatol 9(9):1142–1144PubMed

Galanis E, Buckner JC (2010) Enzastaurin in the treatment of recurrent glioblastoma: a promise that did not materialize. J Clin Oncol 28(7):1097–1098PubMedCrossRef

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):491–501CrossRef

11.

Murray LJ, Bridgewater CH, Levy D (2011) Carboplatin chemotherapy in patients with recurrent high-grade glioma. Clin Oncol 23(1):55–61CrossRef

12.

Denny WA (2002) Acridine derivatives as chemotherapeutic agents. Curr Med Chem 9(18):1655–1665PubMed

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):139–169CrossRef

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):476–482

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):640–645PubMedCrossRef

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):2978–2986PubMed

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):439–444PubMedCrossRef

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):32–36PubMedCrossRef

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):70–74PubMedCrossRef

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):330–334PubMedCrossRef

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):347–352PubMedCrossRef

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):777–780PubMedCrossRef

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):761–770PubMed

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):495–503PubMedCrossRef

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):5467–5480PubMedCrossRef

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):179–182PubMedCrossRef

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):223–229PubMedCrossRef

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):E3PubMedCrossRef

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):4800–4808

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):4459–4462PubMedCrossRef

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):22–76PubMedCrossRef

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):392–398PubMed

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):717–727PubMedCrossRef

Titel: 9-Amino acridine pharmacokinetics, brain distribution, and in vitro/in vivo efficacy against malignant glioma
verfasst von: 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
Publikationsdatum: 01.06.2012
Verlag: Springer-Verlag
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 6/2012
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-012-1855-5

Springer Medizin

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