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DT-diaphorase activity correlates with sensitivity to the indoloquinone EO9 in mouse and human colon carcinomas
M I Walton1, M C Bibby, J A Double
1Department of Medical Oncology, University of Glasgow, U.K.
Abstract:
The indoloquinone EO9 exhibits promising in vitro and in vivo antitumour activity. EO9 is metabolised to DNA damaging species by DT-diaphorase in vitro. In the present study DT-diaphorase specific activity was 16 fold higher in the mouse adenocarcinoma MAC 16, a tumour which is quite responsive to EO9 in vivo, compared with levels in the more resistant mouse adenocarcinoma MAC 26. This order of responsiveness is the reverse of that seen with the most active of the clinically used agents in these tumours [chloroethylnitrosoureas and 5-fluorouracil (5-FU)]. In addition, when the in vitro sensitivity of two human colon carcinoma cell lines was compared, EO9 was 15-30 fold more active in the DT-diaphorase rich HT29 line than in the enzyme-deficient BE cell line counterpart. These results are consistent with the hypothesis that DT-diaphorase expression may be a major determinant of the sensitivity of tumours to EO9. This should be considered in the clinical development of the drug.
Insights
The antitumour drug EO9 shows effectiveness linked to DT-diaphorase enzyme levels. Higher enzyme activity in tumors correlates with better drug response, suggesting DT-diaphorase as a key factor for EO9
Area of Science:
- Biochemistry
- Pharmacology
- Oncology
Background:
- The indoloquinone EO9 demonstrates significant in vitro and in vivo anticancer properties.
- EO9's mechanism involves metabolic activation to DNA-damaging compounds by the enzyme DT-diaphorase.
- Tumor responsiveness to EO9 may be influenced by DT-diaphorase expression levels.
Purpose of the Study:
- To investigate the correlation between DT-diaphorase activity and tumor sensitivity to EO9.
- To evaluate the potential of DT-diaphorase as a predictive biomarker for EO9 therapy.
Main Methods:
- Assessing DT-diaphorase specific activity in responsive (MAC 16) and resistant (MAC 26) mouse adenocarcinoma models.
- Comparing in vitro sensitivity of human colon carcinoma cell lines (HT29 and BE) with differing DT-diaphorase expression.
- Correlating enzyme activity with drug efficacy in preclinical models.
Main Results:
- DT-diaphorase specific activity was 16-fold higher in the EO9-responsive MAC 16 tumors compared to MAC 26 tumors.
- EO9 exhibited 15-30 fold greater activity against the DT-diaphorase-rich HT29 cell line versus the enzyme-deficient BE cell line.
- The observed sensitivity patterns suggest a direct relationship between DT-diaphorase levels and EO9 efficacy.
Conclusions:
- DT-diaphorase expression appears to be a significant determinant of tumor sensitivity to the antitumour agent EO9.
- These findings support the consideration of DT-diaphorase levels in the clinical development and patient selection for EO9 therapy.
- Targeting or selecting based on DT-diaphorase activity could optimize EO9's therapeutic potential.