Banoxantrone| AQ4N | CAS#136470-65-0

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Banoxantrone (AQ4N)

Banoxantrone is a bioreductive, alkylaminoanthraquinone prodrug with antineoplastic activity. Under hypoxic conditions, often seen in solid tumors, banoxantrone (AQ4N) is converted and activated by cytochrome P450 enzymes, which are upregulated in certain tumors, to the cytotoxic DNA-binding agent AQ4. Banoxantrone intercalates into and crosslinks DNA, and inhibits topoisomerase II. This results in an inhibition of DNA replication and repair in tumor cells. Combined with conventional therapeutic agents, both oxygenic and hypoxic regions of tumors can be targeted. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Current developer: Novacea, Inc.

MedKoo Code#: 200430

Name: Banoxantrone (AQ4N)

CAS#: 136470-65-0

Synonym: AQ4N

IUPAC/Chemical name:

2,2'-(5,8-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-1,4-diyl)bis(azanediyl)bis(N,N-dimethylethanamine oxide)

Chemical structure

Theoretical analysis

MedKoo Code#: 200430
Name: Banoxantrone (AQ4N)
CAS#: 136470-65-0

Chemical Formula: C22H28N4O6

Exact Mass: 444.20088

Molecular Weight: 444.48

Elemental Analysis: C, 59.45; H, 6.35; N, 12.60; O, 21.60

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Quality control data:

Product will be shipped with supporting analytical data.

Highlight of recent study of Banoxantrone

Phase I study of Banoxantrone (AQ4N). Dr. Papadopoulos's group at University of Texas reported the phase I study of Banoxantrone (AQ4N). The results were described as the following: Sixteen patients were treated with cumulative doses of AQ4N ranging from 61.6 through 9,099.1 mg/m(2). A single patient per cohort was treated up to 384 mg/m(2) without toxicities. At 1,200 mg/m(2), two of five patients experienced a dose-limiting toxicity (grade 5 respiratory failure and grade 3 fatigue). Five cohort assigned patients were treated without toxicity at 768 mg/m(2), establishing this dose as the maximum tolerated dose. Among the most common adverse events observed were fatigue (38%), diarrhea (31%), nausea (25%), vomiting (25%), and anorexia (13%). Anticipated blue coloration of body fluids or skin was observed in all patients. The pharmacokinetics of AQ4N were dose proportional over all doses studied. Three patients experienced stable disease, including a patient with collecting duct renal cancer stable for 25 months. AQ4N is well tolerated when administered weekly on a 3-of-4-week schedule at 768 mg/m(2). Further combination studies investigating the safety and efficacy of AQ4N are ongoing. (source: Clin Cancer Res. 2008 Nov 1;14(21):7110-5.).

References:

1: Nishida CR, Lee M, de Montellano PR. Efficient hypoxic activation of the anticancer agent AQ4N by CYP2S1 and CYP2W1. Mol Pharmacol. 2010 Sep;78(3):497-502. Epub 2010 Jun 21. PubMed PMID: 20566689; PubMed Central PMCID: PMC2939484.

2: Williams KJ, Albertella MR, Fitzpatrick B, Loadman PM, Shnyder SD, Chinje EC, Telfer BA, Dunk CR, Harris PA, Stratford IJ. In vivo activation of the hypoxia-targeted cytotoxin AQ4N in human tumor xenografts. Mol Cancer Ther. 2009 Dec;8(12):3266-75. Epub . PubMed PMID: 19996276.

3: Mehibel M, Singh S, Chinje EC, Cowen RL, Stratford IJ. Effects of cytokine-induced macrophages on the response of tumor cells to banoxantrone (AQ4N). Mol Cancer Ther. 2009 May;8(5):1261-9. Epub 2009 May 12. PubMed PMID: 19435866.

4: Trédan O, Garbens AB, Lalani AS, Tannock IF. The hypoxia-activated ProDrug AQ4N penetrates deeply in tumor tissues and complements the limited distribution of mitoxantrone. Cancer Res. 2009 Feb 1;69(3):940-7. Epub 2009 Jan 27. PubMed PMID: 19176397.

