Does reductive metabolism predict response to tirapazamine (SR 4233) in human non-small-cell lung cancer cell lines?

The bioreductive drug tirapazamine (TPZ, SR 4233, WIN 59075) is a lead comp ound in a series of potent cytotoxins that selectively kill hypoxic rodent and human solid tumour cells in vitro and in vivo. Phases II and III trials have demonstrated its efficacy in combination with both fractionated radio therapy and some chemotherapy. We have evaluated the generality of an enzym e-directed approach to TPZ toxicity by examining the importance of the one- electron reducing enzyme NADPH:cytochrome P450 reductase (P450R) in the met abolism and toxicity of this lead prodrug in a panel of seven human non-sma ll-cell lung cancer cell lines. We relate our findings on TPZ sensitivity i n these lung lines with our previously published results on TPZ sensitivity in six human breast cancer cell lines (Patterson et ai (1995) Br J Cancer 72: 1144-1150) and with the sensitivity of all these cell types to eight un related cancer chemotherapeutic agents with diverse modes of action. Our re sults demonstrate that P450R plays a significant role in the activation of TPZ in this panel of lung lines, which is consistent with previous observat ions in a panel of breast cancer cell lines (Patterson ei at (1995) Br J Ca ncer 72. 1144-1150, Patterson et al (1997) Br J Cancer 76. 1338-1347). Howe ver, in the lung lines it is likely that it is the inherent ability of thes e cells to respond to multiple forms of DNA damage, including that arising from P450R-dependent TPZ metabolism, that underlies the ultimate expression of toxicity. (C) 1999 Cancer Research Campaign.