Cisplatin with tirapazamine

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. 

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. 

There are several parallels in the reduction chemistry of nitroarenes and aromatic N-oxides, such as similar kinetics of electron transfer reactions of the radical-anions and the effects of prototropic equilibria on radical lifetimes in aqueous solution [16]. The benzotriazine di-N-oxide, tirapazamine (Figure 1,16) is currently in Phase III clinical trial as a hypoxic cell cytotoxin in conjunction with cisplatin [132]. The mechanism of its action appears to involve the one-electron reduction product [133] cleaving DNA [134], probably also sensitizing the damage by a radical-addition step [135-138]. 

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