TERTIARY AMINE N-OXIDES AS BIOREDUCTIVE DRUGS - DACA N-OXIDE, NITRACRINE N-OXIDE AND AQ4N

Tertiary amine N-oxides of DNA intercalators with alkylamino sidechain s are a new class of bioreductive drugs. N-oxidation masks the cationi c charge of the amines, forming prodrugs with low DNA binding affinity and low toxicity which can be activated selectively by metabolic redu ction under hypoxic conditions. This study compares three intercalator N-oxides (NC-NO, DACA-NO and AQ4N), which, respectively, give nitracr ine (NC), DACA and AQ4 on reduction. In aerobic cell culture all three N-oxides were much less toxic than the corresponding amines, and show ed large increases in cytotoxicity under hypoxia. The topoisomerase po isons DACA and AQ4 (and their N-oxides) were less active against non-c ycling than cycling cells. However, only AQ4N was active against the m ouse mammary tumour MDAH-MCa-4. This dialkylaminoanthraquinone-di-N-ox ide has activity at least as great as the reference bioreductive drug RE 6145 against this tumour, both with and without radiation and when combined with the tumour blood how inhibitor 5,6-dimethylxanthenone-4- acetic acid (DMXAA). It is suggested that the high in vivo activity of AQ4N relative to the other topoisomerase-targeted N-oxide, DACA-NO, m ay be in part due to release in hypoxic cells of an intracalator with sufficiently high DNA binding affinity that it is retained long enough to kill noncycling cells when they eventually re-enter the cell cycle .