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Tirapazamine plus cisplatin and irradiation in a mouse model: improved tumor control at the cost of increased toxicity

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Tirapazamine (TPZ) reportedly enhances the tumor cell killing effect of cisplatin up to fivefold and it is an attractive drug for combination with radiotherapy. We evaluated the toxicity of a fractionated combined treatment.


Murine RIF-1 fibrosarcomas growing on the right hind foot of C3-H mice were used. Within 2 weeks, animals were treated with six i.p. injections of TPZ (43.2–172.8 mg/kg total), and/or cisplatin (24 mg/kg total) and ten fractions of 2 Gy to the tumor. All treatments were carried out under anesthesia. Maximum follow-up was 35 days. The local tumor control was determined by calculating the tumor doubling time t 2vo. In addition to standard toxicity assessment, the major inner organs were examined histologically.


The administration of low TPZ doses to the cisplatin/radiotherapy treatment caused only little changes in tumor doubling time (t 2vo) and led to a lethality rate of 15–30%. Higher TPZ doses caused an increase in t 2vo, but also a further increase in lethality and toxicity in particular to the heart, liver, kidney and stomach. Cisplatin/radiotherapy treatment without TPZ produced no severe toxicity.


This is a detailed study of both the acute and delayed toxicities of combined TPZ treatment in a mouse model. In our study the addition of TPZ to the cisplatin/radiotherapy treatment caused a significant increase in toxicity with only moderate effect on the tumor.

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  1. Adam M, Dorie MJ, Brown JM (1999a) Oxygen tension measurements of tumors growing in mice. Int J Radiat Oncol Biol Phys 1:171–180

  2. Adam M, Gabalski EC, Bloch DA, Oehlert JW, Brown JM, Elsaid AA, Pinto HA, Terris DJ (1999b) Tissue oxygen distribution in head and neck cancer patients. Head and Neck 21:146–153

  3. Adam M, Henke J, Hieber E, Ottenjann S, Nieder C, Erhard W, Molls M (2005) Setup for precise simultaneous chemoradiation under inhalation anesthesia in an experimental mouse tumor model. Anticancer Res 2815–2820

  4. Aghajanian C, Brown C, O’Flaherty C, Fleischauer A, Curtin J, Roemeling R, Spriggs DR (1997) Phase I study of tirapazamine and cisplatin in patients with recurrent cervical cancer. Gynecol Oncol 2:127–130

  5. Aquino VM, Weitman SD, Winick NJ, Blaney S, Furman WL, Kepner JL, Bonate P, Krailo M, Qu W et al (2004) Phase I trial of tirapazamine and cyclophosphamide in children with refractory solid tumors: a pediatric oncology group study. J Clin Oncol 8:1413–1419

  6. Arteel GE, Thurman RG, Yates JM, Raleigh JA (1995) Evidence that hypoxia markers detect oxygen gradients in liver: pimonidazole and retrograde perfusion of rat liver. Br J Cancer 4:889–895

  7. Brown JM (1993) SR 4233 (tirapazamine): a new anticancer drug exploiting hypoxia in solid tumours. Br J Cancer 6:1163–1170

  8. Brown JM, Lemmon MJ (1990) Potentiation by the hypoxic cytotoxin SR 4233 of cell killing produced by fractionated irradiation of mouse tumors. Cancer Res 24:7745–7749

  9. Brown JM, Lemmon MJ (1991a) SR 4233: a tumor specific radiosensitizer active in fractionated radiation regimes. Radiother Oncol 151–156

  10. Brown JM, Lemmon MJ (1991b) Tumor hypoxia can be exploited to preferentially sensitize tumors to fractionated irradiation. Int J Radiat Onc Biol Phys 3:457–461

  11. Brown JM, Giaccia AJ (1998) The unique physiology of solid tumors: opportunities (and problems) for cancer therapy. Cancer Res 7:1408–1416

  12. Brown JM, Wang LH (1998) Tirapazamine: laboratory data relevant to clinical activity. Anticancer Drug Des 6:529–539

  13. Craighead PS, Pearcey R, Stuart G (2000) A phase I/II evaluation of tirapazamine administered intravenously concurrent with cisplatin and radiotherapy in women with locally advanced cervical cancer. Int J Radiat Onc Biol Phys 3:791–795

  14. Deuse U (2004) Comparison of two inhalation anesthesia devices for mice with respect to clinical usefulness (German). Thesis at the Institute for Experimental Oncology and Therapy Research, Klinikum rechts der Isar, Technical Univ. Munich, Germany

