title: Does reductive metabolism predict response to tirapazamine (SR 4233) in human non-small-cell lung cancer cell lines?
abstract: The bioreductive drug tirapazamine (TPZ, SR 4233, WIN 59075) is a lead compound 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 radiotherapy and some chemotherapy. We have evaluated the generality of an enzyme-directed approach to TPZ toxicity by examining the importance of the one-electron reducing enzyme NADPH:cytochrome P450 reductase (P450R) in the metabolism and toxicity of this lead prodrug in a panel of seven human non-small-cell lung cancer cell lines. We relate our findings on TPZ sensitivity in these lung lines with our previously published results on TPZ sensitivity in six human breast cancer cell lines (Patterson et al (1995) Br J Cancer 72: 1144-1150) and with the sensitivity of all these cell types to eight unrelated cancer chemotherapeutic agents with diverse modes of action. Our results demonstrate that P450R plays a significant role in the activation of TPZ in this panel of lung lines, which is consistent with previous observations in a panel of breast cancer cell lines (Patterson et al (1995) Br J Cancer 72: 1144-1150; Patterson et al (1997) Br J Cancer 76: 1338-1347). However, in the lung lines it is likely that it is the inherent ability of these cells to respond to multiple forms of DNA damage, including that arising from P450R-dependent TPZ metabolism, that underlies the ultimate expression of toxicity.
authors.affiliation: Experimental Oncology Group, School of Pharmacy and Pharmaceutical Sciences, University of Manchester, UK.
authors.forename: E C
authors.initials: EC
authors.lastname: Chinje
authors.forename: A V
authors.initials: AV
authors.lastname: Patterson
authors.forename: M P
authors.initials: MP
authors.lastname: Saunders
authors.forename: S D
authors.initials: SD
authors.lastname: Lockyer
authors.forename: A L
authors.initials: AL
authors.lastname: Harris
authors.forename: I J
authors.initials: IJ
authors.lastname: Stratford
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D000077704:Tirapazamine; D014227:Triazines / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D014227:Triazines; D000077704:Tirapazamine