SR-4233: A new bioreductive agent with high selective toxicity for hypoxic mammalian cells

Tirapazamine-induced DNA damage measured using the comet assay correlates with cytotoxicity towards hypoxic tumour cells in vitro

“…The present study demonstrates a good correlation between tirapazamineinduced DNA ssbs and hypoxic cell killing by tirapazamine in vitro, suggesting fulfillment of the requirement that the ratio of DNA ssbs to dsbs would have to be constant across cell lines, and the number of initial dsbs and ssbs predictive of cell kill. The observed 2 to 3-fold greater sensitivity of the murine tumour cell lines to killing by tirapazamine under hypoxic conditions compared with the human lines is consistent with previously published data (Zeman et al, 1986;Biedermann et al, 1991) and appears to underlie the lower hypoxic cytotoxicity ratios (ratio of drug concentrations required to give the same level of killing under aerobic and hypoxic conditions) reported for tirapazamine in human than in murine cell lines (Zeman et al, 1986). It should be recognised that, although the hypoxic selective cytotoxicity of tirapazamine is generally lower in human than murine cell lines, it is still substantial, with hypoxic cytotoxicity ratios of around 50 being common (Zeman et al, 1986).…”

“…The observed 2 to 3-fold greater sensitivity of the murine tumour cell lines to killing by tirapazamine under hypoxic conditions compared with the human lines is consistent with previously published data (Zeman et al, 1986;Biedermann et al, 1991) and appears to underlie the lower hypoxic cytotoxicity ratios (ratio of drug concentrations required to give the same level of killing under aerobic and hypoxic conditions) reported for tirapazamine in human than in murine cell lines (Zeman et al, 1986). It should be recognised that, although the hypoxic selective cytotoxicity of tirapazamine is generally lower in human than murine cell lines, it is still substantial, with hypoxic cytotoxicity ratios of around 50 being common (Zeman et al, 1986). Tirapazamine induced 2-to 3-fold more DNA damage in the hypoxic murine cell lines than in the human cell lines, indicating that the variation in hypoxic sensitivity could be entirely accounted for by the production of DNA strand breaks.…”

“…Tirapazamine exhibits high hypoxia-selective cytotoxicity in the order of 50 to 200-fold in most rodent and human cell lines (Zeman et al, 1986(Zeman et al, , 1988Stratford and Stephens, 1989). Tirapazamine also kills hypoxic cells in transplanted tumours in mice (Zeman et al, 1988;Kim and Brown, 1994;Durand, 1994) and has been shown to potentiate the effects of modalities that are more toxic towards aerobic tumour cells.…”

The effect of tirapazamine (SR-4233) alone or combined with chemotherapeutic agents on xenografted human tumours

“…A higher aerobic-hypoxic ratio (concentration in air -concentration in nitrogen to obtain the same cytotoxicity) have been found in murine than in human tumours (Zeman et al, 1986). More recent data on murine tumours have shown that the cytotoxicity of tirapazamine in vitro and in vivo is significantly increased when combined with other chemotherapy drugs such as cisplatinum, a frequently used drug in the treatment of malignancies (mainly embryonal tumours and squamous carcinoma) (Holden et al, 1992;Dorie and Brown, 1993).…”

“…The bioreductive drug tirapazamine (SR4233, WIN 59075) has been investigated in vitro and in vivo for its cytotoxic and/or radiosensitising activity against tumour cells in air and in hypoxia (Zeman et al, 1986(Zeman et al, , 1988(Zeman et al, , 1990Brown, 1993;Koch, 1993). A higher aerobic-hypoxic ratio (concentration in air -concentration in nitrogen to obtain the same cytotoxicity) have been found in murine than in human tumours (Zeman et al, 1986).…”