Session: FP34-Molecular Mechanisms in Thyroid Hormone Action & Cancer
Room 103 (Moscone Center)
Poster Board MON-419
Methods. The CLM29 anti-proliferative and proapoptotic effects (5, 10, 30, 50 µmol/L) were tested in vitro in P-MTC cells obtained at surgery, in TT cells harboring (C634W) RETmutation, and in human dermal microvascular endothelial cells (HMVEC-d). TT cells were then injected in CD nu/nu mice which were subsequently treated with CLM29.
Results. Proliferation assays in TT and P-MTC cells showed a significant reduction of proliferation by CLM29 (p<0.001, ANOVA). CLM29 increased the percentage of apoptotic cells both in TT and in P-MTC cells dose-dependently (p<0.001, ANOVA), while had no effect on migration and invasion in both cell types. CLM29 determined a significant inhibition of HMVEC-d proliferation, blocking extracellular-signal-regulated kinases 1/2 phosphorylation, and induced, significantly, the apoptotic process in these cells. RET mutations were observed in 2 P-MTCs: the inhibition of proliferation by CLM29, obtained in P-MTC from tumors with RET mutation, were similar to those from tumors without. TT cells were injected s.c. in CD nu/nu mice and tumor masses became detectable between 20 and 30 days after xenotransplantation. CLM29 (50 mg/kg· die) inhibited significantly tumor growth and weight and the therapeutic effect was significant starting on the 48thday after cell implantation (18 days after the beginning of treatment). The CLM29-treated group of animals showed a slight, but not significant, weight loss if compared to the control one. A significant reduction of Ki-67 immunostaining and of microvessel density was observed in the CLM29 treated tumors.
Conclusion. The anti-tumor activity of a “pyrazolo[3,4-d]pyrimidine” compound, CLM29, has been shown in MTC in vitro, testing primary and continuous cell cultures, and in vivo, in nude mice, opening the way to a future clinical evaluation.
Nothing to Disclose: AA, PF, SMF, GB, CL, AC, CM, RD, FD, PM
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