  15. Dorie MJ, Brown JM (1993) Tumor-specific, schedule-dependent interaction between tirapazamine (SR 4233) and cisplatin. Cancer Res 19:4633–4636

  16. Dorie MJ, Brown JM (1997) Modification of the anti-tumor activity of chemotherapeutic drugs by the hypoxic cytotoxic agent tirapazamine. Cancer Chemother Pharmacol 4:361–366

  17. Gatineau M, Rixe O, Chevalier TL (2005) Tirapazamine with cisplatin and vinorelbine in patients with advanced non-small cell lung cancer: a phase I/II study. Clin Lung Cancer 5:293–298

  18. Gatzemeier U, Rodriguez G, Treat J, Miller V, von Roemeling R, Viallet J, Rey A (1998) Tirapazamine-cisplatin: the synergy. Br J Cancer 15–17

  19. Graeber TG, Osmanian C, Jacks T, Housman DE, Koch CJ, Lowe SW, Giaccia AJ (1996) Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature 6560:88–91

  20. Hicks KO, Siim BG, Pruijn FB, Wilson WR (2004) Oxygen dependence of the metabolic activation and cytotoxicity of tirapazamine: implications for extravascular transport and activity in tumors. Radiat Res 6:656–666

  21. Hockel M, Knoop C, Schlenger K, Vorndran B, Baussmann E, Mitze M, Knapstein PG, Vaupel P (1993) Intratumoral pO2 predicts survival in advanced cancer of the uterine cervix. Radiother Oncol 1:45–50

  22. Koch CJ (1993) Unusual oxygen concentration dependence of toxicity of SR-4233, a hypoxic cell toxin. Cancer Res 17:3992–3997

  23. Kovacs MS, Hocking D, Evans JW, Brown JM (1998) Mechanism of the tumor-specific enhancement of cell kill by cisplatin produced by the hypoxic cytotoxin tirapazamine. Proc Am Assoc Cancer Res 39:156

  24. Lara PN Jr, Frankel P, Mack PC, Gumerlock PH, Galvin I, Martel CL, Longmate J, Doroshow JH, Lenz HJ et al (2003) Tirapazamine plus carboplatin and paclitaxel in advanced malignant solid tumors: a california cancer consortium phase I and molecular correlative study. Clin Cancer Res 12:4356–4362

  25. Larsen R (2001) Anästhesie, 6. Auflage. Urban & Schwarzenberg, München, pp 249–60

  26. Lartigau E, Guichard M (1996) The effect of tirapazamine (SR-4233) alone or combined with chemotherapeutic agents on xenografted human tumours. Br J Cancer 12:1480–1485

  27. Le QT, McCoy J, Williamson S, Ryu J, Gaspar LE, Edelman MJ, Dakhil SR, Sides SD, Crowley JJ et al (2004) Phase I study of tirapazamine plus cisplatin/etoposide and concurrent thoracic radiotherapy in limited-stage small cell lung cancer (S0004): a southwest oncology group study. Clin Cancer Res 16:5418–5424

  28. Le QT, Taira A, Budenz S, Jo DM, Goffinet DR, Fee WE, Goode R, Bloch D, Koong A et al (2006) Mature results from a randomized Phase II trial of cisplatin plus 5-fluorouracil and radiotherapy with or without tirapazamine in patients with resectable stage IV head and neck squamous cell carcinomas. Cancer 9:1940–1949

  29. Lee AE, Wilson WR (2000) Hypoxia-dependent retinal toxicity of bioreductive anticancer prodrugs in mice. Toxicol Appl Pharmacol 1:50–59

  30. Nordsmark M, Overgaard M, Overgaard J (1996) Pretreatment oxygenation predicts radiation response in advanced squamous cell carcinoma of the head and neck. Radiother Oncol 1:31–39

  31. Reck M, von Pawel J, Nimmermann C, Groth G, Gatzemeier U (2004) Phase II-trial of tirapazamine in combination with cisplatin and gemcitabine in patients with advanced non-small cell lung cancer (NSCLC) (German). Pneumologie 12:845–849

  32. Rischin D, Peters L, Hicks R, Hughes P, Fisher R, Hart R, Sexton M, D’Costa I, von Roemeling R (2001) Phase I trial of concurrent tirapazamine, cisplatin, and radiotherapy in patients with advanced head and neck cancer. J Clin Oncol 2:535–542

  33. Rischin D, Peters L, Fisher R, Macann A, Denham J, Poulsen M, Jackson M, Kenny L, Penniment M et al (2005) Tirapazamine, cisplatin, and radiation versus fluorouracil, cisplatin, and radiation in patients with locally advanced head and neck cancer: a randomized phase II trial of the trans-tasman radiation oncology group (TROG 98.02). J Clin Oncol 1:79–87

