Reductase Enzyme Expression Across the National Cancer Institute Tumor Cell Line Panel: Correlation With Sensitivity to Mitomycin C and EO9

Fitzsimmons, Sara A.; Workman, Paul; Grever, Michael R.; Paull, Kenneth D.; Camalier, Richard F.; Lewis, Alexander D.

doi:10.1093/jnci/88.5.259

Cited by 212 publications

(164 citation statements)

References 29 publications

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“…In general, cell lines (Begleiter et al, 1989;Malkinson et al, 1992;Ross et al, 1993;Mikami et al, 1996) or tumour specimens (Nishiyama et al, 1993) with higher levels of DT-diaphorase are more sensitive to MMC. A significant correlation was found between the level of DTdiaphorase activity and sensitivity to MMC and E09 in the human tumour cell lines of the National Cancer Institute Tumour Cell Line Panel (Fitzsimmons et al, 1996). E09 activity appears to be particularly sensitive to the level of DT-diaphorase under oxygenated conditions (Plumb et al, 1994).…”

mentioning

confidence: 93%

Induction of DT-diaphorase by 1,2-dithiole-3-thiones in human tumour and normal cells and effect on anti-tumour activity of bioreductive agents

Doherty

Leith²,

Wang³

et al. 1998

Br J Cancer

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Summary DT-diaphorase is a two-electron-reducing enzyme that is an important activator of bioreductive anti-tumour agents, such as mitomycin C (MMC) and E09, and is inducible by many compounds, including 1,2-dithiole-3-thiones (D3Ts). We showed previously that D3T selectively increased DT-diaphorase activity in mouse lymphoma cells compared with normal mouse marrow cells, and also increased MMC or E09 cytotoxic activity in the lymphoma cells with only minor effects in the marrow cells. In this study, we found that D3T significantly increased DT-diaphorase activity in 28 of 38 human tumour cell lines representing ten tissue types with no obvious relationships between the tumour type, or the base level of DT-diaphorase activity, and the ability of D3T to increase the enzyme activity. Induction of DT-diaphorase activity in human tumour cell lines by 12 D3T analogues varied markedly with the D3T structure. D3T also increased DT-diaphorase activity in normal human bone marrow and kidney cells but the increases were small in these cells. In addition, D3T increased the level of enzyme activity in normal human lung cells. Pretreatment of human tumour cells with D3T analogues significantly increased the cytotoxic activity of MMC or E09 in these cells, and the level of enhancement of anti-tumour activity paralleled the level of DT-diaphorase induction. In contrast, D3T did not effect the toxicity of E09 in normal kidney cells. These results demonstrate that D3T analogues can increase DT-diaphorase activity in a wide variety of human tumour cells and that this effect can enhance the anti-tumour activity of the bioreductive agents MMC and E09.

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mentioning

confidence: 93%

Induction of DT-diaphorase by 1,2-dithiole-3-thiones in human tumour and normal cells and effect on anti-tumour activity of bioreductive agents

Doherty

Leith²,

Wang³

et al. 1998

Br J Cancer

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“…16 DTD is a bioreductive enzyme that can activate a variety of prodrugs, including quinone -based drugs, to DNA alkylating agents. DTD activity has been reported to be elevated in a range of tumor types 30 such as in human non -small cell lung cancer, 13,14 breast, liver, 31 and colon tumors relative to surrounding normal tissue. It has been proposed that various prodrugs that are substrates for DTD could be useful for the treatment of tumors with high DTD activity.…”

Section: Discussionmentioning

confidence: 99%

“…Heterogeneity in DTD expression has been reported in the National Cancer Institute ( USA ) human tumor cell line panel, which includes cell lines derived from leukemic, lung, colon, and breast tumors. 30 This conclusion was based on both DTD mRNA expression levels and Western blot analysis. Heterogeneity was observed both within and across tumor cell types, but a correlation was observed between DTD expression and MMC sensitivity in this panel.…”

Section: Discussionmentioning

confidence: 99%

Expression of the prodrug-activating enzyme DT-diaphorase via Ad5 delivery to human colon carcinoma cells in vitro

2002

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Intratumoral injection of recombinant adenoviral type 5 ( Ad5 ) vectors that carry prodrug -activating enzymes like DT -diaphorase ( DTD ) could be used to selectively target tumor cells for chemotherapy. To demonstrate the feasibility of this approach, Ad5 vectors were constructed, which express human DTD minigenes for both wild -type and mutant ( C -to -T change in nucleotide 609 in DTD cDNA ) DTD under the control of the cytomegalovirus ( CMV ) promoter. HT29 human colon carcinoma cells express wild -type DTD, whereas BE human colon carcinoma cells express mutant DTD, have low to undetectable DTD activity, and are 4 -to 6 -fold more resistant to mitomycin C ( MMC ) than HT29 cells. A test of the ability of Ad5 to infect these cells ( using a -galactosidase CMVdriven minigene ) indicated that 90 -100% of BE cells were infected at a multiplicity of infection ( MOI ) of 100, whereas only 15 -40% of HT29 cells were infected at this MOI. Infection of BE cells in vitro with recombinant Ad5 carrying a minigene for wild -type DTD at MOIs of 3 -100 resulted in a progressive increase in DTD activity and a maximal 8 -fold increase in sensitivity to MMC as measured by a colony -forming assay. HT29 cells were sensitized 2 -to 3 -fold following treatment with Ad5.DTD at an MOI of 100. These results indicate that adenovirus -mediated gene transfer and expression of wild -type DTD can sensitize resistant tumor cells to MMC and that this therapeutic strategy may exert a significant bystander effect.

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“…Cancer cells frequently overexpress reductive enzymes, particularly the quinone reductase DT-diaphorase or NQO1 (Fitzsimmons et al, 1996). This led to the concept of enzyme-directed bioreductive drug development (Workman, 1994).…”

Section: XIImentioning

confidence: 99%

“…This led to the concept of enzyme-directed bioreductive drug development (Workman, 1994). A number of agents undergo activation by NQO1, including the clinically used agent mitomycin C, simpler quinones such as AZQ, RH1 and EO9, and also CB1954 (Riley and Workman, 1992;Fitzsimmons et al, 1996;Sharp et al, 2000, see below). EO9 was developed for clinical trials under the auspices of EORTC (Hendriks et al, 1993;Plumb and Workman, 1994).…”

Section: XIImentioning

confidence: 99%

Professor Tom Connors and the development of novel cancer therapies by the Phase I/II Clinical Trials Committee of Cancer Research UK

et al. 2003

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Reductase Enzyme Expression Across the National Cancer Institute Tumor Cell Line Panel: Correlation With Sensitivity to Mitomycin C and EO9

Cited by 212 publications

References 29 publications

Induction of DT-diaphorase by 1,2-dithiole-3-thiones in human tumour and normal cells and effect on anti-tumour activity of bioreductive agents

Induction of DT-diaphorase by 1,2-dithiole-3-thiones in human tumour and normal cells and effect on anti-tumour activity of bioreductive agents

Expression of the prodrug-activating enzyme DT-diaphorase via Ad5 delivery to human colon carcinoma cells in vitro

Professor Tom Connors and the development of novel cancer therapies by the Phase I/II Clinical Trials Committee of Cancer Research UK

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