Enhancement of the action of the antivascular drug 5,6-dimethylxanthenone-4-acetic acid (DMXAA; ASA404) by non-steroidal anti-inflammatory drugs

Abstract

5,6-Dimethylxanthenone-4-acetic acid (DMXAA) (ASA404), a low molecular weight antivascular drug currently in clinical trial, acts both directly on the tumour vascular endothelium and indirectly through the induction of inflammatory cytokines and other vasoactive molecules from macrophages and other host cells. We wished to determine whether co-administration of non-steroidal anti-inflammatory drugs (NSAIDs) could modulate the antivascular effects of DMXAA in mice. The effects of diclofenac, salicylate, ibuprofen, celecoxib and rofecoxib on the antitumour response to DMXAA were compared using growth delay assays of Colon 38 adenocarcinomas in C57Bl mice. Concentrations of DMXAA in mice were measured by high performance liquid chromatography. Administration of DMXAA alone (25 mg/kg i.p.) or of NSAIDs alone induced small tumour growth delays from 2 to 7 days. Co-administration of each of the NSAIDs augmented DMXAA effects with tumour growth delays from 4.5 to >20 days. The possibility of a pharmacokinetic interaction was investigated using diclofenac and it was found that diclofenac did not affect DMXAA pharmacokinetics. NSAIDs increase the antitumour activity of DMXAA in a murine tumour model. The effects are consistent with hypothesis that NSAIDs antagonises some of the protective effects of prostaglandins released in response to vascular injury. Co-administration of NSAIDs with DMXAA might be considered as a possible strategy for use in combination cancer therapy.