Examination of the distribution of the bioreductive drug AQ4N and its active metabolite AQ4 in solid tumours by imaging matrix-assisted laser desorption/ionisation mass spectrometry.
AQ4N (banoxatrone) (1,4-bis-{[2-(dimethylamino-N-oxide)ethyl]amino}-5,8-dihydroxyanthracene-9,10-dione) is an example of a bioreductive prodrug in clinical development. In hypoxic cells AQ4N is reduced to the topoisomerase II inhibitor AQ4 (1,4-bis- {[2-(dimethylamino)ethyl]amino}-5,8-dihydroxyanthracene-9,10-dione). By inhibition of topoisomerase II within these hypoxic areas, AQ4N has been shown to sensitise tumours to existing chemo- and radiotherapy treatments. In this study the distribution of AQ4N and AQ4 in treated H460 human tumour xenografts has been examined by imaging matrix-assisted laser desorption/ionisation mass spectrometry. Images of the distribution of AQ4N and AQ4 have been produced that show little overlap. The distribution of ATP in the tumour xenografts was also studied as an endogenous marker of regions of hypoxia since concentrations of ATP are known to be decreased in these regions. The distribution of ATP was similar to that of AQ4N, i.e. in regions of abundant ATP there was no evidence of conversion of AQ4N into AQ4. This indicates that the cytotoxic metabolite AQ4 is confined to hypoxic regions of the tumour as intended.
Atkinson
Sally J
SJ
Biomedical Research Centre, Sheffield Hallam University, Howard Street, Sheffield S1 1WB, UK.
Loadman
Paul M
PM
Sutton
Chris
C
Patterson
Laurence H
LH
Clench
Malcolm R
MR
D000880:Anthraquinones / Q000493:pharmacokinetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism*; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Q000379:methods*; D014018:Tissue Distribution
D000880:Anthraquinones; C094428:AQ4N; D010100:Oxygen