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 Tirapazamine

Tirapazamine is a benzotriazine di-N-oxide with potential antineoplastic activity. Tirapazamine is selectively activated by multiple reductases to form free radicals in hypoxic cells, thereby inducing single-and double-strand breaks in DNA, base damage, and cell death. This agent also sensitizes hypoxic cells to ionizing radiation and inhibits the repair of radiation-induced DNA strand breaks via inhibition of topoisomerase II. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Current developer:    Sanofi-Synthelabo (Originator), SRI (Originator), National Cancer Institute (Not Determined)

Phase I study of Tirapazamine: Eleven patients were enrolled. The median age was 52 years (range, 31-65 years). Ten patients had squamous cell carcinoma and 1 patient had adenocarcinoma; 5 patients had stage 1B2 disease, 1 had stage IIA, 3 had stage IIB-3, 1 had stage IIIB, and 1 had stage IVA. The first 2 patients on dose level 1 experienced a dose-limiting toxicity (DLT): 1 experienced grade 3 alanine amino transferase elevation and grade 4 pulmonary embolism, and 1 experienced grade 3 ototoxicity. Doses were decreased to dose level -1 with a 30-mg/m dose of cisplatin and a 260-mg/m dose of tirapazamine. Three patients were treated without any DLTs. Six patients were then treated on dose level -1a: a 35-mg/m dose of cisplatin and a 260-mg/m doses of tirapazamine with 2 DLTs--grade 3 neutropenia with dose omission and grade 4 pulmonary embolism with major hemodynamic compromise. Three of 10 evaluable patients have experienced locoregional failure. The combination of weekly tirapazamine and cisplatin with radiation for locally advanced cervical cancer was associated with more toxicity than anticipated with the recommended dose level being tirapazamine 260 mg/m and cisplatin 30 mg/m. Further study of this weekly schedule is not warranted. (source: Int J Gynecol Cancer. 2010 Jul;20(5):827-33.)

1: Sonoda A, Nitta N, Ohta S, Nitta-Seko A, Nagatani Y, Takahashi M, Murata K. Enhanced antitumor effect of tirapazamine delivered intraperitoneally to VX2 liver tumor-bearing rabbits subjected to transarterial hepatic embolization. Cardiovasc Intervent Radiol. 2011 Dec;34(6):1272-7. Epub 2011 Apr 9. PubMed PMID: 21479745.

2: Papadopoulou MV, Ji M, Bloomer WD. Hypoxia-dependent retinal toxicity of NLCQ-1 (NSC 709257) in BALB/c mice. Comparison with tirapazamine. Basic Clin Pharmacol Toxicol. 2011 Jun;108(6):396-9. doi: 10.1111/j.1742-7843.2010.00667.x. Epub 2011 Jan 26. PubMed PMID: 21205223.

3: Zhang J, Cao J, Weng Q, Wu R, Yan Y, Jing H, Zhu H, He Q, Yang B. Suppression of hypoxia-inducible factor 1α (HIF-1α) by tirapazamine is dependent on eIF2α phosphorylation rather than the mTORC1/4E-BP1 pathway. PLoS One. 2010 Nov 9;5(11):e13910. PubMed PMID: 21085474; PubMed Central PMCID: PMC2976688.

4: Hicks KO, Siim BG, Jaiswal JK, Pruijn FB, Fraser AM, Patel R, Hogg A, Liyanage HD, Dorie MJ, Brown JM, Denny WA, Hay MP, Wilson WR. Pharmacokinetic/pharmacodynamic modeling identifies SN30000 and SN29751 as tirapazamine analogues with improved tissue penetration and hypoxic cell killing in tumors. Clin Cancer Res. 2010 Oct 15;16(20):4946-57. Epub 2010 Aug 20. PubMed PMID: 20732963.

5: Rischin D, Narayan K, Oza AM, Mileshkin L, Bernshaw D, Choi J, Hicks R, McClure B, Fyles A. Phase 1 study of tirapazamine in combination with radiation and weekly cisplatin in patients with locally advanced cervical cancer. Int J Gynecol Cancer. 2010 Jul;20(5):827-33. PubMed PMID: 20606530.

6: Rischin D, Peters LJ, O'Sullivan B, Giralt J, Fisher R, Yuen K, Trotti A, Bernier J, Bourhis J, Ringash J, Henke M, Kenny L. Tirapazamine, cisplatin, and radiation versus cisplatin and radiation for advanced squamous cell carcinoma of the head and neck (TROG 02.02, HeadSTART): a phase III trial of the Trans-Tasman Radiation Oncology Group. J Clin Oncol. 2010 Jun 20;28(18):2989-95. Epub 2010 May 17. PubMed PMID: 20479425.

7: Shinde SS, Maroz A, Hay MP, Patterson AV, Denny WA, Anderson RF. Characterization of radicals formed following enzymatic reduction of 3-substituted analogues of the hypoxia-selective cytotoxin 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine). J Am Chem Soc. 2010 Mar 3;132(8):2591-9. PubMed PMID: 20141134.

8: Epperly MW, Lai SY, Kanai AJ, Mason N, Lopresi B, Dixon T, Franicola D, Niu Y, Wilson WR, Greenberger JS. Effectiveness of combined modality radiotherapy of orthotopic human squamous cell carcinomas in Nu/Nu mice using cetuximab, tirapazamine and MnSOD-plasmid liposome gene therapy. In Vivo. 2010 Jan-Feb;24(1):1-8. PubMed PMID: 20133969; PubMed Central PMCID: PMC2899489.

9: Xu P, Huang JM, Ren Y, Zha X, Deng BF, Wu JH, Lang JY. Regulation of hypoxia-induced mRNA expressions of HIF-1alpha and osteopontin and in vitro radiosensitization by tirapazamine in human nasopharyngeal carcinoma HNE-1 and CNE-1 cells. Chin J Cancer. 2010 Feb;29(2):126-30. PubMed PMID: 20109337.

10: Hong B, Lui VW, Hui EP, Ng MH, Cheng SH, Sung FL, Tsang CM, Tsao SW, Chan AT. Hypoxia-targeting by tirapazamine (TPZ) induces preferential growth inhibition of nasopharyngeal carcinoma cells with Chk1/2 activation. Invest New Drugs. 2011 Jun;29(3):401-10. Epub 2009 Dec 16. PubMed PMID: 20013349.

11: Shinde SS, Hay MP, Patterson AV, Denny WA, Anderson RF. Spin trapping of radicals other than the *OH radical upon reduction of the anticancer agent tirapazamine by cytochrome P450 reductase. J Am Chem Soc. 2009 Oct 14;131(40):14220-1. PubMed PMID: 19772319.

12: Doloff JC, Khan N, Ma J, Demidenko E, Swartz HM, Jounaidi Y. Increased tumor oxygenation and drug uptake during anti-angiogenic weekly low dose cyclophosphamide enhances the anti-tumor effect of weekly tirapazamine. Curr Cancer Drug Targets. 2009 Sep;9(6):777-88. PubMed PMID: 19754361; PubMed Central PMCID: PMC2912211.

13: Bains LJ, Baker JH, Kyle AH, Minchinton AI, Reinsberg SA. Detecting vascular-targeting effects of the hypoxic cytotoxin tirapazamine in tumor xenografts using magnetic resonance imaging. Int J Radiat Oncol Biol Phys. 2009 Jul 1;74(3):957-65. PubMed PMID: 19480975.

14: Hu G, Guo Y, Shao S. Ultrasensitive electrochemical sensing of the anticancer drug tirapazamine using an ordered mesoporous carbon modified pyrolytic graphite electrode. Biosens Bioelectron. 2009 Jul 15;24(11):3391-4. Epub 2009 May 3. PubMed PMID: 19450968.

