Bioactivation of quinones by DT-diaphorase, molecular, biochemical, and chemical studies

D Ross, H Beall, R D Traver, D Siegel, R M Phillips, N W Gibson

Research output: Contribution to journalReview article

103 Citations (Scopus)

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-be ta-en- alpha-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 H596 human NSCLC cells. This mutation and resulting lack of DTD activity complicates the use of agents designed to target DTD in tumors.(ABSTRACT TRUNCATED AT 250 WORDS)

Original languageEnglish
Pages (from-to)493-500
Number of pages8
JournalOncology Research
Volume6
Issue number10-11
Publication statusPublished - 1994
Externally publishedYes

Fingerprint

NAD(P)H Dehydrogenase (Quinone)
Quinones
Mitomycin
Streptonigrin
Neoplasms
Mutation
Point Mutation
Proline
Non-Small Cell Lung Carcinoma
Serine

Cite this

Ross, D., Beall, H., Traver, R. D., Siegel, D., Phillips, R. M., & Gibson, N. W. (1994). Bioactivation of quinones by DT-diaphorase, molecular, biochemical, and chemical studies. Oncology Research, 6(10-11), 493-500.
Ross, D ; Beall, H ; Traver, R D ; Siegel, D ; Phillips, R M ; Gibson, N W. / Bioactivation of quinones by DT-diaphorase, molecular, biochemical, and chemical studies. In: Oncology Research. 1994 ; Vol. 6, No. 10-11. pp. 493-500.
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Ross, D, Beall, H, Traver, RD, Siegel, D, Phillips, RM & Gibson, NW 1994, 'Bioactivation of quinones by DT-diaphorase, molecular, biochemical, and chemical studies', Oncology Research, vol. 6, no. 10-11, pp. 493-500.

Bioactivation of quinones by DT-diaphorase, molecular, biochemical, and chemical studies. / Ross, D; Beall, H; Traver, R D; Siegel, D; Phillips, R M; Gibson, N W.

In: Oncology Research, Vol. 6, No. 10-11, 1994, p. 493-500.

Research output: Contribution to journalReview article

TY - JOUR

T1 - Bioactivation of quinones by DT-diaphorase, molecular, biochemical, and chemical studies

AU - Ross, D

AU - Beall, H

AU - Traver, R D

AU - Siegel, D

AU - Phillips, R M

AU - Gibson, N W

PY - 1994

Y1 - 1994

N2 - 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-be ta-en- alpha-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 H596 human NSCLC cells. This mutation and resulting lack of DTD activity complicates the use of agents designed to target DTD in tumors.(ABSTRACT TRUNCATED AT 250 WORDS)

AB - 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-be ta-en- alpha-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 H596 human NSCLC cells. This mutation and resulting lack of DTD activity complicates the use of agents designed to target DTD in tumors.(ABSTRACT TRUNCATED AT 250 WORDS)

KW - Animals

KW - Antineoplastic Agents/pharmacokinetics

KW - Biotransformation

KW - Gene Expression

KW - Humans

KW - NAD(P)H Dehydrogenase (Quinone)/metabolism

KW - Neoplasms/drug therapy

KW - Neoplasms, Experimental/drug therapy

KW - Oxidation-Reduction

KW - Quinones/pharmacokinetics

M3 - Review article

VL - 6

SP - 493

EP - 500

JO - Oncology Research

JF - Oncology Research

SN - 0965-0407

IS - 10-11

ER -