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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Wang
L-C Steve
LC
Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.
Ching
Lai-Ming
LM
Paxton
James W
JW
Kestell
Philip
P
Sutherland
Rachel
R
Zhuang
Li
L
Baguley
Bruce C
BC
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000627:therapeutic use*; D003110:Colonic Neoplasms / Q000188:drug therapy; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D004008:Diclofenac / Q000627:therapeutic use; D004354:Drug Screening Assays, Antitumor; D004359:Drug Therapy, Combination; D051379:Mice; D008810:Mice, Inbred C57BL; D044004:Xanthones / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*
D020533:Angiogenesis Inhibitors; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D044004:Xanthones; C066668:vadimezan; D004008:Diclofenac