15: Le QT, Moon J, Redman M, Williamson SK, Lara PN Jr, Goldberg Z, Gaspar LE, Crowley JJ, Moore DF Jr, Gandara DR. Phase II study of tirapazamine, cisplatin, and etoposide and concurrent thoracic radiotherapy for limited-stage small-cell lung cancer: SWOG 0222. J Clin Oncol. 2009 Jun 20;27(18):3014-9. Epub 2009 Apr 13. PubMed PMID: 19364954; PubMed Central PMCID: PMC2702233.

16: Masunaga S, Tano K, Watanabe M, Kashino G, Suzuki M, Kinashi Y, Ono K, Nakamura J. Evaluation of the potential of hexamethylenetetramine, compared with tirapazamine, as a combined agent with {gamma}-irradiation and cisplatin treatment in vivo. Br J Radiol. 2009 May;82(977):392-400. Epub 2009 Jan 19. PubMed PMID: 19153181.

17: Reddy SB, Williamson SK. Tirapazamine: a novel agent targeting hypoxic tumor cells. Expert Opin Investig Drugs. 2009 Jan;18(1):77-87. Review. PubMed PMID: 19053884.

18: Nakashima H, Uto Y, Nakata E, Nagasawa H, Ikkyu K, Hiraoka N, Nakashima K, Sasaki Y, Sugimoto H, Shiro Y, Hashimoto T, Okamoto Y, Asakawa Y, Hori H. Synthesis and biological activity of 1-methyl-tryptophan-tirapazamine hybrids as hypoxia-targeting indoleamine 2,3-dioxygenase inhibitors. Bioorg Med Chem. 2008 Sep 15;16(18):8661-9. Epub 2008 Aug 5. PubMed PMID: 18715787.

19: Bhattacharya A, Tóth K, Durrani FA, Cao S, Slocum HK, Chintala S, Rustum YM. Hypoxia-specific drug tirapazamine does not abrogate hypoxic tumor cells in combination therapy with irinotecan and methylselenocysteine in well-differentiated human head and neck squamous cell carcinoma a253 xenografts. Neoplasia. 2008 Aug;10(8):857-65. PubMed PMID: 18670644; PubMed Central PMCID: PMC2481573.

20: Marcu L, Olver I. Tirapazamine: from bench to clinical trials. Curr Clin Pharmacol. 2006 Jan;1(1):71-9. Review. PubMed PMID: 18666379.

21: Evans JW, Chernikova SB, Kachnic LA, Banath JP, Sordet O, Delahoussaye YM, Treszezamsky A, Chon BH, Feng Z, Gu Y, Wilson WR, Pommier Y, Olive PL, Powell SN, Brown JM. Homologous recombination is the principal pathway for the repair of DNA damage induced by tirapazamine in mammalian cells. Cancer Res. 2008 Jan 1;68(1):257-65. PubMed PMID: 18172318.

22: Huxham LA, Kyle AH, Baker JH, McNicol KL, Minchinton AI. Exploring vascular dysfunction caused by tirapazamine. Microvasc Res. 2008 Mar;75(2):247-55. Epub 2007 Oct 11. PubMed PMID: 18023823.

23: Chowdhury G, Junnotula V, Daniels JS, Greenberg MM, Gates KS. DNA strand damage product analysis provides evidence that the tumor cell-specific cytotoxin tirapazamine produces hydroxyl radical and acts as a surrogate for O(2). J Am Chem Soc. 2007 Oct 24;129(42):12870-7. Epub 2007 Sep 27. PubMed PMID: 17900117; PubMed Central PMCID: PMC2821206.

24: Hicks KO, Myint H, Patterson AV, Pruijn FB, Siim BG, Patel K, Wilson WR. Oxygen dependence and extravascular transport of hypoxia-activated prodrugs: comparison of the dinitrobenzamide mustard PR-104A and tirapazamine. Int J Radiat Oncol Biol Phys. 2007 Oct 1;69(2):560-71. PubMed PMID: 17869669.

25: Shin HJ, Kim JY, Yoo CW, Roberts SA, Lee S, Choi SJ, Lee HY, Lee DH, Kim TH, Cho KH. Carbonic anhydrase 9 (CA9) expression in tumor cells enhances sensitivity to tirapazamine. J Cancer Res Clin Oncol. 2008 Mar;134(3):397-404. Epub 2007 Aug 28. PubMed PMID: 17724612.

26: Ren Y, Zha X, Zhang GN. [Inhibitory effect of tirapazamine combined with phosphatidylinositol 3-kinase inhibitor LY294002 to ovarian cancer cells]. Zhonghua Yi Xue Za Zhi. 2007 May 8;87(17):1204-6. Chinese. PubMed PMID: 17686243.

27: Adam M, Bayer C, Henke J, Grosu A, Molls M, Nieder C. Tirapazamine plus cisplatin and irradiation in a mouse model: improved tumor control at the cost of increased toxicity. J Cancer Res Clin Oncol. 2008 Feb;134(2):137-46. Epub 2007 Jul 11. PubMed PMID: 17622558.

28: Masunaga S, Nagasawa H, Uto Y, Hori H, Nagata K, Suzuki M, Kashino G, Kinashi Y, Ono K. The usefulness of mild temperature hyperthermia combined with continuous tirapazamine administration under reduced dose-rate irradiation with gamma-rays. Int J Hyperthermia. 2007 Feb;23(1):29-35. PubMed PMID: 17575721.

29: Beck R, Röper B, Carlsen JM, Huisman MC, Lebschi JA, Andratschke N, Picchio M, Souvatzoglou M, Machulla HJ, Piert M. Pretreatment 18F-FAZA PET predicts success of hypoxia-directed radiochemotherapy using tirapazamine. J Nucl Med. 2007 Jun;48(6):973-80. PubMed PMID: 17536108.

30: Shi X, Mandel SM, Platz MS. On the mechanism of reaction of radicals with tirapazamine. J Am Chem Soc. 2007 Apr 18;129(15):4542-50. Epub 2007 Mar 24. PubMed PMID: 17381087.

31: Cohen EE, Rosine D, Haraf DJ, Loh E, Shen L, Lusinchi A, Vokes EE, Bourhis J. Phase I trial of tirapazamine, cisplatin, and concurrent accelerated boost reirradiation in patients with recurrent head and neck cancer. Int J Radiat Oncol Biol Phys. 2007 Mar 1;67(3):678-84. PubMed PMID: 17293229.

32: Cárdenas-Navia LI, Secomb TW, Dewhirst MW. Effects of fluctuating oxygenation on tirapazamine efficacy: Theoretical predictions. Int J Radiat Oncol Biol Phys. 2007 Feb 1;67(2):581-6. PubMed PMID: 17236974.

33: Masunaga S, Nagasawa H, Nagata K, Suzuki M, Uto Y, Hori H, Kinashi Y, Ono K. Dependency of the effect of a vascular disrupting agent on sensitivity to tirapazamine and gamma-ray irradiation upon the timing of its administration and tumor size, with reference to the effect on intratumor quiescent cells. J Cancer Res Clin Oncol. 2007 Jan;133(1):47-55. Epub 2006 Aug 22. PubMed PMID: 16924543.

34: Masunaga S, Sakurai Y, Nagata K, Suzuki M, Maruhashi A, Kinashi Y, Nagasawa H, Uto Y, Hori H, Ono K. The usefulness of a continuous administration of tirapazamine combined with reduced dose-rate irradiation using {gamma}-rays or reactor thermal neutrons. Br J Radiol. 2006 Dec;79(948):991-8. Epub 2006 Aug 17. PubMed PMID: 16916808.

