DT-diaphorase activity correlates with sensitivity to the indoloquinone EO9 in mouse and human colon carcinomas.
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.
Walton
M I
MI
Department of Medical Oncology, University of Glasgow, U.K.
Bibby
M C
MC
Double
J A
JA
Plumb
J A
JA
Workman
P
P
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001388:Aziridines / Q000627:therapeutic use*; D002460:Cell Line; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D045563:Indolequinones; D007211:Indoles / Q000627:therapeutic use*; D051379:Mice; D008815:Mice, Inbred Strains; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D001388:Aziridines; D045563:Indolequinones; D007211:Indoles; D016660:NAD(P)H Dehydrogenase (Quinone); C060817:apaziquone