Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1996 Jun;73(12):1480–1485. doi: 10.1038/bjc.1996.280

The effect of tirapazamine (SR-4233) alone or combined with chemotherapeutic agents on xenografted human tumours.

E Lartigau 1, M Guichard 1
PMCID: PMC2074534  PMID: 8664116

Abstract

Recent data have shown that the in vitro and in vivo cytotoxicity of bioreductive drugs could be significantly increased when combined with chemotherapy drugs such as cisplatinum, depending on the timing of administration. The aim of this study was to define the toxicity (animal lethality) and the activity (growth delay assay, excision assay) of a bioreductive drug, tirapazamine, alone and combined with chemotherapy agents (5-FU, VP16, bleo, DTIC and c-DDP) on nude mice bearing xenografted human tumours: a rectal carcinoma (HRT18) and a melanoma (Na11+). Animal lethality was markedly increased when tirapazamine at the lethal dose 10% was combined with the other drugs. For the HRT18 tumour the combination of tirapazamine and bleomycin significantly increased the delay of regrowth compared with bleomycin alone (P = 0.04) and was more cytotoxic than tirapazamine alone (P = 0.04). For the Na11+ tumours the combination of tirapazamine with VP16 significantly increased tumour doubling time compared with the controls (P = 0.001) or VP16 alone. The combination of tirapazamine and VP16 was more cytotoxic than VP16 alone (P = 0.0001). When compared with c-DDP or tirapazamine alone, there was a significant decrease in plating efficiency when tirapazamine and c-DDP were given at the same time (P = 0.04), but not when tirapazamine was given 3 h before c-DDP. In conclusion, tirapazamine was shown to be cytotoxic against clonogenic human tumour cells. Its efficacy in vivo may depend on its combination with already active chemotherapy drugs on the tumour model used. The timing of administration may be less important than previously thought.