35: Boyd M, Hay MP, Boyd PD. Complete 1H, 13C and 15N NMR assignment of tirapazamine and related 1,2,4-benzotriazine N-oxides. Magn Reson Chem. 2006 Oct;44(10):948-54. PubMed PMID: 16900565.

36: Shi X, Poole JS, Emenike I, Burdzinski G, Platz MS. Time-resolved spectroscopy of the excited singlet states of tirapazamine and desoxytirapazamine. J Phys Chem A. 2005 Mar 3;109(8):1491-6. PubMed PMID: 16833470.

37: Maluf FC, Leiser AL, Aghajanian C, Sabbatini P, Pezzulli S, Chi DS, Wolf JK, Levenback C, Loh E, Spriggs DR. Phase II study of tirapazamine plus cisplatin in patients with advanced or recurrent cervical cancer. Int J Gynecol Cancer. 2006 May-Jun;16(3):1165-71. PubMed PMID: 16803501.

38: Rischin D, Hicks RJ, Fisher R, Binns D, Corry J, Porceddu S, Peters LJ; Trans-Tasman Radiation Oncology Group Study 98.02. Prognostic significance of [18F]-misonidazole positron emission tomography-detected tumor hypoxia in patients with advanced head and neck cancer randomly assigned to chemoradiation with or without tirapazamine: a substudy of Trans-Tasman Radiation Oncology Group Study 98.02. J Clin Oncol. 2006 May 1;24(13):2098-104. PubMed PMID: 16648512.

39: Adam M, Ottenjann S, Künzel G, Busch R, Erhardt W, Nieder C, Molls M. [Evaluation of the toxicity of tirapazamine plus cisplatin in a mouse tumor model]. Strahlenther Onkol. 2006 Apr;182(4):231-9. German. PubMed PMID: 16622625.

40: Le QT, Taira A, Budenz S, Jo Dorie M, Goffinet DR, Fee WE, Goode R, Bloch D, Koong A, Martin Brown J, Pinto HA. 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. 2006 May 1;106(9):1940-9. PubMed PMID: 16532436.

41: Chen H, Zhang D. [Determination of the related substances in tirapazamine by high performance liquid chromatography]. Se Pu. 2005 Nov;23(6):681. Chinese. PubMed PMID: 16499006.

42: Huxham LA, Kyle AH, Baker JH, McNicol KL, Minchinton AI. Tirapazamine causes vascular dysfunction in HCT-116 tumour xenografts. Radiother Oncol. 2006 Feb;78(2):138-45. Epub 2006 Feb 7. PubMed PMID: 16455148.

43: Emmenegger U, Morton GC, Francia G, Shaked Y, Franco M, Weinerman A, Man S, Kerbel RS. Low-dose metronomic daily cyclophosphamide and weekly tirapazamine: a well-tolerated combination regimen with enhanced efficacy that exploits tumor hypoxia. Cancer Res. 2006 Feb 1;66(3):1664-74. PubMed PMID: 16452226.

44: Smith HO, Jiang CS, Weiss GR, Hallum AV 3rd, Liu PY, Robinson WR 3rd, Cheng PC, Scudder SA, Markman M, Alberts DS. Tirapazamine plus cisplatin in advanced or recurrent carcinoma of the uterine cervix: a Southwest Oncology Group study. Int J Gynecol Cancer. 2006 Jan-Feb;16(1):298-305. PubMed PMID: 16445649.

45: Anderson RF, Shinde SS, Hay MP, Denny WA. Potentiation of the cytotoxicity of the anticancer agent tirapazamine by benzotriazine N-oxides: the role of redox equilibria. J Am Chem Soc. 2006 Jan 11;128(1):245-9. PubMed PMID: 16390153.

46: Williamson SK, Crowley JJ, Lara PN Jr, McCoy J, Lau DH, Tucker RW, Mills GM, Gandara DR; Southwest Oncology Group Trial S0003. Phase III trial of paclitaxel plus carboplatin with or without tirapazamine in advanced non-small-cell lung cancer: Southwest Oncology Group Trial S0003. J Clin Oncol. 2005 Dec 20;23(36):9097-104. PubMed PMID: 16361616.

47: Covens A, Blessing J, Bender D, Mannel R, Morgan M; Gynecologic Oncology Group. A phase II evaluation of tirapazamine plus cisplatin in the treatment of recurrent platinum-sensitive ovarian or primary peritoneal cancer: a Gynecologic Oncology Group study. Gynecol Oncol. 2006 Mar;100(3):586-90. Epub 2005 Oct 24. PubMed PMID: 16249022.

48: Hellauer K, Lesage G, Sdicu AM, Turcotte B. Large-scale analysis of genes that alter sensitivity to the anticancer drug tirapazamine in Saccharomyces cerevisiae. Mol Pharmacol. 2005 Nov;68(5):1365-75. Epub 2005 Aug 1. PubMed PMID: 16061773.

49: Lunt SJ, Telfer BA, Fitzmaurice RJ, Stratford IJ, Williams KJ. Tirapazamine administered as a neoadjuvant to radiotherapy reduces metastatic dissemination. Clin Cancer Res. 2005 Jun 1;11(11):4212-6. PubMed PMID: 15930359.

50: Gatineau M, Rixe O, Chevalier TL. Tirapazamine with cisplatin and vinorelbine in patients with advanced non-small-cell lung cancer: a phase I/II study. Clin Lung Cancer. 2005 Mar;6(5):293-8. PubMed PMID: 15845180.

51: Yang B, Reynolds CP. Tirapazamine cytotoxicity for neuroblastoma is p53 dependent. Clin Cancer Res. 2005 Apr 1;11(7):2774-80. PubMed PMID: 15814660.

52: Pruijn FB, Sturman JR, Liyanage HD, Hicks KO, Hay MP, Wilson WR. Extravascular transport of drugs in tumor tissue: effect of lipophilicity on diffusion of tirapazamine analogues in multicellular layer cultures. J Med Chem. 2005 Feb 24;48(4):1079-87. PubMed PMID: 15715475.

53: Rischin D, Peters L, Fisher R, Macann A, Denham J, Poulsen M, Jackson M, Kenny L, Penniment M, Corry J, Lamb D, McClure B. 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. 2005 Jan 1;23(1):79-87. PubMed PMID: 15625362.

54: Reck M, von Pawel J, Nimmermann C, Groth G, Gatzemeier U. [Phase II-trial of tirapazamine in combination with cisplatin and gemcitabine in patients with advanced non-small-cell-lung-cancer (NSCLC)]. Pneumologie. 2004 Dec;58(12):845-9. German. PubMed PMID: 15597251.

55: Maxim PG, Carson JJ, Ning S, Knox SJ, Boyer AL, Hsu CP, Benaron DA, Walleczek J. Enhanced effectiveness of radiochemotherapy with tirapazamine by local application of electric pulses to tumors. Radiat Res. 2004 Aug;162(2):185-93. PubMed PMID: 15387146.

56: Le QT, McCoy J, Williamson S, Ryu J, Gaspar LE, Edelman MJ, Dakhil SR, Sides SD, Crowley JJ, Gandara DR; Southwest oncology group. 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. 2004 Aug 15;10(16):5418-24. PubMed PMID: 15328179.

57: Hicks KO, Siim BG, Pruijn FB, Wilson WR. Oxygen dependence of the metabolic activation and cytotoxicity of tirapazamine: implications for extravascular transport and activity in tumors. Radiat Res. 2004 Jun;161(6):656-66. PubMed PMID: 15161354.

