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Br J Cancer. 1999 June; 80(8): 1245–1251.
PMCID: PMC2362366

Cisplatin anti-tumour potentiation by tirapazamine results from a hypoxia-dependent cellular sensitization to cisplatin


Tirapazamine (TPZ) is a new anticancer drug that is activated specifically at the low oxygen level typically found in solid tumours. It exhibits preferential cytotoxicity towards hypoxic cells and has been shown in preclinical studies with transplanted tumours and in phase II and III clinical trials to potentiate the anti-tumour efficacy of cisplatin without increasing its systemic toxicity. At present, the mechanism for this potentiation is unknown. Here we show that there is a schedule-dependent enhancement of cisplatin cytotoxicity by TPZ for cells in vitro that is similar to that seen with transplanted murine tumours. This cisplatin potentiation depends on the TPZ exposure being at oxygen concentrations below 1%, which are typical of many cells in tumours but not in normal tissues. Also, the interaction between TPZ and cisplatin does not occur in cells mutant in ERCC4, a protein essential for repair of DNA interstrand cross-links. Incubation of the cells with TPZ under hypoxia prior to cisplatin treatment increases cisplatin-induced DNA interstrand cross-links with kinetics suggesting that TPZ inhibits or delays repair of the DNA cross-links. In conclusion, we show that the tumour-specific potentiation of cisplatin cytotoxicity is likely the result of an interaction between TPZ and cisplatin at the cellular level that requires the low oxygen levels typical of those in solid tumours. The mechanism of the interaction appears to be through a potentiation of cisplatin-induced DNA interstrand cross-links, possibly as a result of a diminished or delayed repair of these lesions © 1999 Cancer Research Campaign

Keywords: tirapazamine, cisplatin, hypoxia, DNA interstrand cross-links, nucleotide excision repair

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Selected References

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  • Adam MF, Gabalski EC, Bloch DA, Oehlert JW, Brown JM, Elsaid AA, Pinto HA, Terris DJ. Tissue oxygen distribution in head and neck cancer patients. Head Neck. 1999 Mar;21(2):146–153. [PubMed]
  • Andersson BS, Sadeghi T, Siciliano MJ, Legerski R, Murray D. Nucleotide excision repair genes as determinants of cellular sensitivity to cyclophosphamide analogs. Cancer Chemother Pharmacol. 1996;38(5):406–416. [PubMed]
  • Berezney R, Coffey DS. Nuclear protein matrix: association with newly synthesized DNA. Science. 1975 Jul 25;189(4199):291–293. [PubMed]
  • Brizel DM, Rosner GL, Harrelson J, Prosnitz LR, Dewhirst MW. Pretreatment oxygenation profiles of human soft tissue sarcomas. Int J Radiat Oncol Biol Phys. 1994 Oct 15;30(3):635–642. [PubMed]
  • Brizel DM, Sibley GS, Prosnitz LR, Scher RL, Dewhirst MW. Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck. Int J Radiat Oncol Biol Phys. 1997 May 1;38(2):285–289. [PubMed]
  • Brown JM. SR 4233 (tirapazamine): a new anticancer drug exploiting hypoxia in solid tumours. Br J Cancer. 1993 Jun;67(6):1163–1170. [PMC free article] [PubMed]
  • Brown JM, Lemmon MJ. Potentiation by the hypoxic cytotoxin SR 4233 of cell killing produced by fractionated irradiation of mouse tumors. Cancer Res. 1990 Dec 15;50(24):7745–7749. [PubMed]
  • Brown JM, Lemmon MJ. Tumor hypoxia can be exploited to preferentially sensitize tumors to fractionated irradiation. Int J Radiat Oncol Biol Phys. 1991 Mar;20(3):457–461. [PubMed]
  • Cook PR. The nucleoskeleton and the topology of transcription. Eur J Biochem. 1989 Nov 20;185(3):487–501. [PubMed]
  • Cruickshank GS, Rampling RP, Cowans W. Direct measurement of the PO2 distribution in human malignant brain tumours. Adv Exp Med Biol. 1994;345:465–470. [PubMed]
  • Dabholkar M, Bostick-Bruton F, Weber C, Bohr VA, Egwuagu C, Reed E. ERCC1 and ERCC2 expression in malignant tissues from ovarian cancer patients. J Natl Cancer Inst. 1992 Oct 7;84(19):1512–1517. [PubMed]
  • Damia G, Imperatori L, Stefanini M, D'Incalci M. Sensitivity of CHO mutant cell lines with specific defects in nucleotide excision repair to different anti-cancer agents. Int J Cancer. 1996 Jun 11;66(6):779–783. [PubMed]
  • Dorie MJ, Brown JM. Tumor-specific, schedule-dependent interaction between tirapazamine (SR 4233) and cisplatin. Cancer Res. 1993 Oct 1;53(19):4633–4636. [PubMed]
  • Dorie MJ, Brown JM. Modification of the antitumor activity of chemotherapeutic drugs by the hypoxic cytotoxic agent tirapazamine. Cancer Chemother Pharmacol. 1997;39(4):361–366. [PubMed]
  • Durand RE. The influence of microenvironmental factors during cancer therapy. In Vivo. 1994 Nov-Dec;8(5):691–702. [PubMed]
  • Evans JW, Yudoh K, Delahoussaye YM, Brown JM. Tirapazamine is metabolized to its DNA-damaging radical by intranuclear enzymes. Cancer Res. 1998 May 15;58(10):2098–2101. [PubMed]
  • Ewig RA, Kohn KW. DNA-protein cross-linking and DNA interstrand cross-linking by haloethylnitrosoureas in L1210 cells. Cancer Res. 1978 Oct;38(10):3197–3203. [PubMed]
  • Gatenby RA, Kessler HB, Rosenblum JS, Coia LR, Moldofsky PJ, Hartz WH, Broder GJ. 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. [PubMed]
  • Graham MA, Senan S, Robin H, Jr, Eckhardt N, Lendrem D, Hincks J, Greenslade D, Rampling R, Kaye SB, von Roemeling R, et al. Pharmacokinetics of the hypoxic cell cytotoxic agent tirapazamine and its major bioreductive metabolites in mice and humans: retrospective analysis of a pharmacokinetically guided dose-escalation strategy in a phase I trial. Cancer Chemother Pharmacol. 1997;40(1):1–10. [PubMed]
  • Grau C, Overgaard J. Effect of cancer chemotherapy on the hypoxic fraction of a solid tumor measured using a local tumor control assay. Radiother Oncol. 1988 Dec;13(4):301–309. [PubMed]
  • Hansson J, Lewensohn R, Ringborg U, Nilsson B. Formation and removal of DNA cross-links induced by melphalan and nitrogen mustard in relation to drug-induced cytotoxicity in human melanoma cells. Cancer Res. 1987 May 15;47(10):2631–2637. [PubMed]
  • Helmlinger G, Yuan F, Dellian M, Jain RK. Interstitial pH and pO2 gradients in solid tumors in vivo: high-resolution measurements reveal a lack of correlation. Nat Med. 1997 Feb;3(2):177–182. [PubMed]
  • Höckel M, Schlenger K, Knoop C, Vaupel P. Oxygenation of carcinomas of the uterine cervix: evaluation by computerized O2 tension measurements. Cancer Res. 1991 Nov 15;51(22):6098–6102. [PubMed]
  • Jones NJ, Stewart SA, Thompson LH. Biochemical and genetic analysis of the Chinese hamster mutants irs1 and irs2 and their comparison to cultured ataxia telangiectasia cells. Mutagenesis. 1990 Jan;5(1):15–23. [PubMed]
  • Kim IH, Brown JM. Reoxygenation and rehypoxiation in the SCCVII mouse tumor. Int J Radiat Oncol Biol Phys. 1994 Jun 15;29(3):493–497. [PubMed]
  • Koch CJ. Unusual oxygen concentration dependence of toxicity of SR-4233, a hypoxic cell toxin. Cancer Res. 1993 Sep 1;53(17):3992–3997. [PubMed]
  • Miller VA, Ng KK, Grant SC, Kindler H, Pizzo B, Heelan RT, von Roemeling R, Kris MG. Phase II study of the combination of the novel bioreductive agent, tirapazamine, with cisplatin in patients with advanced non-small-cell lung cancer. Ann Oncol. 1997 Dec;8(12):1269–1271. [PubMed]
  • Nordsmark M, Bentzen SM, Overgaard J. Measurement of human tumour oxygenation status by a polarographic needle electrode. An analysis of inter- and intratumour heterogeneity. Acta Oncol. 1994;33(4):383–389. [PubMed]
  • Nordsmark M, Overgaard M, Overgaard J. Pretreatment oxygenation predicts radiation response in advanced squamous cell carcinoma of the head and neck. Radiother Oncol. 1996 Oct;41(1):31–39. [PubMed]
  • Siemann DW, Hinchman CA. Potentiation of cisplatin activity by the bioreductive agent tirapazamine. Radiother Oncol. 1998 May;47(2):215–220. [PubMed]
  • Treat J, Johnson E, Langer C, Belani C, Haynes B, Greenberg R, Rodriquez R, Drobins P, Miller W, Jr, Meehan L, et al. Tirapazamine with cisplatin in patients with advanced non-small-cell lung cancer: a phase II study. J Clin Oncol. 1998 Nov;16(11):3524–3527. [PubMed]
  • Urtasun RC, Chapman JD, Raleigh JA, Franko AJ, Koch CJ. Binding of 3H-misonidazole to solid human tumors as a measure of tumor hypoxia. Int J Radiat Oncol Biol Phys. 1986 Jul;12(7):1263–1267. [PubMed]
  • Vaupel P, Schlenger K, Knoop C, Höckel M. Oxygenation of human tumors: evaluation of tissue oxygen distribution in breast cancers by computerized O2 tension measurements. Cancer Res. 1991 Jun 15;51(12):3316–3322. [PubMed]
  • Zeman EM, Brown JM, Lemmon MJ, Hirst VK, Lee WW. 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. [PubMed]

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