NVPAST inhibits calcitonin mRNA abundance in TT cells in vitro. The relatively slow kinetics of calcitonin mRNA decay may be due to the previously reported prolongedt of the transcript, which we confirmed.NVPAST inhibited calcitonin gene transcription directed by a CT promoter fragment that contained an element previously reported to be activated via RAS. As RET activates RAS and MAPK, it is possible that this pathway may be a primary driver of calcitonin gene transcription.Clearly, other Flunisolide factors contribute significantly to calcitonin gene regulation, which can also be activated through cyclic AMP. The evidence that RET kinase inhibition Revefenacin blocked calcitonin gene expression led us to explore the hypothesis that ligandinduced RET activation resulted in a reciprocal effect.To this end, it was critical to identify a C cell line that expressed wildtype RET because activated mutants of this tyrosine kinase receptor oncogene are either constitutively fully active or show attenuated responses to ligand.The mouse MTCM cell line was found to express a wildtype RET gene product, and was thus suitable for these experiments.By contrast, treatment with persephin alone was sufficient to stimulate calcitonin gene expression.RET kinase activity was required for ligandinduced calcitonin gene expression because it was blocked by NVPAST.These animals had a normal number of C cells with apparently preserved morphology, but had decreased calcitonin content in the thyroid of neonates and young animals.Further evidence that this novel calcitonin regulatory pathway is physiologic is provided by our observation that NVPAST markedly reduced plasma calcitonin levels in normal mice.Oral administration of NVPAST was associated with a significant decline in plasma calcitonin levels at h.A similar early drop in plasma human calcitonin was seen in athymic mice with TT cell xenografted tumors. In view of the prolongedt of calcitonin mRNA, this suggests that RET signaling may be mediating distinct effects on calcitonin secretion and gene expression.Although the former mechanism remains to be proven, a dual mechanism of regulation of calcitonin gene expression and secretion by gastrin has also been proposed. The findings reported here are of potential clinical significance because plasma calcitonin is used routinely as an indicator of progression in patients with persistent or recurrent MTC, as it is believed to be roughly proportional to tumor mass.Now that smallmolecule RET kinase inhibitors are being evaluated for therapeutic effectiveness in patients with metastatic MTC, our data raises the possibility that measurement of calcitonin may not accurately reflect tumor burden in these patients.On the other hand, evidence of a rapid decrease in calcitonin levels after shortterm treatment with a RET kinase inhibitor may provide indirect evidence that the kinase has been effectively targeted.The costs of publication of this article were defrayed in part by the payment of page charges.Characterization of a multicomponent receptor for GDNF.Click on Request Permissions which will take you to the Copyright Clearance Centers Downloaded from on April. American Association for Cancer Research. Corresponding experiments were conducted with established tumor xenografts.The variability and specificity of pharmacodynamic markers in human peripheral blood lymphocytes were studied.Xenograft experiments confirmed tumor growth inhibition in vivo.This information formed the basis of a pharmacokineticpharmacodynamicdriven phase I trial.

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