58: Aquino VM, Weitman SD, Winick NJ, Blaney S, Furman WL, Kepner JL, Bonate P, Krailo M, Qu W, Bernstein M. Phase I trial of tirapazamine and cyclophosphamide in children with refractory solid tumors: a pediatric oncology group study. J Clin Oncol. 2004 Apr 15;22(8):1413-9. PubMed PMID: 15084615.

59: Cowen RL, Williams KJ, Chinje EC, Jaffar M, Sheppard FC, Telfer BA, Wind NS, Stratford IJ. Hypoxia targeted gene therapy to increase the efficacy of tirapazamine as an adjuvant to radiotherapy: reversing tumor radioresistance and effecting cure. Cancer Res. 2004 Feb 15;64(4):1396-402. PubMed PMID: 14973055.

60: Siim BG, Pruijn FB, Sturman JR, Hogg A, Hay MP, Brown JM, Wilson WR. Selective potentiation of the hypoxic cytotoxicity of tirapazamine by its 1-N-oxide metabolite SR 4317. Cancer Res. 2004 Jan 15;64(2):736-42. PubMed PMID: 14744792.

61: Hay MP, Pruijn FB, Gamage SA, Liyanage HD, Kovacs MS, Patterson AV, Wilson WR, Brown JM, Denny WA. DNA-targeted 1,2,4-benzotriazine 1,4-dioxides: potent analogues of the hypoxia-selective cytotoxin tirapazamine. J Med Chem. 2004 Jan 15;47(2):475-88. PubMed PMID: 14711317.

62: Anderson RF, Harris TA, Hay MP, Denny WA. Enhanced conversion of DNA radical damage to double strand breaks by 1,2,4-benzotriazine 1,4-dioxides linked to a DNA binder compared to tirapazamine. Chem Res Toxicol. 2003 Nov;16(11):1477-83. PubMed PMID: 14615975.

63: Lara PN Jr, Frankel P, Mack PC, Gumerlock PH, Galvin I, Martel CL, Longmate J, Doroshow JH, Lenz HJ, Lau DH, Gandara DR. Tirapazamine plus carboplatin and paclitaxel in advanced malignant solid tumors: a california cancer consortium phase I and molecular correlative study. Clin Cancer Res. 2003 Oct 1;9(12):4356-62. PubMed PMID: 14555506.

64: Hicks KO, Pruijn FB, Sturman JR, Denny WA, Wilson WR. Multicellular resistance to tirapazamine is due to restricted extravascular transport: a pharmacokinetic/pharmacodynamic study in HT29 multicellular layer cultures. Cancer Res. 2003 Sep 15;63(18):5970-7. PubMed PMID: 14522924.

65: Birincioglu M, Jaruga P, Chowdhury G, Rodriguez H, Dizdaroglu M, Gates KS. DNA base damage by the antitumor agent 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine). J Am Chem Soc. 2003 Sep 24;125(38):11607-15. PubMed PMID: 13129365.

66: Ho KC, Leach JK, Eley K, Mikkelsen RB, Lin PS. A simple method of producing low oxygen conditions with oxyrase for cultured cells exposed to radiation and tirapazamine. Am J Clin Oncol. 2003 Aug;26(4):e86-91. PubMed PMID: 12902904.

67: Zagorevskii D, Song M, Breneman C, Yuan Y, Fuchs T, Gates KS, Greenlief CM. A mass spectrometry study of tirapazamine and its metabolites. insights into the mechanism of metabolic transformations and the characterization of reaction intermediates. J Am Soc Mass Spectrom. 2003 Aug;14(8):881-92. PubMed PMID: 12892912.

68: Delahoussaye YM, Hay MP, Pruijn FB, Denny WA, Brown JM. Improved potency of the hypoxic cytotoxin tirapazamine by DNA-targeting. Biochem Pharmacol. 2003 Jun 1;65(11):1807-15. PubMed PMID: 12781332; PubMed Central PMCID: PMC2941974.

69: Chinje EC, Cowen RL, Feng J, Sharma SP, Wind NS, Harris AL, Stratford IJ. Non-nuclear localized human NOSII enhances the bioactivation and toxicity of tirapazamine (SR4233) in vitro. Mol Pharmacol. 2003 Jun;63(6):1248-55. PubMed PMID: 12761334.

70: Masunaga S, Ono K, Takahashi A, Ohnishi K, Ohnishi T, Suzuki M, Nagata K, Kinashi Y, Nagasawa H, Uto Y, Hori H. Usefulness of combined treatment with mild temperature hyperthermia and/or tirapazamine in the treatment of solid tumors: its independence of p53 status. Cancer Sci. 2003 Jan;94(1):125-33. PubMed PMID: 12708486.

71: Yang B, Keshelava N, Anderson CP, Reynolds CP. Antagonism of buthionine sulfoximine cytotoxicity for human neuroblastoma cell lines by hypoxia is reversed by the bioreductive agent tirapazamine. Cancer Res. 2003 Apr 1;63(7):1520-6. PubMed PMID: 12670899.

72: Inbaraj JJ, Motten AG, Chignell CF. Photochemical and photobiological studies of tirapazamine (SR 4233) and related quinoxaline 1,4-Di-N-oxide analogues. Chem Res Toxicol. 2003 Feb;16(2):164-70. PubMed PMID: 12588187.

73: Hay MP, Gamage SA, Kovacs MS, Pruijn FB, Anderson RF, Patterson AV, Wilson WR, Brown JM, Denny WA. Structure-activity relationships of 1,2,4-benzotriazine 1,4-dioxides as hypoxia-selective analogues of tirapazamine. J Med Chem. 2003 Jan 2;46(1):169-82. PubMed PMID: 12502371.

74: Papadopoulou MV, Ji M, Ji X, Bloomer WD. Therapeutic advantage from combining 5-fluorouracil with the hypoxia-selective cytotoxin NLCQ-1 in vivo; comparison with tirapazamine. Cancer Chemother Pharmacol. 2002 Oct;50(4):291-8. Epub 2002 Jul 24. PubMed PMID: 12357303.

75: Peters KB, Brown JM. Tirapazamine: a hypoxia-activated topoisomerase II poison. Cancer Res. 2002 Sep 15;62(18):5248-53. PubMed PMID: 12234992.

76: Papadopoulou MV, Ji M, Bloomer WD. Synergistic enhancement of the antitumor effect of taxol by the bioreductive compound NLCQ-1, in vivo: comparison with tirapazamine. Oncol Res. 2002;13(1):47-54. PubMed PMID: 12201674.

77: Kotandeniya D, Ganley B, Gates KS. Oxidative DNA base damage by the antitumor agent 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine). Bioorg Med Chem Lett. 2002 Sep 2;12(17):2325-9. PubMed PMID: 12161126.

78: Minchinton AI, Tonn DA, Sutherland DP, Kyle AH. Carbogen breathing after irradiation enhances the effectiveness of tirapazamine in SiHa tumors but not SCCVII tumors in mice. Radiat Res. 2002 Jul;158(1):94-100. PubMed PMID: 12071808.

79: Poole JS, Hadad CM, Platz MS, Fredin ZP, Pickard L, Guerrero EL, Kessler M, Chowdhury G, Kotandeniya D, Gates KS. Photochemical electron transfer reactions of tirapazamine. Photochem Photobiol. 2002 Apr;75(4):339-45. PubMed PMID: 12003122.