  34. Romeis B, Böck P (1989) Mikroskopische Technik. Urban & Fischer Verlag, Jena

  35. Senan S (1995) Vasoactivity, a potentially important variable in the sequencing of tirapazamine (SR 4233) and radiation. Int J Radiat Onc Biol Phys 1:209–210

  36. Shepherd FA, Koschel G, von Pawel J, Gatzemeier U, Van Zandwiyk N, Well P, Van Klavren R, Krasko P, Desimone P et al (2000) Comparison of tirazone (tirapazamine) and cisplatin versus etoposide and cisplatin in advanced non-small cell lung cancer (NSCLC): final results of the international phase III CATAPULT II trial. Abstract publication in 9th world conference on lung cancer, Tokyo

  37. Shulman LN, Buswell L, Riese N, Doherty N, Loeffler JS, von Roemeling RW, Coleman CN (1999) Phase I trial of the hypoxic cell cytotoxin tirapazamine with concurrent radiation therapy in the treatment of refractory solid tumors. Int J Radiat Onc Biol Phys 2:349–353

  38. Siemann DW, Hinchman CA (1998) Potentiation of cisplatin activity by the bioreductive agent tirapazamine. Radiother Oncol 2:215–220

  39. Smith HO, Jiang CS, Weiss GR, Hallum AV III, Liu PY, Robinson WR III, Cheng PC, Scudder SA, Markman M et al (2006) Tirapazamine plus cisplatin in advanced or recurrent carcinoma of the uterine cervix: a southwest oncology group study. Int J Gynecol Cancer 1:298–305

  40. Stadler P, Becker A, Feldmann HJ, Haensgen G, Dunst J, Wueschmidt F, Molls M (1999) Influence of the hypoxic subvolume on the survival of patients with head and neck cancer. Int J Radiat Onc Biol Phys 4:749–754

  41. Stone HB, Brown JM, Phillips TL, Sutherland RM (1993) Oxygen in human tumors: correlations between methods of measurement and response to therapy. Summary of a workshop held 19–20 November 1992, at the National Cancer Institute, Bethesda, Maryland. Radiat Res 3:422–434

  42. Tercel M, Lee AE, Hogg A, Anderson RF, Lee HH, Siim BG, Denny WA, Wilson WR (2001) Hypoxia-selective antitumor agents. 16. Nitroarylmethyl quaternary salts as bioreductive prodrugs of the alkylating agent mechlorethamine. J Med Chem 21:3511–3522

  43. Vaupel P, Schlenger K, Hoeckel M (1992) Blood flow and tissue oxygenation of human tumors: an update. Adv Exp Med Biol 139–151

  44. von Pawel J, von Roemeling R, Gatzemeier U, Boyer M, Elisson LO, Clark P, Talbot D, Rey A, Butler TW et al (2000) Tirapazamine plus cisplatin versus cisplatin in advanced non-small cell lung cancer: a report of the international CATAPULT I study group. Cisplatin and tirapazamine in subjects with advanced previously untreated non-small cell lung tumors. J Clin Oncol 6:1351–1359

  45. Wouters BG, Brown JM (1997) Cells at intermediate oxygen levels can be more important than the hypoxic fraction in determining tumor response to fractionated radiotherapy. Radiat Res 5:541–550

  46. Wouters BG, Delahoussaye YM, Evans JW, Birrell GW, Dorie MJ, Wang J, MacDermed D, Chiu RK, Brown JM (2001) Mitochondrial dysfunction after aerobic exposure to the hypoxic cytotoxin tirapazamine. Cancer Res 1:145–152

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We would like to thank Georg Künzel, Sigrid Ottenjann and Ewald Hieber for taking care of the animals and providing great help in performing the experiments and histological examinations. This project would not have been possible without their excellent work.

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Correspondence to Markus Adam.

Additional information

This work was supported by: Deutsche Forschungsgemeinschaft (DFG grant Ad132/2-1).

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Adam, M., Bayer, C., Henke, J. et al. Tirapazamine plus cisplatin and irradiation in a mouse model: improved tumor control at the cost of increased toxicity. J Cancer Res Clin Oncol 134, 137–146 (2008). https://doi.org/10.1007/s00432-007-0260-7

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  • Tirapazamine
  • Cisplatin
  • Radiotherapy
  • Mouse tumors
  • Toxicity
  • Growth delay
  • Dose fractionation