EO9: relationship between DT-diaphorase levels and response in vitro and in vivo.

EO9 [3-hydroxy-5-aziridinyl-1-methyl-2(1H-indole-4,7-dione)-prop-beta-en- alpha-ol] was selected for clinical trial in Europe because of its preclinical profile but also because of its distinct mechanism of bioactivation. Several studies have shown that cells rich in DT-diaphorase may be particularl...

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Main Authors:	Collard, J., Matthew, A. M., Double, J. A., Bibby, M. C.
Format:	Online
Language:	English
Published:	1995
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2033862/

id	pubmed-2033862
recordtype	oai_dc
spelling	pubmed-20338622009-09-10 EO9: relationship between DT-diaphorase levels and response in vitro and in vivo. Collard, J. Matthew, A. M. Double, J. A. Bibby, M. C. Research Article EO9 [3-hydroxy-5-aziridinyl-1-methyl-2(1H-indole-4,7-dione)-prop-beta-en- alpha-ol] was selected for clinical trial in Europe because of its preclinical profile but also because of its distinct mechanism of bioactivation. Several studies have shown that cells rich in DT-diaphorase may be particularly sensitive to EO9. The present study examined the relationship between DT-diaphorase activity and sensitivity to EO9 in a panel of cell lines largely derived from human and rodent leukaemias/lymphoma and solid tumours. A possible relationship between chemosensitivity and enzyme activity was demonstrated (correlation coefficient 0.796). A number of the human cell lines were established as xenografts in nude mice but, with the exception of HT29, DT-diaphorase specific activity was greatly reduced compared with the corresponding cell lines. These data suggest that in vitro studies of bioactivation of drugs by specific enzymes is unlikely 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-dichlorophenol-indophenol (DCPIP) reduced per min per mg of protein] to the cell line (337) but failed to respond to a single dose or daily dose schedule. A preliminary attempt to investigate an hourly dose schedule demonstrated a modest anti-tumour effect accompanied by enhanced toxicity. Attempts to optimise EO9 exposure parameters to potentiate activity in tumours 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. 1995-06 /pmc/articles/PMC2033862/ /pubmed/7779711 Text en
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Collard, J. Matthew, A. M. Double, J. A. Bibby, M. C.
spellingShingle	Collard, J. Matthew, A. M. Double, J. A. Bibby, M. C. EO9: relationship between DT-diaphorase levels and response in vitro and in vivo.
author_facet	Collard, J. Matthew, A. M. Double, J. A. Bibby, M. C.
author_sort	Collard, J.
title	EO9: relationship between DT-diaphorase levels and response in vitro and in vivo.
title_short	EO9: relationship between DT-diaphorase levels and response in vitro and in vivo.
title_full	EO9: relationship between DT-diaphorase levels and response in vitro and in vivo.
title_fullStr	EO9: relationship between DT-diaphorase levels and response in vitro and in vivo.
title_full_unstemmed	EO9: relationship between DT-diaphorase levels and response in vitro and in vivo.
title_sort	eo9: relationship between dt-diaphorase levels and response in vitro and in vivo.
description	EO9 [3-hydroxy-5-aziridinyl-1-methyl-2(1H-indole-4,7-dione)-prop-beta-en- alpha-ol] was selected for clinical trial in Europe because of its preclinical profile but also because of its distinct mechanism of bioactivation. Several studies have shown that cells rich in DT-diaphorase may be particularly sensitive to EO9. The present study examined the relationship between DT-diaphorase activity and sensitivity to EO9 in a panel of cell lines largely derived from human and rodent leukaemias/lymphoma and solid tumours. A possible relationship between chemosensitivity and enzyme activity was demonstrated (correlation coefficient 0.796). A number of the human cell lines were established as xenografts in nude mice but, with the exception of HT29, DT-diaphorase specific activity was greatly reduced compared with the corresponding cell lines. These data suggest that in vitro studies of bioactivation of drugs by specific enzymes is unlikely 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-dichlorophenol-indophenol (DCPIP) reduced per min per mg of protein] to the cell line (337) but failed to respond to a single dose or daily dose schedule. A preliminary attempt to investigate an hourly dose schedule demonstrated a modest anti-tumour effect accompanied by enhanced toxicity. Attempts to optimise EO9 exposure parameters to potentiate activity in tumours 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.
publishDate	1995
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2033862/
_version_	1611405112045993984

EO9: relationship between DT-diaphorase levels and response in vitro and in vivo.

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