80: Gandara DR, Lara PN Jr, Goldberg Z, Le QT, Mack PC, Lau DH, Gumerlock PH. Tirapazamine: prototype for a novel class of therapeutic agents targeting tumor hypoxia. Semin Oncol. 2002 Feb;29(1 Suppl 4):102-9. Review. PubMed PMID: 11894020.

81: Delahoussaye YM, Evans JW, Brown JM. Metabolism of tirapazamine by multiple reductases in the nucleus. Biochem Pharmacol. 2001 Nov 1;62(9):1201-9. PubMed PMID: 11705453.

82: Tocher JH. Selective interaction of tirapazamine with DNA bases and DNA. A comparison of cyclic voltammetry and electrolysis techniques. Free Radic Res. 2001 Aug;35(2):159-66. PubMed PMID: 11697196.

83: Papadopoulou MV, Ji M, Rao MK, Bloomer WD. 4-[3-(2-Nitro-1-imidazolyl)propylamino]-7-chloroquinoline hydrochloride (NLCQ-1), a novel bioreductive agent as radiosensitizer in vitro and in vivo: comparison with tirapazamine. Oncol Res. 2001;12(8):325-33. PubMed PMID: 11589303.

84: Papadopoulou MV, Ji M, Bloomer WD. Schedule-dependent potentiation of chemotherapeutic drugs by the bioreductive compounds NLCQ-1 and tirapazamine against EMT6 tumors in mice. Cancer Chemother Pharmacol. 2001 Aug;48(2):160-8. PubMed PMID: 11561782.

85: Ban F, Gauld JW, Boyd RJ. Modeling the action of an antitumor drug: a density functional theory study of the mechanism of tirapazamine. J Am Chem Soc. 2001 Aug 1;123(30):7320-5. PubMed PMID: 11472160.

86: Hoff PM, Saad ED, Ravandi-Kashani F, Czerny E, Pazdur R. Phase I trial of i.v. administered tirapazamine plus cyclophosphamide. Anticancer Drugs. 2001 Jul;12(6):499-503. PubMed PMID: 11459995.

87: Peters KB, Wang H, Brown JM, Iliakis G. Inhibition of DNA replication by tirapazamine. Cancer Res. 2001 Jul 15;61(14):5425-31. PubMed PMID: 11454687.

88: Fuchs T, Chowdhury G, Barnes CL, Gates KS. 3-amino-1,2,4-benzotriazine 4-oxide: characterization of a new metabolite arising from bioreductive processing of the antitumor agent 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine). J Org Chem. 2001 Jan 12;66(1):107-14. PubMed PMID: 11429885.

89: Cemazar M, Parkins CS, Holder AL, Kranjc S, Chaplin DJ, Sersa G. Cytotoxicity of bioreductive drug tirapazamine is increased by application of electric pulses in SA-1 tumours in mice. Anticancer Res. 2001 Mar-Apr;21(2A):1151-6. PubMed PMID: 11396155.

90: Wouters BG, Delahoussaye YM, Evans JW, Birrell GW, Dorie MJ, Wang J, MacDermed D, Chiu RK, Brown JM. Mitochondrial dysfunction after aerobic exposure to the hypoxic cytotoxin tirapazamine. Cancer Res. 2001 Jan 1;61(1):145-52. PubMed PMID: 11196153.

91: Rischin D, Peters L, Hicks R, Hughes P, Fisher R, Hart R, Sexton M, D'Costa I, von Roemeling R. Phase I trial of concurrent tirapazamine, cisplatin, and radiotherapy in patients with advanced head and neck cancer. J Clin Oncol. 2001 Jan 15;19(2):535-42. PubMed PMID: 11208848.

92: Goldberg Z, Evans J, Birrell G, Brown JM. An investigation of the molecular basis for the synergistic interaction of tirapazamine and cisplatin. Int J Radiat Oncol Biol Phys. 2001 Jan 1;49(1):175-82. PubMed PMID: 11163512.

93: Patterson LH, Taiwo FA. Electron paramagnetic resonance spectrometry evidence for bioreduction of tirapazamine to oxidising free radicals under anaerobic conditions. Biochem Pharmacol. 2000 Dec 15;60(12):1933-5. PubMed PMID: 11108810.

94: Denny WA, Wilson WR. Tirapazamine: a bioreductive anticancer drug that exploits tumour hypoxia. Expert Opin Investig Drugs. 2000 Dec;9(12):2889-901. Review. PubMed PMID: 11093359.

95: Masunaga S, Ono K, Hori H, Suzuki M, Kinashi Y, Takagaki M, Kasai S, Nagasawa H, Uto Y. Change in oxygenation status in intratumour total and quiescent cells following gamma-ray irradiation, tirapazamine administration, cisplatin injection and bleomycin treatment. Br J Radiol. 2000 Sep;73(873):978-86. PubMed PMID: 11064652.

96: Craighead PS, Pearcey R, Stuart G. A phase I/II evaluation of tirapazamine administered intravenously concurrent with cisplatin and radiotherapy in women with locally advanced cervical cancer. Int J Radiat Oncol Biol Phys. 2000 Oct 1;48(3):791-5. PubMed PMID: 11020576.

97: Dorie MJ, Kovacs MS, Gabalski EC, Adam M, Le QT, Bloch DA, Pinto HA, Terris DJ, Brown JM. DNA damage measured by the comet assay in head and neck cancer patients treated with tirapazamine. Neoplasia. 1999 Nov;1(5):461-7. PubMed PMID: 10933062; PubMed Central PMCID: PMC1508108.

98: Jounaidi Y, Waxman DJ. Combination of the bioreductive drug tirapazamine with the chemotherapeutic prodrug cyclophosphamide for P450/P450-reductase-based cancer gene therapy. Cancer Res. 2000 Jul 15;60(14):3761-9. PubMed PMID: 10919648.

99: Masunaga S, Ono K, Suzuki M, Kinashi Y, Takagaki M, Kasai S, Nagasawa H, Uto Y, Hori H. Changes in the sensitivity of intratumor cells during fractionated tirapazamine administration. Jpn J Cancer Res. 2000 Jul;91(7):731-6. PubMed PMID: 10920281.

100: Lartigau E, Stern S, Guichard M. [In vitro oxygen-dependent survival of 2 human cell lines after radiation combined with tirapazamine (SR-4233) and cisplatin]. Cancer Radiother. 2000 May-Jun;4(3):217-22. French. PubMed PMID: 10897765.

101: McLaughlin KJ, Faibushevich AA, Lunte CE. Microdialysis sampling with on-line microbore HPLC for the determination of tirapazamine and its reduced metabolites in rats. Analyst. 2000 Jan;125(1):105-10. PubMed PMID: 10885067; PubMed Central PMCID: PMC2519821.

102: Masunaga S, Ono K, Nishimura Y, Kanamori S, Saga T, Suzuki M, Kinashi Y, Takagaki M, Kasai S, Nagasawa H, Uto Y, Hori H. Combined effects of tirapazamine and mild hyperthermia on anti-angiogenic agent (TNP-470) treated tumors-reference to the effect on intratumor quiescent cells. Int J Radiat Oncol Biol Phys. 2000 Jun 1;47(3):799-807. PubMed PMID: 10837967.

103: Masunaga SI, Ono K, Suzuki M, Kinashi Y, Takagaki M, Hori H, Kasai S, Nagasawa H, Uto Y. Usefulness of tirapazamine as a combined agent in chemoradiation and thermo-chemoradiation therapy at mild temperatures: reference to the effect on intratumor quiescent cells. Jpn J Cancer Res. 2000 May;91(5):566-72. PubMed PMID: 10835503.

