EO9 - RELATIONSHIP BETWEEN DT-DIAPHORASE LEVELS AND RESPONSE IN-VITROAND IN-VIVO

EO9 thyl-2(1H-indole-4,7-dione)-prop-beta-en-alpha-ol] was selected fo r clinical trial in Europe because of its preclinical profile but also because or its distinct mechanism of bioactivation. Several studies h ave shown that cells rich in DT-diaphorase may be particularly sensiti ve to EO9. The present study examined the relationship between DT-diap horase activity and sensitivity to EO9 in a panel of cell lines largel y derived from human and rodent leukaemias/lymphoma and solid rumours. A possible relationship between chemosensitivity and enzyme activity was demonstrated (correlation coefficient 0.796). A number of the huma n cell lines were established as xenografts in nude mice but, with the exception of HT29, DT-diaphorase specific activity was greatly reduce d compared with the corresponding cell lines. These data suggest that in vitro studies of bioactivation of drugs by specific enzymes is unli kely to be relevant for the same tumour in vivo. Except for HCLO, all xenografts failed to respond to EO9 as a single dose. HT29 tumours in vivo had similar DT-diaphorase activity [359 nmol of 2,6-dichloropheno l-indophenol (DCP1P) reduced per min per mg of protein] to the cell li ne (337) but failed to respond to a single dose or daily dose schedule . A preliminary attempt to investigate an hourly dose schedule demonst rated a modest anti-tumour effect accompanied by enhanced toxicity. At tempts to optimise EO9 exposure parameters to potentiate activity in t umours with high DT-diaphorase activity are under way, but as yet the relevance of this particular enzyme for in vivo EO9 activity requires further investigation.