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Tirapazamine

A Hypoxia-activated Topoisomerase II Poison¹

Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California 94305-5152

Tirapazamine (TPZ), a hypoxia-selective cytotoxin, has demonstrated activity in cancer clinical trials. Under hypoxic conditions, TPZ is reduced to a radical that leads to DNA double-strand breaks (DSBs), single-strand breaks, and base damage. A previous finding of an association of the DSBs with protein led us to investigate the involvement of topoisomerase II (topo II) in their formation. Nuclear extracts from human lung cancer cells treated with either the topo II poison etoposide or TPZ under hypoxic conditions had markedly reduced topo II activity as judged by an inability to convert kinetoplast DNA from the catenated to the decatenated form. Because topo II poisons, such as etoposide, cause DNA DSBs, we hypothesized that pretreatment of cells with merbarone or aclarubicin, known catalytic inhibitors of topo II, would abrogate DNA DSBs caused by topo II. Cells pretreated with these catalytic inhibitors abrogated both DNA DSBs and cell kill induced by etoposide or by TPZ. Etoposide- and TPZ-mediated DSBs were also greatly reduced in a small cell lung cancer cell line with low levels of nuclear topo II. We also showed that topo II becomes covalently bound to DNA after TPZ treatment under hypoxic conditions, and that the cleavable complexes formed by TPZ are more stable over time than those formed by etoposide. Taken together, these data suggest that TPZ exerts its cytotoxic effect at least in part through poisoning topo II. Because TPZ is activated only under hypoxic conditions, which are characteristic of solid tumors, these data implicate TPZ as a tumor-specific topo II poison.

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