Full text

PDF
1480

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bremner J. C., Stratford I. J., Bowler J., Adams G. E. Bioreductive drugs and the selective induction of tumour hypoxia. Br J Cancer. 1990 May;61(5):717–721. doi: 10.1038/bjc.1990.161. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Brown J. M., Lemmon M. J. Tumor hypoxia can be exploited to preferentially sensitize tumors to fractionated irradiation. Int J Radiat Oncol Biol Phys. 1991 Mar;20(3):457–461. doi: 10.1016/0360-3016(91)90057-b. [DOI] [PubMed] [Google Scholar]
  3. Brown J. M. SR 4233 (tirapazamine): a new anticancer drug exploiting hypoxia in solid tumours. Br J Cancer. 1993 Jun;67(6):1163–1170. doi: 10.1038/bjc.1993.220. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Coleman C. N. Hypoxia in tumors: a paradigm for the approach to biochemical and physiologic heterogeneity. J Natl Cancer Inst. 1988 May 4;80(5):310–317. doi: 10.1093/jnci/80.5.310. [DOI] [PubMed] [Google Scholar]
  5. Costa A. K., Baker M. A., Brown J. M., Trudell J. R. In vitro hepatotoxicity of SR 4233 (3-amino-1,2,4-benzotriazine-1,4-dioxide), a hypoxic cytotoxin and potential antitumor agent. Cancer Res. 1989 Feb 15;49(4):925–929. [PubMed] [Google Scholar]
  6. Doherty N., Hancock S. L., Kaye S., Coleman C. N., Shulman L., Marquez C., Mariscal C., Rampling R., Senan S., Roemeling R. V. Muscle cramping in phase I clinical trials of tirapazamine (SR 4233) with and without radiation. Int J Radiat Oncol Biol Phys. 1994 May 15;29(2):379–382. doi: 10.1016/0360-3016(94)90293-3. [DOI] [PubMed] [Google Scholar]
  7. 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]
  8. Gatenby R. A., Kessler H. B., Rosenblum J. S., Coia L. R., Moldofsky P. J., Hartz W. H., Broder G. J. Oxygen distribution in squamous cell carcinoma metastases and its relationship to outcome of radiation therapy. Int J Radiat Oncol Biol Phys. 1988 May;14(5):831–838. doi: 10.1016/0360-3016(88)90002-8. [DOI] [PubMed] [Google Scholar]
  9. Guichard M. Comparison of the radiobiological properties of human tumour xenografts and rodent tumours. Int J Radiat Biol. 1989 Nov;56(5):583–586. doi: 10.1080/09553008914551771. [DOI] [PubMed] [Google Scholar]
  10. Guichard M., Dertinger H., Malaise E. P. Radiosensitivity of four human tumor xenografts. Influence of hypoxia and cell-cell contact. Radiat Res. 1983 Sep;95(3):602–609. [PubMed] [Google Scholar]
  11. Guichard M., Gosse C., Malaise E. P. Survival curve of a human melanoma in nude mice. J Natl Cancer Inst. 1977 Jun;58(6):1665–1669. doi: 10.1093/jnci/58.6.1665. [DOI] [PubMed] [Google Scholar]
  12. 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]
  13. Höckel M., Vorndran B., Schlenger K., Baussmann E., Knapstein P. G. Tumor oxygenation: a new predictive parameter in locally advanced cancer of the uterine cervix. Gynecol Oncol. 1993 Nov;51(2):141–149. doi: 10.1006/gyno.1993.1262. [DOI] [PubMed] [Google Scholar]
  14. Koch C. J. Unusual oxygen concentration dependence of toxicity of SR-4233, a hypoxic cell toxin. Cancer Res. 1993 Sep 1;53(17):3992–3997. [PubMed] [Google Scholar]
  15. Lartigau E., Guichard M. Does tirapazamine (SR-4233) have any cytotoxic or sensitizing effect on three human tumour cell lines at clinically relevant partial oxygen pressure? Int J Radiat Biol. 1995 Feb;67(2):211–216. doi: 10.1080/09553009514550261. [DOI] [PubMed] [Google Scholar]
  16. Lartigau E., Le Ridant A. M., Lambin P., Weeger P., Martin L., Sigal R., Lusinchi A., Luboinski B., Eschwege F., Guichard M. Oxygenation of head and neck tumors. Cancer. 1993 Apr 1;71(7):2319–2325. doi: 10.1002/1097-0142(19930401)71:7<2319::aid-cncr2820710724>3.0.co;2-c. [DOI] [PubMed] [Google Scholar]
  17. Minchinton A. I., Lemmon M. J., Tracy M., Pollart D. J., Martinez A. P., Tosto L. M., Brown J. M. Second-generation 1,2,4-benzotriazine 1,4-di-N-oxide bioreductive anti-tumor agents: pharmacology and activity in vitro and in vivo. Int J Radiat Oncol Biol Phys. 1992;22(4):701–705. doi: 10.1016/0360-3016(92)90507-e. [DOI] [PubMed] [Google Scholar]
  18. Rockwell S., Moulder J. E. Hypoxic fractions of human tumors xenografted into mice: a review. Int J Radiat Oncol Biol Phys. 1990 Jul;19(1):197–202. doi: 10.1016/0360-3016(90)90154-c. [DOI] [PubMed] [Google Scholar]
  19. Rockwell S. Use of hypoxia-directed drugs in the therapy of solid tumors. Semin Oncol. 1992 Aug;19(4 Suppl 11):29–40. [PubMed] [Google Scholar]
  20. Sakata K., Kwok T. T., Murphy B. J., Laderoute K. R., Gordon G. R., Sutherland R. M. Hypoxia-induced drug resistance: comparison to P-glycoprotein-associated drug resistance. Br J Cancer. 1991 Nov;64(5):809–814. doi: 10.1038/bjc.1991.405. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Spiegel J. F., Spear M. A., Brown J. M. Toxicology of daily administration to mice of the radiation potentiator SR 4233 (WIN 59075). Radiother Oncol. 1993 Jan;26(1):79–81. doi: 10.1016/0167-8140(93)90031-3. [DOI] [PubMed] [Google Scholar]
  22. Teicher B. A., Lazo J. S., Sartorelli A. C. Classification of antineoplastic agents by their selective toxicities toward oxygenated and hypoxic tumor cells. Cancer Res. 1981 Jan;41(1):73–81. [PubMed] [Google Scholar]
  23. Vaupel P. Oxygenation of human tumors. Strahlenther Onkol. 1990 Jun;166(6):377–386. [PubMed] [Google Scholar]
  24. Workman P., Stratford I. J. The experimental development of bioreductive drugs and their role in cancer therapy. Cancer Metastasis Rev. 1993 Jun;12(2):73–82. doi: 10.1007/BF00689802. [DOI] [PubMed] [Google Scholar]
  25. Zeman E. M., Brown J. M., Lemmon M. J., Hirst V. K., Lee W. W. SR-4233: a new bioreductive agent with high selective toxicity for hypoxic mammalian cells. Int J Radiat Oncol Biol Phys. 1986 Jul;12(7):1239–1242. doi: 10.1016/0360-3016(86)90267-1. [DOI] [PubMed] [Google Scholar]
  26. Zeman E. M., Hirst V. K., Lemmon M. J., Brown J. M. Enhancement of radiation-induced tumor cell killing by the hypoxic cell toxin SR 4233. Radiother Oncol. 1988 Jul;12(3):209–218. doi: 10.1016/0167-8140(88)90263-0. [DOI] [PubMed] [Google Scholar]
  27. Zeman E. M., Lemmon M. J., Brown J. M. Aerobic radiosensitization by SR 4233 in vitro and in vivo. Int J Radiat Oncol Biol Phys. 1990 Jan;18(1):125–132. doi: 10.1016/0360-3016(90)90276-p. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES