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Submitted on July 21, 2003
Accepted on January 12, 2004
INSERM U.349, Hôpital Lariboisière, 2 rue Ambroise Paré, 75475 Paris cedex 10, FRANCE.
* To whom correspondence should be addressed. E-mail: sylvielausson{at}aol.com.
Medullary thyroid cancer (MTC) is a C cell neoplasm secreting calcitonin (CT). The only treatment remains surgical as the primary tumor and metastases resist to radio- and chemotherapies. MTC produces high amounts of prostaglandins (PGs). Non Steroidal Anti-Inflammatory Drugs (NSAIDs) have an anti-tumoral effect, generally related to the decrease of PG levels. We assessed the therapeutic potential of indomethacin in a model of human (TT cells) tumors in nude mice. Indomethacin (1.5 or 2.0 mg/kg body weight/day for 7 weeks) inhibited tumor volume by respectively 49 or 77% and decreased plasma level of CT. While TUNEL method revealed few apoptotic nuclei, the number of proliferating cells was significantly decreased (Ki-67 antigen study). Immunological effector recruitment and vascular network was not modified by treatment. The inducible synthesis enzyme, cyclooxygenase-2 (COX-2), was revealed only in infiltrating cells, both in treated and control tumors. The expression of the constitutive synthesis enzyme COX-1, was diminished and the expression of 15-prostaglandin dehydrogenase (15-PGDH), the key enzyme catabolizing PGs was increased in treated tumors. Thus, our results demonstrated the potential of indomethacin, inhibitor of COX-1 and COX-2, to prevent MTC growth. The synthesis enzyme, COX-1 and the catabolism enzyme 15-PGDH, could be involved in MTC development.
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