Tirapazamine

A few interesting organic molecules may possess the ability to release hydroxyl radical under physiological conditions. The most extensively studied of these is 3-amino-l,2,4-benzotriazine 1,4-dioxide (tirapazamine, 95, Scheme 8.32). Tirapazamine is a bioreductively activated DNA-damaging agent that selectively kills the oxygen-poor (hypoxic) cells found in solid tumors. The biological activity of... 

In addition to causing DNA strand breaks, tirapazamine damages the heterocyclic base residues of double-stranded DNA.2 " 2 Similar to authentic, radiolytically generated hydroxyl radical, the drug causes approximately four times more base... 

The bioreductively-activated, hypoxia-selective DNA-damaging properties found in tirapazamine are not uniqne to this nitrogen heterocycle. Analogous properties have been observed for quinoxaline di-A-oxides snch as 99 and In addi-... 

The evidence presented earlier, on the effects of combined modality therapy in carcinoma of the anal canal, may exploit to some extent the properties of mitomycin C as a hypoxic cell cytotoxin. This strategy remains valid, as many human tumors are less well oxygenated than the tissues from which they arose. The literature suggests that not only are these hypoxic tumors more difficult to control locally with therapy but that they may possess a more malignant phenotype with a higher propensity for distant spread. Tirapazamine is a drug developed and introduced into the clinic for its ability to target... 

Del Rowe J, Scott C, Werner-Wasik M, et al. A single-arm open label phase II study of intravenously administered tirapazamine plus radiation therapy for glioblastoma multiforme. / Clin Oncol 2000 18(6) 1254-1259. 

Novel mechanisms of interest include sensitizing hypoxic tumor cell lines to enhance radiotoxicity. Tirapazamine is a hypoxia-selective compound 1-2-fold greater in magnitude in comparison to mitomycin C or porfiromycin (84). Its mechanism of action results in a one-electron reduction inducing DNA double-strand breaks and cell death under hypoxic conditions. The free radical is oxidized back to the parent compound under aerobic conditions. When combined with the platinum compounds, the cytotoxic effects may be equivalent to that seen with five times the dose of cisplatin without the toxicities that would be encountered if actually administered (85). 

Rishin and colleagues have recently reported results of a phase I trial of conventional fractionated radiotherapy with concurrent tirapazamine (290 mg/m2), cisplatin (75 mg/m2) wk 1, 4, and 7, and tirapazemine alone (160 mg/m2, three times per wk) wk 2, 3, 5, and 6 for untreated stage IV HNC patients (86). The cohort was small at 20 patients. Dose... 

Based on this initial study by Rischin et al., the University of Chicago is currently accruing for a phase I trial of previously irradiated patients. Patients will receive standard daily radiotherapy and tirapazamine (wk 1-3) combined with cisplatin (wk 3 and 5), converting to hyperfractionated radiotherapy for wk 4—6. 

Dorie MJ, Brown JM. Tumor-specific, schedule-dependent interaction between tirapazamine (SR 4233) and cisplatin. Cancer Res 1993 53 4633-4636. 

Rishchin D, Peters L, Hicks R, et al. Phase I trial of concurrent tirapazamine, cisplatin, and radiotherapy in patients with advanced head and neck cancer. J Clin Oncol 2001 19 535-542. 

Von Pawel J, Von Roemeling T. Survival benefit from Tirazone (tirapazamine) and cisplatin in advanced non small cell lung cancer (NSCLC) patients Final results from the phase III CATAPULT trial. Proc Am Soc Clin Oncol 1998 17 454a (abstr 1749). 

The one-electron reduction of a chemical to cytotoxic products is the basis of certain anticancer drugs. This is because tumor cells tend to be anaerobic, and so reduction is favored. However, anaerobic conditions can induce DT diaphorase, which carries out two-electron reduction reactions. For example, the anticancer drug tirapazamine is activated by a one-electron reduction catalyzed by NADPH cytochrome P-450 reductase in anaerobic conditions to a nitroxide radical, which is toxic to tumor cells. It is detoxified however, by DT diaphorase, to another product. 

Tirapazamine (SR 4233) is the lead compound to a class of bioreductive anticancer drugs that makes use of the fact that solid tumors are hypoxic (Brown 1990, 1993 Brown and Wang 1998) and clinical phase III trials are under the way (Gandara et al. 2002). With an anticancer drug that is that far advanced in clinical trials one would like to know the mechanism of its action. Obviously, this has attracted many research teams that are expert in different techniques to tackle the problem. It will be shown below that there is now a host of first-class information, but it is as yet difficult, if not impossible, to arrive at a conclusive mechanism of its action. 

Under hypoxic conditions, cellular enzymes reduce the benzotriazine di-N-oxide [(reaction (68) P450 reductase Cahill and White 1990 and NADPH may be involved Walton et al. 1992 Wang et al. 1993]. Upon microsomal reduction of tirapazamine the radical formed in reaction (68) has been identified by EPR (Lloyd et al. 1991). Using the pulse radiolysis technique, it has been shown that this radical has a pKd of 6 (Laderoute et al. 1988), and it is the protonated form that undergoes the DNA damaging reaction (Wardman et al. 2003). The rate constants of the bimolecular decay of the radical [reaction (70)] has been found to be 2.7 x 107 dm3 mol-1 s 1. The reaction with its anion is somewhat faster (8.0 x 108 dm3 mol-1 s 1), while the deprotonated radicals do not react with one another at an appreciable rate. From another set of pulse radiolysis data, a first-order process has been extracted (k = 112 s 1) that has been attributed to the water elimination reaction (72), and the tirapazamine action on DNA [reaction (74)] has been considered to be due to the resulting radical (Anderson et al. 2003). 

Anderson RF, Fisher LJ, Elara Y, Harris T, Mak WB, Melton LD, Packer JE (2001) Green tea catechins partially protect DNA from OEI radical-induced strand breaks and base damage through fast chemical repair of DNA radicals. Carcinogenesis 22 1189-1193 Anderson RF, ElarrisTA, Elay MP, Denny WA (2003a) 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 16 1477-1483... 

Birincioglu M, Jaruga P, Chowdhury G, Rodriguez G, Dizdaroglu M, Gates KS (2003) DNA base dan-age by the antitumor agent 3-amino-1,2,4-benzotriazine 1,4-doxide (tirapazamine). J Am Chem Soc 125 11607-11615... 

Brown JM (1993) SR 4233 (Tirapazamin) a new anticancer drug exploiting hypoxia in solid tumors. BrJ Cancer 67 1163-1170... 

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