Abstract:
:Four novel 4-substituted 5-nitrophthalimides (5-substituted-6-nitro-1,3-dihydro-isoindol-1,3-diones), 6, 7, 10 and 11, and the known 5 are prepared as analogs of the dinitrobenzamide prodrug CB 1954, 1, and considered as potential candidates for gene-directed enzyme prodrug therapy. All the phthalimides are poor substrates for Escherichia coli nitroreductase compared to CB 1954. However, 6, 7, 10 and 11 are reduced by both the human and rat forms of DT-diaphorase; 10 is a particularly good substrate but 7 decomposes in phosphate buffer. A cell-line panel consisting of V79 cells that have been engineered to express various levels of either the human or rat forms of DT-diaphorase in an identical cellular background was used to evaluate these compounds as prodrugs activated by this enzyme. The cytotoxic effect of CB 1954 is proportional to the activity of either the rat or human enzyme but cells expressing the rat enzyme were much more sensitive (10000-fold at higher levels of DT-diaphorase activity) than cells expressing comparable levels of the human enzyme. These results demonstrate that the resistance of human tumors to CB 1954 can be accounted for solely by the kinetic properties of the enzyme for this prodrug. The nitrophthalimide analogs overcome this kinetic failing of CB 1954. However, these compounds are not activated to produce cytotoxicity in these DT-diaphorase-expressing cell lines. It is postulated their reduction products fail to undergo an acylation reaction in a manner analogous to CB 1954. Thus, reduction by DT-diaphorase is not predictive of cytotoxicity in this class of prodrugs.
journal_name
Anticancer Drugsjournal_title
Anti-cancer drugsauthors
Mehta LK,Hobbs S,Chen S,Knox RJ,Parrick Jdoi
10.1097/00001813-199909000-00011subject
Has Abstractpub_date
1999-09-01 00:00:00pages
777-83issue
8eissn
0959-4973issn
1473-5741journal_volume
10pub_type
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journal_title:Anti-cancer drugs
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