104: Friery OP, Gallagher R, Murray MM, Hughes CM, Galligan ES, McIntyre IA, Patterson LH, Hirst DG, McKeown SR. Enhancement of the anti-tumour effect of cyclophosphamide by the bioreductive drugs AQ4N and tirapazamine. Br J Cancer. 2000 Apr;82(8):1469-73. PubMed PMID: 10780528; PubMed Central PMCID: PMC2363362.

105: Shulman LN, Buswell L, Riese N, Doherty N, Loeffler JS, von Roemeling RW, Coleman CN. Phase I trial of the hypoxic cell cytotoxin tirapazamine with concurrent radiation therapy in the treatment of refractory solid tumors. Int J Radiat Oncol Biol Phys. 1999 May 1;44(2):349-53. PubMed PMID: 10760430.

106: von Pawel J, von Roemeling R, Gatzemeier U, Boyer M, Elisson LO, Clark P, Talbot D, Rey A, Butler TW, Hirsh V, Olver I, Bergman B, Ayoub J, Richardson G, Dunlop D, Arcenas A, Vescio R, Viallet J, Treat J. 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. 2000 Mar;18(6):1351-9. PubMed PMID: 10715308.

107: Del Rowe J, Scott C, Werner-Wasik M, Bahary JP, Curran WJ, Urtasun RC, Fisher B. Single-arm, open-label phase II study of intravenously administered tirapazamine and radiation therapy for glioblastoma multiforme. J Clin Oncol. 2000 Mar;18(6):1254-9. PubMed PMID: 10715295.

108: Saunders MP, Patterson AV, Chinje EC, Harris AL, Stratford IJ. NADPH:cytochrome c (P450) reductase activates tirapazamine (SR4233) to restore hypoxic and oxic cytotoxicity in an aerobic resistant derivative of the A549 lung cancer cell line. Br J Cancer. 2000 Feb;82(3):651-6. PubMed PMID: 10682679; PubMed Central PMCID: PMC2363339.

109: Yapp DT, Lloyd DK, Zhu J, Lehnert S. Radiosensitization of a mouse tumor model by sustained intra-tumoral release of etanidazole and tirapazamine using a biodegradable polymer implant device. Radiother Oncol. 1999 Oct;53(1):77-84. PubMed PMID: 10624857.

110: Chinje EC, Patterson AV, Saunders MP, Lockyer SD, Harris AL, Stratford IJ. Does reductive metabolism predict response to tirapazamine (SR 4233) in human non-small-cell lung cancer cell lines? Br J Cancer. 1999 Dec;81(7):1127-33. PubMed PMID: 10584872; PubMed Central PMCID: PMC2374320.

111: Wouters BG, Wang LH, Brown JM. Tirapazamine: a new drug producing tumor specific enhancement of platinum-based chemotherapy in non-small-cell lung cancer. Ann Oncol. 1999;10 Suppl 5:S29-33. PubMed PMID: 10582136.

112: Bedikian AY, Legha SS, Eton O, Buzaid AC, Papadopoulos N, Plager C, McIntyre S, Viallet J. Phase II trial of escalated dose of tirapazamine combined with cisplatin in advanced malignant melanoma. Anticancer Drugs. 1999 Sep;10(8):735-9. PubMed PMID: 10573206.

113: Hwang JT, Greenberg MM, Fuchs T, Gates KS. Reaction of the hypoxia-selective antitumor agent tirapazamine with a C1'-radical in single-stranded and double-stranded DNA: the drug and its metabolites can serve as surrogates for molecular oxygen in radical-mediated DNA damage reactions. Biochemistry. 1999 Oct 26;38(43):14248-55. PubMed PMID: 10571998.

114: Yuan X, Tabassi K, Williams JA. Implantable polymers for tirapazamine treatments of experimental intracranial malignant glioma. Radiat Oncol Investig. 1999;7(4):218-30. PubMed PMID: 10492162.

115: el-Said A, Menke D, Dorie MJ, Brown JM. Comparison of the effectiveness of tirapazamine and carbogen with nicotinamide in enhancing the response of a human tumor xenograft to fractionated irradiation. Radiat Oncol Investig. 1999;7(3):163-9. PubMed PMID: 10406058.

116: Kovacs MS, Hocking DJ, Evans JW, Siim BG, Wouters BG, Brown JM. Cisplatin anti-tumour potentiation by tirapazamine results from a hypoxia-dependent cellular sensitization to cisplatin. Br J Cancer. 1999 Jun;80(8):1245-51. PubMed PMID: 10376978; PubMed Central PMCID: PMC2362366.

117: Masunaga S, Ono K, Hori H, Kinashi Y, Suzuki M, Takagaki M, Kasai S, Nagasawa H, Uto Y. Modification of tirapazamine-induced cytotoxicity in combination with mild hyperthermia and/or nicotinamide: reference to effect on quiescent tumour cells. Int J Hyperthermia. 1999 Jan-Feb;15(1):7-16. PubMed PMID: 10193753.

118: Weitman S, Mangold G, Marty J, Dexter D, Hilsenbeck S, Rake J, Juniewicz P, Von Hoff D. Evidence of enhanced in vivo activity using tirapazamine with paclitaxel and paraplatin regimens against the MV-522 human lung cancer xenograft. Cancer Chemother Pharmacol. 1999;43(5):402-8. PubMed PMID: 10100596.

119: Masunaga S, Ono K, Hori H, Akaboshi M, Kawai K, Suzuki M, Kinashi Y, Kasai S, Nagasawa H, Uto Y. Enhancement of cisplatin sensitivity of quiescent cells in solid tumors by combined treatment with tirapazamine and low-temperature hyperthermia. Radiat Med. 1998 Nov-Dec;16(6):441-8. PubMed PMID: 9929144.

120: Kyle AH, Minchinton AI. Measurement of delivery and metabolism of tirapazamine to tumour tissue using the multilayered cell culture model. Cancer Chemother Pharmacol. 1999;43(3):213-20. PubMed PMID: 9923551.

121: Zhang M, Stevens G. Effect of radiation and tirapazamine (SR-4233) on three melanoma cell lines. Melanoma Res. 1998 Dec;8(6):510-5. PubMed PMID: 9918413.

122: Aboagye EO, Dillehay LE, Bhujwalla ZM, Lee DJ. Hypoxic cell cytotoxin tirapazamine induces acute changes in tumor energy metabolism and pH: a 31P magnetic resonance spectroscopy study. Radiat Oncol Investig. 1998;6(6):249-54. PubMed PMID: 9885940.

123: Prager TC, Kellaway J, Zou Y, Urso RG, McIntyre S, Bedikian AY. Evaluation of ocular safety: tirapazamine plus cisplatin in patients with metastatic melanomas. Anticancer Drugs. 1998 Jul;9(6):515-24. PubMed PMID: 9877239.

124: Lee DJ, Trotti A, Spencer S, Rostock R, Fisher C, von Roemeling R, Harvey E, Groves E. Concurrent tirapazamine and radiotherapy for advanced head and neck carcinomas: a Phase II study. Int J Radiat Oncol Biol Phys. 1998 Nov 1;42(4):811-5. PubMed PMID: 9845102.

125: Treat J, Johnson E, Langer C, Belani C, Haynes B, Greenberg R, Rodriquez R, Drobins P, Miller W Jr, Meehan L, McKeon A, Devin J, von Roemeling R, Viallet J. Tirapazamine with cisplatin in patients with advanced non-small-cell lung cancer: a phase II study. J Clin Oncol. 1998 Nov;16(11):3524-7. PubMed PMID: 9817270.

