Tumor growth inhibition by indomethacin in a mouse model of human medullary thyroid cancer: implication of cyclooxygenases and 15-hydroxyprostaglandin dehydrogenase.
Medullary thyroid cancer (MTC) is a C cell neoplasm-secreting calcitonin. Surgery remains the only treatment as the primary tumor and metastases resist radio- and chemotherapies. MTC produces high amounts of prostaglandins (PGs). Nonsteroidal antiinflammatory drugs have an antitumoral 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.d for 7 wk) inhibited tumor volume by 49 or 77%, respectively, and decreased the plasma level of CT. Although the terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate nick end labeling 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, 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-prostaglandin dehydrogenase, could be involved in MTC development.
Quidville
Virginie
V
Institut National de la Santé et de la Recherche Médicale Unité 349, Hôpital Lariboisière, Centre Viggo Petersen, 2 rue Ambroise Paré, 75475 Paris Cedex 10, France.
Segond
Nadine
N
Pidoux
Elisabeth
E
Cohen
Regis
R
Jullienne
Annick
A
Lausson
Sylvie
S
D000818:Animals; D017209:Apoptosis; D002116:Calcitonin / Q000097:blood; D018276:Carcinoma, Medullary / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000032:analysis / Q000502:physiology*; D020287:In Situ Nick-End Labeling; D007213:Indomethacin / Q000627:therapeutic use*; D007527:Isoenzymes / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D008565:Membrane Proteins; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011451:Prostaglandin-Endoperoxide Synthases / Q000032:analysis / Q000502:physiology*; D013964:Thyroid Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D014407:Tumor Cells, Cultured
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D002116:Calcitonin; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse; D007213:Indomethacin