5: Papadopoulos KP, Goel S, Beeram M, Wong A, Desai K, Haigentz M, Milián ML, Mani S, Tolcher A, Lalani AS, Sarantopoulos J. A phase 1 open-label, accelerated dose-escalation study of the hypoxia-activated prodrug AQ4N in patients with advanced malignancies. Clin Cancer Res. 2008 Nov 1;14(21):7110-5. PubMed PMID: 18981010.

6: Nishida CR, Ortiz de Montellano PR. Reductive heme-dependent activation of the n-oxide prodrug AQ4N by nitric oxide synthase. J Med Chem. 2008 Aug 28;51(16):5118-20. Epub 2008 Aug 6. PubMed PMID: 18681417; PubMed Central PMCID: PMC2730118.

7: O'Rourke M, Ward C, Worthington J, McKenna J, Valentine A, Robson T, Hirst DG, McKeown SR. Evaluation of the antiangiogenic potential of AQ4N. Clin Cancer Res. 2008 Mar 1;14(5):1502-9. PubMed PMID: 18316575.

8: Albertella MR, Loadman PM, Jones PH, Phillips RM, Rampling R, Burnet N, Alcock C, Anthoney A, Vjaters E, Dunk CR, Harris PA, Wong A, Lalani AS, Twelves CJ. Hypoxia-selective targeting by the bioreductive prodrug AQ4N in patients with solid tumors: results of a phase I study. Clin Cancer Res. 2008 Feb 15;14(4):1096-104. PubMed PMID: 18281542.

9: Steward WP, Middleton M, Benghiat A, Loadman PM, Hayward C, Waller S, Ford S, Halbert G, Patterson LH, Talbot D. The use of pharmacokinetic and pharmacodynamic end points to determine the dose of AQ4N, a novel hypoxic cell cytotoxin, given with fractionated radiotherapy in a phase I study. Ann Oncol. 2007 Jun;18(6):1098-103. Epub 2007 Apr 17. PubMed PMID: 17442658.

10: Lalani AS, Alters SE, Wong A, Albertella MR, Cleland JL, Henner WD. Selective tumor targeting by the hypoxia-activated prodrug AQ4N blocks tumor growth and metastasis in preclinical models of pancreatic cancer. Clin Cancer Res. 2007 Apr 1;13(7):2216-25. PubMed PMID: 17404106.

11: Atkinson SJ, Loadman PM, Sutton C, Patterson LH, Clench MR. Examination of the distribution of the bioreductive drug AQ4N and its active metabolite AQ4 in solid tumours by imaging matrix-assisted laser desorption/ionisation mass spectrometry. Rapid Commun Mass Spectrom. 2007;21(7):1271-6. PubMed PMID: 17340571.

12: Yakkundi A, McErlane V, Murray M, McCarthy HO, Ward C, Hughes CM, Patterson LH, Hirst DG, McKeown SR, Robson T. Tumor-selective drug activation: a GDEPT approach utilizing cytochrome P450 1A1 and AQ4N. Cancer Gene Ther. 2006 Jun;13(6):598-605. PubMed PMID: 16410820.

13: McErlane V, Yakkundi A, McCarthy HO, Hughes CM, Patterson LH, Hirst DG, Robson T, McKeown SR. A cytochrome P450 2B6 meditated gene therapy strategy to enhance the effects of radiation or cyclophosphamide when combined with the bioreductive drug AQ4N. J Gene Med. 2005 Jul;7(7):851-9. PubMed PMID: 15712360.

14: McCarthy HO, Yakkundi A, McErlane V, Hughes CM, Keilty G, Murray M, Patterson LH, Hirst DG, McKeown SR, Robson T. Bioreductive GDEPT using cytochrome P450 3A4 in combination with AQ4N. Cancer Gene Ther. 2003 Jan;10(1):40-8. PubMed PMID: 12489027.

15: Patterson LH. Bioreductively activated antitumor N-oxides: the case of AQ4N, a unique approach to hypoxia-activated cancer chemotherapy. Drug Metab Rev. 2002 Aug;34(3):581-92. Review. PubMed PMID: 12214668.

16: Gallagher R, Hughes CM, Murray MM, Friery OP, Patterson LH, Hirst DG, McKeown SR. The chemopotentiation of cisplatin by the novel bioreductive drug AQ4N. Br J Cancer. 2001 Aug 17;85(4):625-9. Erratum in: Br J Cancer 2002 Nov 18;87(11):1339. PubMed PMID: 11506506; PubMed Central PMCID: PMC2364091.

