In vivo activation of the hypoxia-targeted cytotoxin AQ4N in human tumor xenografts

Molecular Cancer Therapeutics

Volumn 8, Issue 12, 2009, Pages 3266-3275

  Williams, Kaye J ^a   Albertella, Mark R ^c   Fitzpatrick, Brian ^a   Loadman, Paul M ^b   Shnyder, Steven D ^b   Chinje, Edwin C ^a   Telfer, Brian A ^a   Dunk, Chris R ^c   Harris, Peter A ^c   Stratford, Ian J ^a  

^a UNIVERSITY OF MANCHESTER   (United Kingdom)

^b UNIVERSITY OF BRADFORD   (United Kingdom)

^c ASTRAZENECA   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

1,4 BIS[[2 (DIMETHYLAMINO N OXIDE)ETHYL]AMINO] 5,8 DIHYDROXYANTHRAQUINONE; AQ4; CISPLATIN; DRUG METABOLITE; GLUCOSE TRANSPORTER 1; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BLADDER CARCINOMA; CANCER CHEMOTHERAPY; CANCER MODEL; CANCER RADIOTHERAPY; CANCER SURGERY; CANCER TISSUE; CONCENTRATION RESPONSE; CONFOCAL MICROSCOPY; CONTROLLED STUDY; DRUG ACTIVATION; DRUG CYTOTOXICITY; DRUG DETERMINATION; DRUG EFFICACY; DRUG EXPOSURE; DRUG POTENTIATION; DRUG TUMOR LEVEL; EX VIVO STUDY; FEMALE; FLUORESCENCE ANALYSIS; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; HUMAN; HUMAN CELL; HYPOXEMIA; IMMUNOHISTOCHEMISTRY; IN VITRO STUDY; LUNG CARCINOMA; LUNG NON SMALL CELL CANCER; MASS SPECTROMETRY; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROTEIN DETERMINATION; PROTEIN LOCALIZATION; RADIATION RESPONSE; SINGLE DRUG DOSE; TREATMENT RESPONSE; TUMOR BLOOD FLOW; TUMOR XENOGRAFT; X RAY;

ANIMALS; ANOXIA; ANTHRAQUINONES; ANTINEOPLASTIC AGENTS; CELL LINE, TUMOR; CHROMATOGRAPHY, HIGH PRESSURE LIQUID; CISPLATIN; COMBINED MODALITY THERAPY; CYTOTOXINS; DRUG SYNERGISM; FEMALE; HUMANS; MASS SPECTROMETRY; MICE; MICE, NUDE; MICROSCOPY, CONFOCAL; NEOPLASMS; PRODRUGS; RADIOTHERAPY; TREATMENT OUTCOME; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 73149107238     PISSN: 15357163     EISSN: None     Source Type: Journal    
DOI: 10.1158/1535-7163.MCT-09-0396     Document Type: Article

References (27)