126: Daniels JS, Gates KS, Tronche C, Greenberg MM. Direct evidence for bimodal DNA damage induced by tirapazamine. Chem Res Toxicol. 1998 Nov;11(11):1254-7. PubMed PMID: 9815184.

127: Hicks KO, Fleming Y, Siim BG, Koch CJ, Wilson WR. Extravascular diffusion of tirapazamine: effect of metabolic consumption assessed using the multicellular layer model. Int J Radiat Oncol Biol Phys. 1998 Oct 1;42(3):641-9. PubMed PMID: 9806526.

128: Patterson AV, Saunders MP, Chinje EC, Patterson LH, Stratford IJ. Enzymology of tirapazamine metabolism: a review. Anticancer Drug Des. 1998 Sep;13(6):541-73. Review. PubMed PMID: 9755718.

129: Brown JM, Wang LH. Tirapazamine: laboratory data relevant to clinical activity. Anticancer Drug Des. 1998 Sep;13(6):529-39. Review. PubMed PMID: 9755717.

130: Masunaga S, Ono K, Sakurai Y, Hori H, Kobayashi T, Takagaki M, Suzuki M, Kinashi Y, Akaboshi M. Applicability of combination with tirapazamine in boron neutron capture therapy. Jpn J Cancer Res. 1998 Jul;89(7):768-74. PubMed PMID: 9738984.

131: Siemann DW, Hinchman CA. Potentiation of cisplatin activity by the bioreductive agent tirapazamine. Radiother Oncol. 1998 May;47(2):215-20. PubMed PMID: 9683372.

132: Gatzemeier U, Rodriguez G, Treat J, Miller V, von Roemeling R, Viallet J, Rey A. Tirapazamine-cisplatin: the synergy. Br J Cancer. 1998 Jun;77 Suppl 4:15-7. Review. PubMed PMID: 9647615; PubMed Central PMCID: PMC2149886.

133: Brown JM. Exploiting tumour hypoxia and overcoming mutant p53 with tirapazamine. Br J Cancer. 1998 Jun;77 Suppl 4:12-4. Review. PubMed PMID: 9647614; PubMed Central PMCID: PMC2149884.

134: 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):2098-101. PubMed PMID: 9605751.

135: Cardinale RM, Dillehay LE, Williams JA, Tabassi K, Brem H, Lee DJ. Effect of interstitial and/or systemic delivery of tirapazamine on the radiosensitivity of human glioblastoma multiforme in nude mice. Radiat Oncol Investig. 1998;6(2):63-70. PubMed PMID: 9572682.

136: Lin PS, Ho KC. CuTira brachytherapy: a new combination of radioactive copper isotopes and the hypoxic cytotoxin, tirapazamine, for targeted tumor therapy. J Nucl Med. 1998 Apr;39(4):677-8. PubMed PMID: 9544681.

137: 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):1269-71. PubMed PMID: 9496394.

138: Aghajanian C, Brown C, O'flaherty C, Fleischauer A, Curtin J, Roemeling R, Spriggs DR. Phase I study of tirapazamine and cisplatin in patients with recurrent cervical cancer. Gynecol Oncol. 1997 Nov;67(2):127-30. PubMed PMID: 9367694.

139: Masunaga S, Ono K, Hori H, Shibata T, Suzuki M, Kinashi Y, Takagaki M, Akaboshi M. Effects of bioreductive agents, tirapazamine and mitomycin C, on quiescent cell populations in solid tumors, evaluated by micronucleus assay. Jpn J Cancer Res. 1997 Sep;88(9):907-14. PubMed PMID: 9369940.

140: Elwell JH, Siim BG, Evans JW, Brown JM. Adaptation of human tumor cells to tirapazamine under aerobic conditions: implications of increased antioxidant enzyme activity to mechanism of aerobic cytotoxicity. Biochem Pharmacol. 1997 Jul 15;54(2):249-57. PubMed PMID: 9271329.

141: Siim BG, Menke DR, Dorie MJ, Brown JM. Tirapazamine-induced cytotoxicity and DNA damage in transplanted tumors: relationship to tumor hypoxia. Cancer Res. 1997 Jul 15;57(14):2922-8. PubMed PMID: 9230202.

142: Bedikian AY, Legha SS, Eton O, Buzaid AC, Papadopoulos N, Coates S, Simmons T, Neefe J, von Roemeling R. Phase II trial of tirapazamine combined with cisplatin in chemotherapy of advanced malignant melanoma. Ann Oncol. 1997 Apr;8(4):363-7. PubMed PMID: 9209666.

143: Friery OP, Hejmadi MV, McKeown SR. DNA damage induced in T50/80 tumour cells following exposure to the bioreductive drug Tirapazamine in combination with a single dose of radiation (12Gy). Biochem Soc Trans. 1997 Feb;25(1):135S. PubMed PMID: 9057033.

144: Johnson CA, Kilpatrick D, von Roemeling R, Langer C, Graham MA, Greenslade D, Kennedy G, Keenan E, O'Dwyer PJ. Phase I trial of tirapazamine in combination with cisplatin in a single dose every 3 weeks in patients with solid tumors. J Clin Oncol. 1997 Feb;15(2):773-80. PubMed PMID: 9053504.

145: Senan S, Rampling R, Graham MA, Wilson P, Robin H Jr, Eckardt N, Lawson N, McDonald A, von Roemeling R, Workman P, Kaye SB. Phase I and pharmacokinetic study of tirapazamine (SR 4233) administered every three weeks. Clin Cancer Res. 1997 Jan;3(1):31-8. PubMed PMID: 9815534.

146: Patterson AV, Saunders MP, Chinje EC, Talbot DC, Harris AL, Strafford IJ. Overexpression of human NADPH:cytochrome c (P450) reductase confers enhanced sensitivity to both tirapazamine (SR 4233) and RSU 1069. Br J Cancer. 1997;76(10):1338-47. PubMed PMID: 9374381; PubMed Central PMCID: PMC2228151.

147: Durand RE, Olive PL. Physiologic and cytotoxic effects of tirapazamine in tumor-bearing mice. Radiat Oncol Investig. 1997;5(5):213-9. PubMed PMID: 9372543.

148: Graham MA, Senan S, Robin H Jr, Eckhardt N, Lendrem D, Hincks J, Greenslade D, Rampling R, Kaye SB, von Roemeling R, Workman P. 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 PMID: 9137522.

149: Dorie MJ, Brown JM. Modification of the antitumor activity of chemotherapeutic drugs by the hypoxic cytotoxic agent tirapazamine. Cancer Chemother Pharmacol. 1997;39(4):361-6. PubMed PMID: 9025778.

150: Priyadarsini KI, Tracy M, Wardman P. The one-electron reduction potential of 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine): a hypoxia-selective bioreductive drug. Free Radic Res. 1996 Nov;25(5):393-9. PubMed PMID: 8902537.

151: Olive PL, Vikse CM, Banath JP. Use of the comet assay to identify cells sensitive to tirapazamine in multicell spheroids and tumors in mice. Cancer Res. 1996 Oct 1;56(19):4460-3. PubMed PMID: 8813141.

152: Lin PS, Ho KC, Yang SJ. Tirapazamine (SR 4233) interrupts cell cycle progression and induces apoptosis. Cancer Lett. 1996 Aug 2;105(2):249-55. PubMed PMID: 8697451.

153: Siemann DW. The in situ tumour response to combinations of cyclophosphamide and tirapazamine. Br J Cancer Suppl. 1996 Jul;27:S65-9. PubMed PMID: 8763849; PubMed Central PMCID: PMC2150008.

