@article {Ross:1994:0965-0407:493,
title = "Bioactivation of Quinones by DT-diaphorase, Molecular, Biochemical, and Chemical Studies",
journal = "Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics",
parent_itemid = "infobike://cog/or",
publishercode ="cog",
year = "1994",
volume = "6",
number = "10-11",
publication date ="1994-01-01T00:00:00",
pages = "493-500",
itemtype = "ARTICLE",
issn = "0965-0407",
eissn = "1555-3906",
url = "https://www.ingentaconnect.com/content/cog/or/1994/00000006/f0020010/art00007",
keyword = "DT-diaphorase, antitumor quinones, mutation, mitomycin C, drug development, gene expression",
author = "Ross, David and Beall, Howard and Traver, Robert D. and Siegel, David and Phillips, Roger M. and Gibson, Neil W.",
abstract = "
Abstract
Because of the elevated DT-diaphorase (DTD) activity in certain tumors such as human nonsmall cell lung cancer (NCSLC), DTD is a potential target on which to base the development of new antitumor compounds. Mitomycin C is the most effective single agent used for
the therapy of NSCLC and is metabolized and bioactivated by DTD. Mitomycin C is a poor substrate for DTD, however, and its metabolism is pH-dependent. We have therefore focused on identifying more efficient substrates for DTD. We have developed a metabolic and cytotoxicity screen that identifies
compounds which are efficiently bioactivated by DTD. This screen utilizes both aerobic and hypoxic conditions and cell lines with both elevated and deficient DTD activity as an index of selectivity. Using the screen described above, we have identified [3-hydroxy-5-aziridinyl-1-methyl-2-(1H-indole-4,7-indione)-prop--en--ol]
(E09), 2,5-diaziridinyl-1,4-benzoquinone (MeDZQ), and streptonigrin as compounds that are most efficiently bioactivated by DTD and exert selective cytotoxicity. Although certain tumors such as NSCLC have elevated DTD activity, we have characterized a point mutation at position 609 in the DTD
cDNA, which codes for a proline to serine change in the protein and leads to a loss of enzyme activity. We have characterized this mutation in both BE human colon carcinoma cells and HS96 human NSCLC cells. This mutation and resulting lack of DTD activity complicates the use of agents designed
to target DTD in tumors. An enzyme-directed approach to chemotherapy utilizing DTD as a target is still a viable strategy, however, providing that pretreatment biopsies can be obtained and screened for DTD activity.",
}