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. 2001 Aug;85(4):625–629. doi: 10.1054/bjoc.2001.1975

The chemopotentiation of cisplatin by the novel bioreductive drug AQ4N

R Gallagher 1, C M Hughes 1, M M Murray 1, O P Friery 1, L H Patterson 2, D G Hirst 1, S R McKeown 1
PMCID: PMC2364091  PMID: 11506506

Abstract

AQ4N is a bioreductive drug that can significantly enhance the anti-tumour effect of radiation and cyclophosphamide. The aim of this study was to examine the ability of AQ4N to potentiate the anti-tumour effect of cisplatin and to compare it to the chemopotentiation effect of tirapazamine. In the T50/80 murine tumour model, AQ4N (50–100 mg/kg) was administered 30 min, 2.5 or 6 h prior to cisplatin (4 mg/kg or 8 mg/kg); this produced an anti-tumour effect that was approximately 1.5 to 2 times greater than that achieved by a single 4 or 8 mg/kg dose of cisplatin. Tirapazamine (25 mg/kg) administered 2.5 h prior to cisplatin (4 mg/kg) resulted in a small increase in anti-tumour efficacy. AQ4N was also successful in enhancing the anti-tumour effect of cisplatin in the SCCVII and RIF-1 murine tumour models. This resulted in an increased cell kill of greater than 3 logs in both models; this was a greater cell kill than that observed for tirapazamine with cisplatin. Combination of cisplatin with AQ4N or tirapazamine resulted in no additional bone marrow toxicity compared to cisplatin administered alone. In conclusion, AQ4N has the potential to improve the clinical efficacy of cisplatin. © 2001 Cancer Research Campaign http://www.bjcancer.com

Keywords: AQ4N + cisplatin, chemopotentiation

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Selected References

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  1. Dorie M. J., Brown J. M. Modification of the antitumor activity of chemotherapeutic drugs by the hypoxic cytotoxic agent tirapazamine. Cancer Chemother Pharmacol. 1997;39(4):361–366. doi: 10.1007/s002800050584. [DOI] [PubMed] [Google Scholar]
  2. Dorie M. J., Brown J. M. Tumor-specific, schedule-dependent interaction between tirapazamine (SR 4233) and cisplatin. Cancer Res. 1993 Oct 1;53(19):4633–4636. [PubMed] [Google Scholar]
  3. Friery O. P., Gallagher R., Murray M. M., Hughes C. M., Galligan E. S., McIntyre I. A., Patterson L. H., Hirst D. G., McKeown S. R. Enhancement of the anti-tumour effect of cyclophosphamide by the bioreductive drugs AQ4N and tirapazamine. Br J Cancer. 2000 Apr;82(8):1469–1473. doi: 10.1054/bjoc.1999.1132. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Gervot L., Rochat B., Gautier J. C., Bohnenstengel F., Kroemer H., de Berardinis V., Martin H., Beaune P., de Waziers I. Human CYP2B6: expression, inducibility and catalytic activities. Pharmacogenetics. 1999 Jun;9(3):295–306. [PubMed] [Google Scholar]
  5. Hejmadi M. V., McKeown S. R., Friery O. P., McIntyre I. A., Patterson L. H., Hirst D. G. 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. doi: 10.1038/bjc.1996.87. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Holden S. A., Teicher B. A., Ara G., Herman T. S., Coleman C. N. Enhancement of alkylating agent activity by SR-4233 in the FSaIIC murine fibrosarcoma. J Natl Cancer Inst. 1992 Feb 5;84(3):187–193. doi: 10.1093/jnci/84.3.187. [DOI] [PubMed] [Google Scholar]
  7. Horsman M. R., Evans J. W., Brown J. M. Enhancement of melphalan-induced tumour cell killing by misonidazole: an interaction of competing mechanisms. Br J Cancer. 1984 Sep;50(3):305–316. doi: 10.1038/bjc.1984.177. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Kennedy K. A. Hypoxic cells as specific drug targets for chemotherapy. Anticancer Drug Des. 1987 Oct;2(2):181–194. [PubMed] [Google Scholar]
  9. McAleer J. J., McKeown S. R., MacManus M. P., Lappin T. R., Bridges J. M. Hypobaric hypoxia: a method for testing bioreductive drugs in vivo. Int J Radiat Oncol Biol Phys. 1992;23(3):551–555. doi: 10.1016/0360-3016(92)90010-f. [DOI] [PubMed] [Google Scholar]
  10. McKeown S. R., Friery O. P., McIntyre I. A., Hejmadi M. V., Patterson L. H., Hirst D. G. Evidence for a therapeutic gain when AQ4N or tirapazamine is combined with radiation. Br J Cancer Suppl. 1996 Jul;27:S39–S42. [PMC free article] [PubMed] [Google Scholar]
  11. McKeown S. R., Hejmadi M. V., McIntyre I. A., McAleer J. J., Patterson L. H. AQ4N: an alkylaminoanthraquinone N-oxide showing bioreductive potential and positive interaction with radiation in vivo. Br J Cancer. 1995 Jul;72(1):76–81. doi: 10.1038/bjc.1995.280. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Moore J. V. The dynamics of tumor cords in an irradiated mouse mammary carcinoma with a large hypoxic cell component. Jpn J Cancer Res. 1988 Feb;79(2):236–243. doi: 10.1111/j.1349-7006.1988.tb01582.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Overgaard J., Grau C., Lindegaard J. C., Horsman M. R. The potential of using hyperthermia to eliminate radioresistant hypoxic cells. Radiother Oncol. 1991;20 (Suppl 1):113–116. doi: 10.1016/0167-8140(91)90197-o. [DOI] [PubMed] [Google Scholar]
  14. Patterson L. H. Rationale for the use of aliphatic N-oxides of cytotoxic anthraquinones as prodrug DNA binding agents: a new class of bioreductive agent. Cancer Metastasis Rev. 1993 Jun;12(2):119–134. doi: 10.1007/BF00689805. [DOI] [PubMed] [Google Scholar]
  15. Siemann D. W., Hinchman C. A. Potentiation of cisplatin activity by the bioreductive agent tirapazamine. Radiother Oncol. 1998 May;47(2):215–220. doi: 10.1016/s0167-8140(97)00224-7. [DOI] [PubMed] [Google Scholar]
  16. Smith P. J., Blunt N. J., Desnoyers R., Giles Y., Patterson L. H. DNA topoisomerase II-dependent cytotoxicity of alkylaminoanthraquinones and their N-oxides. Cancer Chemother Pharmacol. 1997;39(5):455–461. doi: 10.1007/s002800050598. [DOI] [PubMed] [Google Scholar]
  17. TILL J. E., McCULLOCH E. A. A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat Res. 1961 Feb;14:213–222. [PubMed] [Google Scholar]
  18. Twentyman P. R., Brown J. M., Gray J. W., Franko A. J., Scoles M. A., Kallman R. F. A new mouse tumor model system (RIF-1) for comparison of end-point studies. J Natl Cancer Inst. 1980 Mar;64(3):595–604. [PubMed] [Google Scholar]
  19. Twentyman P. R. Comparative chemosensitivity of exponential- versus plateau-phase cells in both in vitro model systems. Cancer Treat Rep. 1976 Dec;60(12):1719–1722. [PubMed] [Google Scholar]

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