Neoplasms escape selective COX-2 inhibition in an animal model of breast cancer.
BACKGROUND
Cyclo-oxygenase-2 (COX-2) is up-regulated in malignant tumours rendering it an attractive target for cancer therapeutics. However, whether long-term antagonism maintains its initial efficacy on established tumours is unclear.


METHODS
4T1 cells were injected into the mammary fat pad of BALB/c mice (n = 8). Once tumour deposits were established, animals were randomized into two equal groups to receive either a selective COX-2 inhibitor (SC-236) or a drug vehicle. Further animals similarly treated (n = 7) were studied in diuresis cages allowing urine capture and analysis by mass spectrometry to determine Prostaglandin F-1 levels (PGF-1). In addition, both wild-type receiving SC-236 and COX-2 knockout mice receiving either SC 236 or vehicle were subjected to the same studies to determine whether tumour-derived or host-derived (stromal) COX-2 was the critical element. Finally, BALB/c mice with 4T1 tumours (n = 7) were treated with a combination of COX-2 and lipoxygenase (LOX) inhibition to attenuate this escape phenomenon.


RESULTS
While selective COX-2 inhibition initially retarded tumour growth, a rapid increase in tumour growth rate occurred later (day 9). This escape phenomenon correlated with an increase in urinary PGF-1 levels. An identical trend was also observed whether COX-2 knockout mice received SC-236 or not, suggesting that this effect is due to increased tumour-derived COX-2 production rather than recovery of host COX-2 functional capacity. Finally, dual inhibition of COX and LOX pathways attenuated this escape process.


CONCLUSIONS
The anti-neoplastic effects of selective COX-2 inhibition may not be sustained as tumours demonstrate an escape capacity. However, this phenomenon maybe attenuated by a combination of COX/LOX inhibitors.
Barry
M
M
Department of Surgery, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland. mitchelbarry@hotmail.com
Cahill
R A
RA
Roche-Nagle
G
G
Neilan
T G
TG
Treumann
A
A
Harmey
J H
JH
Bouchier-Hayes
D J
DJ