Abstract
The ability of the bioreductive drugs AQ4N and tirapazamine to enhance the anti-tumour effect of cyclophosphamide was assessed in three murine tumour models. In male BDF mice implanted with the T50/80 mammary carcinoma, AQ4N (50–150 mg kg–1) in combination with cyclophosphamide (100 mg kg–1) produced an effect equivalent to a single 200 mg kg–1dose of cyclophosphamide. Tirapazamine (25 mg kg–1) in combination with cyclophosphamide (100 mg kg–1) produced an effect equivalent to a single 150 mg kg–1dose of cyclophosphamide. In C3H mice implanted with the SCCVII or RIF-1 tumours, enhancement of tumour cell killing was found with both drugs in combination with cyclophosphamide (50–200 mg kg–1); AQ4N (50–200 mg kg–1) produced a more effective combination than tirapazamine (12.5–50 mg kg–1). Unlike tirapazamine, which showed a significant increase in toxicity to bone marrow cells, the combination of AQ4N (100 mg kg–1) 6 h prior to cyclophosphamide (100 mg kg–1) resulted in no additional toxicity towards bone marrow cells compared to that caused by cyclophosphamide alone. In conclusion, AQ4N gave a superior anti-tumour effect compared to tirapazamine when administered with a single dose of cyclophosphamide (100 mg kg–1). © 2000 Cancer Research Campaign
Similar content being viewed by others
Article PDF
Change history
16 November 2011
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
References
Adams GE, Stratford IJ, Edwards HS, Bremner JCM and Cole S (1992) Bioreductive drugs as post-irradiation sensitizers: comparison of dual function agents SR4233 and the mitomycin C analogue EO9. Int J Radiat Oncol Biol Phys 22: 717–720
Brown JM and Lemmon MJ (1990) Potentiation by the hypoxic cytotoxin SR4233 of cell killing produced by fractionated irradiation of mouse tumours. Cancer Res 50: 7745–7749
Dorie MJ and Brown JM (1997) Modification of the anti-tumour activity of chemotherapy drugs by the hypoxic cytotoxic agent tirapazamine. Cancer Chemother Pharmacol 39: 361–266
Holden SA, Teicher BA, Ara G, Herman TS and Coleman CN (1992) Enhancement of alkylating agent activity by SR4233 in the FSaIIC murine fibrosarcoma. J Natl Cancer Inst 84: 187–193
Johnson CA, Kilpatrick D, von Roemeling R, Langer C, Graham MA, Greenslade D, Kennedy G, Keenan E and O'Dwyer PJ (1997) Phase I trial of tirapazamine in combination with cisplatin in a single dose every three weeks in patients with solid tumours. Br J Cancer 73: 1480–1485
Kennedy KA (1987) Hypoxic cells as specific drug targets for chemotherapy. Anticancer Drug Des 2: 181–194
Langmuir VK, Rooker JA, Osen M, Mendonca HL and Laderoute KR (1994) Synergistic interaction between tirapazamine and cyclophosphamide in human breast cancer xenografts. Cancer Res 54: 2845–2847
McAleer JJA, McKeown SR, MacManus MP, Lappin TRJ and Bridges JM (1992) Hypobaric hypoxia: a method for testing bioreductive drugs In vivo. Int J Radiat Oncol Biol Phys 23: 551–555
McKeown SR, Hejmadi MV, McIntyre IA, McAleer JJA and Patterson LH (1995) AQ4N: an alkylaminoanthraquinone N-oxide showing bioreductive potential and positive interaction with radiation In vivo. Br J Cancer 71: 76–81
McKeown SR, Friery OP, McIntyre IA, Hejmadi MV, Patterson LH and Hirst DG (1996) Evidence for a therapeutic gain when AQ4N or tirapazamine is combined with radiation. Br J Cancer 74: S39–S42
Moore JV (1988) The dynamics of tumour cords in an irradiated mouse mammary carcinoma with a large hypoxic cell component. Jpn J Cancer Res (Gann) 79: 236–243
Patterson LH (1993) Rationale for the use of aliphatic N-oxides of cytotoxic anthraquinones as prodrug DNA binding agents: a new class of bioreductive agent. Cancer Metast Rev 12: 119–134
Siemann DW (1994) In vitro cytotoxicity and chemosensitizing activity of the dual function nitroimidazole RB6145. Int J Radiat Oncol Biol Phys 29: 301–306
Siemann DW (1996) The in situ tumour response to combinations of cyclophosphamide and tirapazamine. Br J Cancer 74: S65–S69
Smith PJ, Blunt NJ, Desnoyers R, Giles Y and Patterson LH (1996) DNA topoisomerase II dependent cytotoxicity of alkylaminoanthraquinones and their N-oxides. Cancer Chemother Pharmacol 39: 455–461
Till JE and McCulloch EA (1961) A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat Res 14: 213–222
Workman P and Stratford IJ (1993) The experimental development of bioreductive drugs and their role in cancer therapy. Cancer Metast Rev 12: 73–82
Author information
Authors and Affiliations
Rights and permissions
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
About this article
Cite this article
Friery, O., Gallagher, R., Murray, M. et al. Enhancement of the anti-tumour effect of cyclophosphamide by the bioreductive drugs AQ4N and tirapazamine. Br J Cancer 82, 1469–1473 (2000). https://doi.org/10.1054/bjoc.1999.1132
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1054/bjoc.1999.1132
Keywords
This article is cited by
-
Combinatory anti-tumor activities of 1,4-bis[2-(dimethylamino)ethylamino]-5,8-dihydroxyanthracene-9,10-dione (AQ4) and temsirolimus against colorectal cancer cells
Journal of Cancer Research and Clinical Oncology (2023)
-
Dioscorea bulbifera polysaccharide and cyclophosphamide combination enhances anti-cervical cancer effect and attenuates immunosuppression and oxidative stress in mice
Scientific Reports (2016)
-
Targeting the hypoxic fraction of tumours using hypoxia-activated prodrugs
Cancer Chemotherapy and Pharmacology (2016)
-
Bioreductive GDEPT using cytochrome P450 3A4 in combination with AQ4N
Cancer Gene Therapy (2003)