Preconception Folic Acid Use Modulates Estradiol and Follicular Responses to Ovarian Stimulation

John M. Twigt, Fatima Hammiche, Kevin D. Sinclair, Nicole G. Beckers, Jenny A. Visser, Jan Lindemans, Frank H. de Jong, Joop S. E. Laven, Régine P. Steegers-Theunissen
2011 Endocrinology  
Aim: We have studied the antitumoral activity of two new pyrazolo [3,4-d]pyrimidine compounds (CLM3 and CLM29) in primary papillary dedifferentiated thyroid cancer cells (DePTC cells). Methods: The antiproliferative effect was tested in DePTC cells obtained at reoperation from patients with recurrence of the tumor. The concentrations of CLM3 and CLM29 used in the in vitro experiments were 1, 10, 30, and 50 M. Results: Proliferation assays in DePTC cells showed a significant reduction of
more » ... ation by CLM3 and CLM29, which was by 12% with CLM3 (the most potent compound) 10 M, 43% with CLM3 30 M, and 60% with CLM3 50 M. CLM3 and CLM29 increased the percentage of apoptotic cells in DePTC cells dose dependently (P Ͻ 0.001) and inhibited migration (P Ͻ 0.001). A DePTC cell line (AL) was injected sc in CD nu/nu mice, and tumor masses became detectable 10 d after xenotransplantation. CLM3 (40 mg/kg⅐die) significantly inhibited tumor growth and weight, and the therapeutic effect was significant starting on the 19th day after cell implantation (4 d after the beginning of treatment). The CLM3-treated group of animals did not show any appreciable toxicity. CLM3 and CLM29 increased thrombospondin-1 expression in the AL cell line. A significant reduction of microvessels and in the percentage of antivascular endothelial growth factor antibody immunoreactivity was observed in the CLM3 treated tumors, with a simultaneous increase of the percentage of necrosis. Conclusion: The antitumoral activity of two new pyrazolo[3,4-d]pyrimidine compounds (CLM3, CLM29) in vitro and CLM3 in vivo in DePTC has been shown, opening the way to a future clinical evaluation.
doi:10.1210/endo.152.1.9996 fatcat:db5expxln5eb3pvisdukmvsexa