Pharmacological approach towards the development of indolequinone bioreductive drugs based on the clinically inactive agent EO9

P M Loadman, M C Bibby, R M Phillips

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

The bioreductive drug EO9 (3-hydroxy-5-aziridinyl-1-methyl-2[indole-4,7-dione]-prop-beta-en-alpha-ol) has good pharmacodynamic properties in vitro, modest anti-tumour activity in experimental tumour models, but failed to show activity in clinical trials. Understanding the reasons for its poor efficacy in vivo is important in terms of progressing second generation analogues into the clinic. In two human tumour xenografts, direct intra-tumoural injection resulted in improved anti-tumour activity compared with intravenous administration suggesting that drug delivery to tumours is suboptimal. Compared with Mitomycin C (MMC) and the experimental agent MeDZQ, EO9 was rapidly cleared from the systemic circulation (t1/2=1.8 min) whereas MMC and MeDZQ had significantly increased plasma t1/2 values (14 and 22 min respectively). These three compounds demonstrated similar pharmacodynamic properties in terms of potency towards the NQO1 (NAD(P)H:Quinone oxidoreductase) rich H460 cell line in vitro but differed significantly in their in vivo activity with growth delays of 17.7, 4.5 and 1.0 days for MMC, MeDZQ and EO9 respectively. EO9 was rapidly metabolized by red blood cells in vitro (t1/2=14.5 min) which must contribute to its rapid pharmacokinetic elimination in vivo whereas MMC and MeDZQ were metabolized at comparatively slower rates (t1/2>120 min and 77.0 min respectively). In conclusion, the development of second generation EO9 analogues should address the issue of drug delivery and analysis of drug metabolism by murine whole blood in vitro could be utilized as a preliminary screen to identify lead compounds that are likely to have improved pharmacokinetic profiles in vivo.

Original languageEnglish
Pages (from-to)701-9
Number of pages9
JournalBritish Journal of Pharmacology
Volume137
Issue number5
DOIs
Publication statusPublished - Nov 2002
Externally publishedYes

Fingerprint Dive into the research topics of 'Pharmacological approach towards the development of indolequinone bioreductive drugs based on the clinically inactive agent EO9'. Together they form a unique fingerprint.

Cite this