1. Brown JM. Tumor hypoxia in cancer therapy. Methods Enzymol 2007;435:297-321.
2. Minchinton AI, Tannock IF. Drug penetration in solid tumors. Nat Rev Cancer 2006;6:583-92.
3. 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;69:940-7.
4. McKeown SR, Cowen RL, Williams KJ. Bioreductive drugs: from concept to clinic. Clin Oncol 2007;19:427-42.
5. Patterson LH. Bioreductively activated antitumor N-oxides: the case of AQ4N, a unique approach to hypoxia-activated cancer chemotherapy. Drug Metab Rev 2002;34:581-92.
6. 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 1996;74:S39-42.
7. Patterson LH, McKeown SR, Ruparelia K, et al. Enhancement of chemotherapy and radiotherapy of murine tumors by AQ4N, a bioreductively activated anti-tumor agent. Br J Cancer 2000;82:1984-90.
8. Gallagher R, Hughes CM, Murray MM, et al. The chemopotentiation of cisplatin by the novel bioreductive drug AQ4N. Br J Cancer 2001;85:625-9.
9. Friery OP, Gallagher R, Murray MM, et al. Enhancement of the antitumor effect of cyclophosphamide by the bioreductive drugs AQ4N and tirapazamine. Br J Cancer 2000;82:1469-73.
10. Papadopoulos KP, Goel S, Beeram M, et al. A phase 1 open-label, accelerated dose-escalation study of the hypoxia-activated prodrug AQ4N in patients with advanced malignancies. Clin Cancer Res 2008;14:7110-5.
11. Steward WP, Middleton M, Benghiat A, et al. 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;18:1098-103.
12. Albertella MR, Loadman PM, Jones PH, et al. Hypoxia-selective targeting by the bioreductive prodrug AQ4N in patients with solid tumors: results of a phase I study. Clin Cancer Res 2008;14:1096-104.
13. Wilson WR, Denny WA, Pullen SM, et al. Tertiary amine N-oxides as bioreductive drugs: DACA N-oxide, nitracrine N-oxide and AQ4N. Br J Cancer 1996;74:S43-47.
14. Smith PJ, Blunt NJ, Desnoyers R, Giles Y, Patterson LH. DNA topoisomerase II-dependent cytotoxicity of alkylaminoanthraquinones and their N-oxides. Cancer Chemother Pharmacol 1997;39:455-61.
15. Smith PJ, Desnoyers R, Blunt N, Giles Y, Patterson LH, Watson JV. Flow cytometric analysis and confocal imaging of anticancer alkylaminoanthraquinones and their N-oxides in intact human cells using 647-nm krypton laser excitation. Cytometry 1997;27:43-53.
16. Raleigh SM, Wanogho E, Burke MD, Mckeown SR, Patterson LH. Involvement of human cytochrome P450(CYP)in the reductive metabolism of AQ4N,a hypoxia activated anthraquinone di-n-oxide prodrug. Int J Radiat Oncol Biol Phys 1998;42:763-7.
17. Nishida CR, Ortiz de Montellano PR. Reductive heme-dependent activation of the n-oxide prodrug AQ4N by nitric oxide synthase. J Med Chem 2008;51:5118-20.
18. 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;8:1261-9.
19. Patterson LH, McKeown SR, Robson T, Gallagher R, Raleigh SM, Orr S. Antitumor prodrug development using cytochrome P450 (CYP) mediated activation. Anti-Cancer Drug Des 1999;14:473-86.
20. 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;13:2216-25.
21. Cowen RL, Patterson AV, Telfer BA, et al. Viral delivery of P450 reductase recapitulates the ability of constitutive overexpression of reductase enzymes to potentiate the activity of Mitomycin C in human breast cancer xenografts. Mol Cancer Ther 2003;2:901-9.
22. 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;742:239-45.
23. Loadman PM, Swaine DJ, Bibby MC, Welham KJ, Patterson LH. A preclinical pharmacokinetic study of the bioreductive drug AQ4N. Drug Metab Dispos 2001;29:422-6.
24. Airley R, Loncaster J, Davidson S, et al. Glucose Transporter Glut-1 expression correlates with tumor hypoxia and predicts metastasis-free survival in advanced carcinoma of the cervix. Clin Cancer Res 2001;7:928-34.
25. Hoskin PJ, Sibtain A, Daley FM, Wilson GD. GLUT1 and CAIX as intrinsic markers of hypoxia in bladder cancer: relationship with vascularity and proliferation as predictors of outcome of ARCON. Br J Cancer 2003;89:1290-7.
26. Williams KJ, Parker CA, Stratford IJ. Exogenous and endogenous markers of tumor oxygenation status: definitive markers of tumor hypoxia? Adv Exp Med Biol 2005;566:285-94.
27. Airley RE, Loncaster J, Raleigh JA, et al. Glut-1 and CAIX as intrinsic markers of hypoxia in carcinoma of the cervix: relationship to pimonidazole binding. Int J Cancer 2003;104:85-91.