Reply: Is the dose to inhibit the COX-2 enzyme in nude mice also adequate in human endometrial tissues?
Reproductive Molecular Research Group, Department of Pathology, Tennis Court Road, Cambridge CB2 1QP, UK
Email: mlh30{at}cam.ac.uk
Sir,
Thank you for your comments regarding the paper by Hull et al. (2005)
. In this study, human eutopic endometrium was implanted into immunodeficient mice and the effect of nimesulide administration was examined. Before drug treatment experiments were performed, anti-human COX-2 antibodies that specifically detected human but not mouse COX-2 were used to demonstrate that nude mouse xenografts contained the human COX-2 immunoreactive protein, and thus were similar to human endometriotic tissue. The species specificity of the antibody was confirmed by positive anti-human COX-2 immunostaining of late secretory phase eutopic human endometrium but not of mouse endometrial tissue. Positive anti-human COX-2 immunoreactivity was detected in xenografts harvested from untreated mice.
Matsuzaki and Canis question whether the dose of nimesulide we used was sufficient to inhibit COX-2 activity in human tissue present in nude mouse xenografts. It is difficult to understand how they can infer that the dose used was insufficient based solely on changes in immunohistochemical staining. As Matsuzaki and Canis acknowledge, levels of immunoreactivity do not reflect enzyme activity. For this reason, COX-2 protein levels were not compared in treated and untreated nude mouse lesions.
Our study did not address the hypothesis that COX-2 inhibitors may regulate COX-2 immunoreactive protein levels. However, untreated nude mouse lesions harvested 7 days after implantation showed strong human COX-2 immunostaining whereas minimal COX-2 immunoreactivty was present in untreated lesions harvested 10 and 14 days after tissue implantation (unpublished data). These findings suggest that mechanisms other than nimesulide treatment down-regulate human COX-2 protein levels in the estrogen-supplemented nude mouse model of endometriosis over a 10–14 day time-period.
As discussed by Hull et al. (2005), the high dose of nimesulide used in nude mouse model experiments (25 mg/kg) is sufficient to reduce markers of COX-2 activity (prostaglandin E2 levels and other inflammatory parameters) in rodent models of inflammation (Gilroy et al., 1998; Gupta et al., 1999). Furthermore, the serum levels of nimesulide in the nude mouse model of endometriosis were similar to those identified in humans after administration of therapeutic doses of nimesulide (Davis and Brogden, 1994). It is likely that if therapeutic serum levels of nimesulide were achieved in women with endometriosis, the effect of nimesulide treatment would be similar to that seen in nude mice (no significant difference in ectopic endometrial lesion size was detected when control and treated groups were compared).
Matsuzaki's group introduced myometrium-containing uterine fragments into the peritoneal cavity of cycling rats that had a prolonged exposure to celecoxib (Matsuzaki et al., 2004). In the paper by Hull et al. (2005), ectopic human endometrial lesion size was compared in non-cycling estrogen-supplemented nude mice that had received 10 days of high dose nimesulide. It is likely that the difference in outcomes in these two studies is due to differences in the models of endometriosis, the experimental designs and the administered pharmacological agents used.
References
Davis R and Brogden RN (1994) Nimesulide. An update of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy. Drugs 48, 431–454.[Web of Science][Medline]
Gilroy DW, Tomlinson A and Willoughby DA (1998) Differential effects of inhibition of isoforms of cyclooxygenase (COX-1, COX-2) in chronic inflammation. Inflamm Res 47, 79–85.[CrossRef][Web of Science][Medline]
Gupta SK, Bhardwaj RK, Tyagi P, Sengupta S and Velpandian T (1999) Anti-inflammatory activity and pharmacokinetic profile of a new parenteral formulation of nimesulide. Pharmacol Res 39, 137–141.[CrossRef][Web of Science][Medline]
Hull ML, Prentice A, Wang DY, Butt RP, Phillips SC, Smith SK and Charnock-Jones DS (2005) Nimesulide, a COX-2 inhibitor, does not reduce lesion size or number in a nude mouse model of endometriosis. Hum Reprod 20, 350–358.
Matsuzaki S, Canis M, Darcha C, Dallel R, Okamura K and Mage G (2004) Cyclooxygenase-2 selective inhibitor prevents implantation of eutopic endometrium to ectopic sites in rats. Fertil Steril 82, 1609–1615.[CrossRef][Web of Science][Medline]
Submitted on April 7, 2005; accepted on May 5, 2005.
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