154: Shibata T, Shibamoto Y, Sasai K, Oya N, Murata R, Takagi T, Hiraoka M, Takahashi M, Abe M. Tirapazamine: hypoxic cytotoxicity and interaction with radiation as assessed by the micronucleus assay. Br J Cancer Suppl. 1996 Jul;27:S61-4. PubMed PMID: 8763848; PubMed Central PMCID: PMC2149998.

155: McKeown SR, Friery OP, McIntyre IA, Hejmadi MV, Patterson LH, Hirst DG. Evidence for a therapeutic gain when AQ4N or tirapazamine is combined with radiation. Br J Cancer Suppl. 1996 Jul;27:S39-42. PubMed PMID: 8763843; PubMed Central PMCID: PMC2150042.

156: Lartigau E, Guichard M. The effect of tirapazamine (SR-4233) alone or combined with chemotherapeutic agents on xenografted human tumours. Br J Cancer. 1996 Jun;73(12):1480-5. PubMed PMID: 8664116; PubMed Central PMCID: PMC2074534.

157: Gilbert MS, Rupnow BA, Ramirez DA, Trisler KD, Knox SJ. Over-expression of Bcl-2 protects against apoptosis induced by the bioreductive cytotoxic drug SR4233 (Tirapazamine). Cell Death Differ. 1996 Apr;3(2):215-22. PubMed PMID: 17180085.

158: Siim BG, van Zijl PL, Brown JM. Tirapazamine-induced DNA damage measured using the comet assay correlates with cytotoxicity towards hypoxic tumour cells in vitro. Br J Cancer. 1996 Apr;73(8):952-60. PubMed PMID: 8611431; PubMed Central PMCID: PMC2075810.

159: Jones GD, Weinfeld M. Dual action of tirapazamine in the induction of DNA strand breaks. Cancer Res. 1996 Apr 1;56(7):1584-90. PubMed PMID: 8603406.

160: Shibata T, Shibamoto Y, Sasai K, Oya N, Murata R, Takagi T, Hiraoka M, Abe M. Comparison of in vivo efficacy of hypoxic cytotoxin tirapazamine and hypoxic cell radiosensitizer KU-2285 in combination with single and fractionated irradiation. Jpn J Cancer Res. 1996 Jan;87(1):98-104. PubMed PMID: 8609056.

161: Patterson AV, Barham HM, Chinje EC, Adams GE, Harris AL, Stratford IJ. Importance of P450 reductase activity in determining sensitivity of breast tumour cells to the bioreductive drug, tirapazamine (SR 4233). Br J Cancer. 1995 Nov;72(5):1144-50. PubMed PMID: 7577460; PubMed Central PMCID: PMC2033939.

162: Khan S, O'Brien PJ. Molecular mechanisms of tirapazamine (SR 4233, Win 59075)-induced hepatocyte toxicity under low oxygen concentrations. Br J Cancer. 1995 Apr;71(4):780-5. PubMed PMID: 7710944; PubMed Central PMCID: PMC2033725.

163: Olive PL. Detection of hypoxia by measurement of DNA damage in individual cells from spheroids and murine tumours exposed to bioreductive drugs. I. Tirapazamine. Br J Cancer. 1995 Mar;71(3):529-36. PubMed PMID: 7880735; PubMed Central PMCID: PMC2033654.

164: 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):211-6. PubMed PMID: 7884290.

165: Senan S. Vasoactivity, a potentially important variable in the sequencing of tirapazamine (SR 4233) and radiation. Int J Radiat Oncol Biol Phys. 1995 Jan 1;31(1):209-10. PubMed PMID: 7995763.

166: Robin H Jr, Senan S, Workman P, Graham MA. Development and validation of a sensitive solid-phase-extraction and high-performance liquid chromatography assay for the bioreductive agent tirapazamine and its major metabolites in mouse and human plasma for pharmacokinetically guided dose escalation. Cancer Chemother Pharmacol. 1995;36(3):266-70. PubMed PMID: 7781150.

167: Herscher LL, Krishna MC, Cook JA, Coleman CN, Biaglow JE, Tuttle SW, Gonzalez FJ, Mitchell JB. Protection against SR 4233 (Tirapazamine) aerobic cytotoxicity by the metal chelators desferrioxamine and tiron. Int J Radiat Oncol Biol Phys. 1994 Nov 15;30(4):879-85. PubMed PMID: 7960991.

168: Ara G, Coleman CN, Teicher BA. SR-4233 (Tirapazamine) acts as an uncoupler of oxidative phosphorylation in human MCF-7 breast carcinoma cells. Cancer Lett. 1994 Oct 14;85(2):195-203. PubMed PMID: 7954337.

169: Tocher JH, Edwards DI. Electrochemical studies of tirapazamine: generation of the one-electron reduction product. Free Radic Res. 1994 Oct;21(5):277-83. PubMed PMID: 7842137.

170: Fitzsimmons SA, Lewis AD, Riley RJ, Workman P. Reduction of 3-amino-1,2,4-benzotriazine-1,4-di-N-oxide (tirapazamine, WIN 59075, SR 4233) to a DNA-damaging species: a direct role for NADPH:cytochrome P450 oxidoreductase. Carcinogenesis. 1994 Aug;15(8):1503-10. PubMed PMID: 8055626.

171: Langmuir VK, Rooker JA, Osen M, Mendonca HL, Laderoute KR. Synergistic interaction between tirapazamine and cyclophosphamide in human breast cancer xenografts. Cancer Res. 1994 Jun 1;54(11):2845-7. PubMed PMID: 8187065.

172: Doherty N, Hancock SL, Kaye S, Coleman CN, Shulman L, Marquez C, Mariscal C, Rampling R, Senan S, Roemeling RV. 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):379-82. PubMed PMID: 8195037.

173: Patterson AV, Robertson N, Houlbrook S, Stephens MA, Adams GE, Harris AL, Stratford IJ, Carmichael J. The role of DT-diaphorase in determining the sensitivity of human tumor cells to tirapazamine (SR 4233). Int J Radiat Oncol Biol Phys. 1994 May 15;29(2):369-72. PubMed PMID: 8195035.

174: Dorie MJ, Menke D, Brown JM. Comparison of the enhancement of tumor responses to fractionated irradiation by SR 4233 (tirapazamine) and by nicotinamide with carbogen. Int J Radiat Oncol Biol Phys. 1994 Jan 1;28(1):145-50. PubMed PMID: 8270435.

175: Dorie MJ, Brown JM. Tumor-specific, schedule-dependent interaction between tirapazamine (SR 4233) and cisplatin. Cancer Res. 1993 Oct 1;53(19):4633-6. PubMed PMID: 8402639.

176: Brown JM. SR 4233 (tirapazamine): a new anticancer drug exploiting hypoxia in solid tumours. Br J Cancer. 1993 Jun;67(6):1163-70. Review. PubMed PMID: 8512801; PubMed Central PMCID: PMC1968495.

177: Walton MI, Workman P. Pharmacokinetics and bioreductive metabolism of the novel benzotriazine di-N-oxide hypoxic cell cytotoxin tirapazamine (WIN 59075; SR 4233; NSC 130181) in mice. J Pharmacol Exp Ther. 1993 May;265(2):938-47. PubMed PMID: 8496834.

178: Riley RJ, Hemingway SA, Graham MA, Workman P. Initial characterization of the major mouse cytochrome P450 enzymes involved in the reductive metabolism of the hypoxic cytotoxin 3-amino-1,2,4-benzotriazine-1,4-di-N-oxide (tirapazamine, SR 4233, WIN 59075). Biochem Pharmacol. 1993 Mar 9;45(5):1065-77. PubMed PMID: 8461036.