Tirapazamine (TPZ), a benzotriazine di-N-oxide anti-cancer drug activated to a toxic free radical under hypoxic conditions, is the first drug of this class to enter clinical testing (Brown 1998). In preclinical models it has been shown to extend the activity of traditional cytotoxic chemotherapy, presumably by selective killing of the hypoxic fraction of tumor cells (Dorie and Brown 1993). It has been shown to be safe and effective when combined with cisplatin in adults with NSCLC, although patients receiving the combination experienced significantly more nausea and vomiting (Olgun et al. 2003). A pediatric phase-I trial of the tirapazamine/cyclophosphamide combination was just completed in POG (Yung et al. 1999). The MTD for tirapazamine when combined with 1.5 g/m2 of cyclophosphamide was 325mg/m2. The DLT was reversible ototoxicity. There were 2 children who experienced grade-3 reversible ototoxicity at 420 mg/m2. There were three responses (two in neu-roblastoma and one in rhabdomyosarcoma; Aquino et al. 2004).

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