Background: The benefits of achieving better response by adding tirapazamine, a specific hypoxic cancer cell killer to chemo and or radiotherapy is contradictory. This study aims at analyzing the efficacy and safety of tirapazamine, apart from understanding the reasons for its doubtful and inconsistent benefits.
Methods: Electronic database search in PUBMED, EMBASE, Cochrane library was conducted using search term "tirapazamine". Randomized or cross-over studies comparing effects of tirapazamine vs other active treatment or placebo in patients >18yrs with any type of cancers were included under analysis. Overall Survival rate was the primary outcome measure while the incidences of grade-3 and 4 adverse drug reactions were the secondary outcome measure. Inverse variance method and both random and fixed effect models were used in the analysis by RevMan 5.3 software.
Results: Total six studies were eligible with 1034 patients included in the analysis. Tirapazamine failed to show significant effect on overall survival rate at the end of one year (HR: 0.96, 95% CI: 0.88, 1.05), two year (HR: 1.04, 95% CI: 0.98, 1.12), three year (HR: 1.01, 95% CI: 0.89, 1.15) and five year (HR: 0.97, 95% CI: 0.77, 1.23) compared to placebo group. There was a significantly higher incidence of muscle cramps (Risk Difference, RD: 0.06, 95% CI: 0.02, 0.11) and dermal adverse events (RD: 0.03, 95% CI: 0.01, 0.06) in tirapazamine group.
Conclusions: With the available evidences from clinical trials and preclinical studies, use of tirapazamine may not be justifiable and so is to side line this drug as another failed drug.
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global Cancer Statistics, 2012. CA Cancer J Clin. 2015;65:87-108.
Murthy NS, Chaudhry K, Rath GK. Burden of cancer and projections for 2016, Indian scenario: gaps in the availability of radiotherapy treatment facilities. Asian Pac J Cancer Prev. 2008;9:671-7.
Brown JM. Tumor microenvironment and the response to anticancer therapy. Cancer Biol Ther. 2002;1:453-8.
Phillips RM. Targeting the hypoxic fraction of tumours using hypoxia‑activated prodrugs. Cancer Chemother Pharmacol. 2016;77:441-57.
Marcu L, Olver I. Tirapazamine: From Bench to Clinical Trials. Current Clinical Pharmacol. 2006;1: 71-9.
Le QT, Taira A, Budenz S, Jo Dorie M, Goffinet DR, Fee WE, et al. 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;106:1940-9.
Rischin D, Peters L, Fisher R, Macann A, Denham J, Poulsen M, et al. 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;23:79-87.
Rischin D, Peters LJ, O'Sullivan B, Giralt J, Fisher R, Yuen K, et al. 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;28:2989-95.
Williamson SK, Crowley JJ, Lara PN Jr, McCoy J, Lau DH, Tucker RW, et al. 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;23:9097-104.
von Pawel J, von Roemeling R, Gatzemeier U, Boyer M, Elisson LO, Clark P, et al. 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;18:1351-9.
DiSilvestro PA, Ali S, Craighead PS, Lucci JA, Lee YC, Cohn DE, et al. Phase III randomized trial of weekly cisplatin and irradiation versus cisplatin and tirapazamine and irradiation in stages IB2, IIA, IIB, IIIB, and IVA cervical carcinoma limited to the pelvis: a gynecologic oncology group study. J Clin Oncol. 2014;32:458-64.
Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials. 2007;8:1-16.
Nancy GB, Robert AP. Meta-analysis: neither quick nor easy. BMJ Med Res Methodol. 2002;2:10.
Julian PTH, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ Med Res Methodol. 2011;343:d5928.
Brown JM, Giaccia AJ. The unique physiology of solid tumors: opportunities (and problems) for cancer therapy. Cancer Res. 1998;58:1408-16.
Huxham LA, Kyle AH, Baker JH, McNicol KL, Minchinton AI. Exploring vascular dysfunction caused by tirapazamine. Microvasc Res. 2008;75:247-55.
Bhattacharya A, Tóth K, Durrani FA, Cao S, Slocum HK, Chintala S, et al. 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;10:857-65.
Kazmi N, Hossain MA, Phillips RM. A hybrid cellular automaton model of solid tumor growth and bioreductive drug transport. IEEE/ACM Trans Comput Biol Bioinform. 2012;9:1595-606.
Kazmi N, Hossain MA, Phillips RM, Al-Mamun MA, Bass R. Avascular tumour growth dynamics and the constraints of protein binding for drug transportation. J Theor Biol. 2012;313:142-52.
Masunaga S, Ono K, Suzuki M, Kinashi Y, Takagaki M, Kasai S, et al. Changes in the sensitivity of intratumor cells during fractionated tirapazamine administration. Jpn J Cancer Res. 2000;91:731-6.
Masunaga S, Ono K, Hori H, Akaboshi M, Kawai K, Suzuki M, et al. Enhancement of cisplatin sensitivity of quiescent cells in solid tumors by combined treatment with tirapazamine and low-temperature hyperthermia. Radiat Med. 1998;16:441-8.
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;53:77-84.
Denny WA. Prospects for hypoxia-activated anticancer drugs. Curr Med Chem Anticancer Agents. 2004;4:395-9.
Evans JW, Yudoh K, Delahoussaye YM, Brown JM. Tirapazamine is metabolized to its DNA-damaging radical by intranuclear enzymes. Cancer Res. 1998;58:2098-101.
Biedermann KA, Wang J, Graham RP, Brown JM. SR 4233 cytotoxicity and metabolism in DNA repair-competent and repair-deficient cell cultures. Br J Cancer. 1991;63:358-62.
Skov KA, Adomat H, Farrell NP, Matthews JB. Assessment of toxicity of bis-platinum complexes in hypoxic and aerobic cells. Anticancer Drug Des. 1998;13:207-20.
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;49:175-82.
Giaccia AJ, Biedermann KA, Tosto LM, Minchinton AI, Kovacs MS, Brown JM. Characterization of a CHO cell line resistant to killing by the hypoxic cell cytotoxin SR 4233. Int J Radiat Oncol Biol Phys. 1992;22:681-4.
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;3:215-22.
Fitzpatrick B, Mehibel M, Cowen RL, Stratford IJ. iNOS as a therapeutic target for treatment of human tumors. Nitric Oxide. 2008;19:217-24.
Yang B, Reynolds CP. Tirapazamine cytotoxicity for neuroblastoma is p53 dependent. Clin Cancer Res. 2005;11:2774-80.
Skarsgard LD, Skwarchuk MW, Vinczan A, Chaplin DJ. The effect of pH on the aerobic and hypoxic cytotoxicity of SR4233 in HT-29 cells. Br J Cancer. 1993;68:681-3.
Wouters BG, Delahoussaye YM, Evans JW, Birrell GW, Dorie MJ, Wang J, et al. Mitochondrial dysfunction after aerobic exposure to the hypoxic cytotoxin tirapazamine. Cancer Res. 2001;61:145-52.
Barnard RJ, Youngren JF. Regulation of glucose transport in skeletal muscle. FASEB J. 1992;6:3238-44.