Activity profile of the novel aziridinylbenzoquinones MeDZQ and RH1 in human tumour xenografts.
BACKGROUND
RH1 and MeDZQ represent novel aziridinylbenzoquinones that can be activated by DT-diaphorase to form unique DNA lesions. RH1 is due to enter a phase 1 clinical trial in the United Kingdom in the summer of 2003, where pharmacodynamic monitoring of DT-diaphorase will be performed.


METHODS
The antitumour efficacy of RH1 and MeDZQ has been studied in 4 human xenografts (3 non-small cell lung cancer and 1 colon cancer), and compared to the level of constitutive DT-Diaphorase activity measured by the DCPIP assay.


RESULTS
The 4 xenografts exhibited a wide range of DT-diaphorase activity (4.8-303 nmol/min/mg). Greater antitumour activity was recorded in the xenografts expressing high levels of DT-diaphorase (e.g. NX002, DT-diaphorase activity, 303 +/- 52 nmol/min/mg, T/C to MeDZQ, 33.3% and to RH1, 43.4%).


CONCLUSIONS
These data add in vivo support to a role for DT-Diaphorase in the antitumour activity of RH1.
Cummings
Jeffrey
J
Cancer Research UK, Edinburgh Medical Oncology Unit, Western General Hospital, Edinburgh, EH4 2XR, U.K. jcummings@picr.man.ac.uk
Ritchie
Alison
A
Butler
John
J
Ward
Timothy H
TH
Langdon
Simon
S
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001388:Aziridines / Q000494:pharmacology*; D016227:Benzoquinones / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D051379:Mice; D008819:Mice, Nude; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D014183:Transplantation, Heterologous; D023041:Xenograft Model Antitumor Assays
C117776:2,5-diaziridinyl-3-(hydroxymethyl)-6-methyl-1,4-benzoquinone; D000970:Antineoplastic Agents; D001388:Aziridines; D016227:Benzoquinones; C073715:2,5-dimethyl-3,6-diaziridinyl-1,4-benzoquinone; D016660:NAD(P)H Dehydrogenase (Quinone)