Tirapazamine: laboratory data relevant to clinical activity.

Tirapazamine (TPZ, SR 4233, WIN 59075, 3-amino-1,2,4-benzotriazine 1,4-dioxide, Tirazone) is the lead compound in the benzotriazine di-N-oxide class of bioreductive anticancer agents. Extensive preclinical testing has established that the mechanism for the selective toxicity towards hypoxic cells is the result of a one-electron reduction of the parent molecule to a free radical species that interacts with DNA to produce single- and double-strand breaks and lethal chromosome aberrations. It has also shown activity when combined with fractionated irradiation and when combined with some chemotherapy agents, particularly cisplatin and carboplatin. In this review we address those questions about the drug that are most relevance to the clinical use of the compound. In particular we review the evidence for the mechanism of action of the drug, and also show that a large portion of the synergy seen in experimental tumors when TPZ is combined with cisplatin is the result of a cellular interaction between TPZ and cisplatin that depends on hypoxia. Also of relevance to clinical use is whether the toxicity of TPZ is cumulative such as occurs with nitroimidazoles, another class of hypoxia-activated agents. Such cumulative toxicity is not evident. Finally, we present an analysis based on the area under the curve for mice and humans that demonstrates that the doses being used in current Phase II radiotherapy protocols and Phase III chemotherapy protocols should be sufficient to produce clinical activity. We conclude that the preclinical data suggest that it is likely that TPZ will be active in the clinic, particularly when combined with cisplatin.