17: Loadman PM, Swaine DJ, Bibby MC, Welham KJ, Patterson LH. A preclinical pharmacokinetic study of the bioreductive drug AQ4N. Drug Metab Dispos. 2001 Apr;29(4 Pt 1):422-6. PubMed PMID: 11259326.

18: Patterson LH, McKeown SR. AQ4N: a new approach to hypoxia-activated cancer chemotherapy. Br J Cancer. 2000 Dec;83(12):1589-93. Review. PubMed PMID: 11104551; PubMed Central PMCID: PMC2363465.

19: Swaine DJ, Loadman PM, Bibby MC, Graham MA, Patterson LH. High-performance liquid chromatographic analysis of AQ4N, an alkylaminoanthraquinone N-oxide. J Chromatogr B Biomed Sci Appl. 2000 Jun 9;742(2):239-45. PubMed PMID: 10901128.

20: Patterson LH, McKeown SR, Ruparelia K, Double JA, Bibby MC, Cole S, Stratford IJ. Enhancement of chemotherapy and radiotherapy of murine tumours by AQ4N, a bioreductively activated anti-tumour agent. Br J Cancer. 2000 Jun;82(12):1984-90. PubMed PMID: 10864207; PubMed Central PMCID: PMC2363261.

21: Friery OP, Gallagher R, Murray MM, Hughes CM, Galligan ES, McIntyre IA, Patterson LH, Hirst DG, McKeown SR. Enhancement of the anti-tumour effect of cyclophosphamide by the bioreductive drugs AQ4N and tirapazamine. Br J Cancer. 2000 Apr;82(8):1469-73. PubMed PMID: 10780528; PubMed Central PMCID: PMC2363362.

22: Raleigh SM, Wanogho E, Burke MD, Patterson LH. Rat cytochromes P450 (CYP) specifically contribute to the reductive bioactivation of AQ4N, an alkylaminoanthraquinone-di-N-oxide anticancer prodrug. Xenobiotica. 1999 Nov;29(11):1115-22. PubMed PMID: 10598746.

23: Ali MM, Symons MC, Taiwo FA, Patterson LH. Effects of AQ4N and its reduction product on radiation-mediated DNA strand breakage. Chem Biol Interact. 1999 Nov 15;123(1):1-10. PubMed PMID: 10597898.

24: Raleigh SM, Wanogho E, Burke MD, McKeown SR, Patterson LH. Involvement of human cytochromes P450 (CYP) in the reductive metabolism of AQ4N, a hypoxia activated anthraquinone di-N-oxide prodrug. Int J Radiat Oncol Biol Phys. 1998 Nov 1;42(4):763-7. PubMed PMID: 9845092.

25: Wilson WR, Denny WA, Pullen SM, Thompson KM, Li AE, Patterson LH, Lee HH. Tertiary amine N-oxides as bioreductive drugs: DACA N-oxide, nitracrine N-oxide and AQ4N. Br J Cancer Suppl. 1996 Jul;27:S43-7. PubMed PMID: 8763844; PubMed Central PMCID: PMC2149993.

26: McKeown SR, Friery OP, McIntyre IA, Hejmadi MV, Patterson LH, Hirst DG. Evidence for a therapeutic gain when AQ4N or tirapazamine is combined with radiation. Br J Cancer Suppl. 1996 Jul;27:S39-42. PubMed PMID: 8763843; PubMed Central PMCID: PMC2150042.

27: Hejmadi MV, McKeown SR, Friery OP, McIntyre IA, Patterson LH, Hirst DG. DNA damage following combination of radiation with the bioreductive drug AQ4N: possible selective toxicity to oxic and hypoxic tumour cells. Br J Cancer. 1996 Feb;73(4):499-505. PubMed PMID: 8595165; PubMed Central PMCID: PMC2074454.

28: McKeown SR, Hejmadi MV, McIntyre IA, McAleer JJ, Patterson LH. AQ4N: an alkylaminoanthraquinone N-oxide showing bioreductive potential and positive interaction with radiation in vivo. Br J Cancer. 1995 Jul;72(1):76-81. PubMed PMID: 7599069; PubMed Central PMCID: PMC2034137.

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