title: Oxygen dependence of the cytotoxicity and metabolic activation of 4-alkylamino-5-nitroquinoline bioreductive drugs.
abstract: The cytotoxic potency of 4-alkylamino-5-nitroquinoline drugs in AA8 cell cultures is enhanced up to 60-fold under hypoxia, with wide variations in selectivity for hypoxic cells observed for different members of this series. This study uses three representative 5-nitroquinolines to examine whether these differences in hypoxia-selective cytotoxicity are cell line specific, and to explore quantitatively the oxygen dependence of the cytotoxicity and metabolism of these compounds. The parent compound 5NQ, its 5NQ, its 8-methyl analogue (8Me5NQ) and the 8-methylamino analogue (8NHMe-5NQ) each showed similar hypoxic selectivity (ratio of concentration x time for 90% kill for zero versus 20% oxygen of 13-18-, 30-69- and 1.2-1.4-fold respectively in the three cell lines tested (AA8 Chinese hamster ovary, EMT6/Ak mouse mammary tumour and FME human melanoma). The cytotoxicity and metabolism (covalent binding) of radiolabelled 8Me-5NQ was investigated in AA8 cultures over a range of oxygen tensions (0-95%). The oxygen tension in solution required for 50% inhibition of log cell kill or adduct formation observed under anoxia (C50) was 0.01 and 0.02% oxygen respectively, suggesting that bioreductive alkylation is the mechanism of 8Me-5NQ toxicity. The K-value (oxygen concentration for cytotoxic potency equal to the mean of the potencies at zero and infinite oxygen) was similar (0.02% oxygen). Calculations based on measured rate constants for formation of the nitroradical anion of 8Me-5NQ and rates of radical loss through disproportionation or reaction with oxygen, predict a K-value for 8Me-5NQ of 0.025% oxygen, in good agreement with the experimentally determined value. Modelling of cell killing expected by the combination of 8Me-5NQ plus radiation suggested that tumour cells at intermediate oxygen tensions (0.01-1%) will be partially resistant to this treatment, and would limit the use of these 5-nitroquinolines in combination with radiation, unless sufficient drug could be delivered to cause extensive killing in the anoxic compartment.
authors.affiliation: Department of Pathology, University of Auckland School of Medicine, New Zealand.
authors.forename: B G
authors.initials: BG
authors.lastname: Siim
authors.forename: G J
authors.initials: GJ
authors.lastname: Atwell
authors.forename: W R
authors.initials: WR
authors.lastname: Wilson
mesh_terms: D000818:Animals; D001711:Biotransformation; D016466:CHO Cells / Q000187:drug effects / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D015687:Cell Hypoxia / Q000502:physiology; D006224:Cricetinae; D006801:Humans; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009600:Nitroquinolines / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000633:toxicity*; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism* / Q000494:pharmacology*
chemical_list: C089804:8-methyl-5-nitroquinoline; D009600:Nitroquinolines; C089803:5-nitroquinoline; D010100:Oxygen