Given that molecular changes may be occurring in thyroid tissue at early stages of disease, treatments that might ameliorate the effects of oncogene induced inflammatory mediator production may reduce the morbidity neither associ ated with thyroid inflammation. Presently existing com pounds targeting various signal transduction pathways are available and some, like those that target Ras signaling, have already entered the clinic. Small molecule agents such as the farnesyltransferase inhibitors show target selectivity in many models. FTIs represent a group of compounds that inhibit the enzymatic properties of far nesyltransferase, an enzyme important for the post trans lational lipid modification of membrane associated proteins, including those of the RAS pathway.

FTIs were developed to take advantage of the membrane localiza tion requirements held by many of the molecules in the RAS pathway, known to be some of the most commonly mutated genes in human cancer. By blocking the membrane localization of RAS and associated molecules, FTI functions to suppress proliferation and angiogenesis by inhibiting NF?B activation and expression of NF?B regulated genes induced by carcinogens and inflamma tory stimuli. Despite their potential target specificity, low toxicity, and potential for cancer specific targeting, these compounds have only been marginally successful for the treatment of advanced malignancies in clinical tri als. One explanation for these failures may be that FTIs modulate alternate targets and the assumed dependency on Ras signaling in cancer may not hold up in all stages of tumor development.

Interestingly, recent studies describe FTIs as anti inflammatory agents and found significant efficacy in both cell and animal based models of inflam mation. For this reason, we have chosen to use FTI to study the inhibition of RP3 induced inflammatory mediators produced by oncogene Dacomitinib transfected www.selleckchem.com/products/ganetespib-sta-9090.html thyroid cells. The extension of these studies provide a therapeutic rationale for using FTI in thyroid autoimmune disease. Methods Materials The farnesyltransferase inhibitor tipifarnib, R115777 4 1 methyl 2 quinolinone was supplied by Dr. David End of Johnson Johnson, Beerse, Belgium. For each experiment, stocks were prepared fresh daily from R115777 powder in DMSO and protected from light. Cell culture PC Cl3 rat thyrocytes previously obtained from Dr. Jeffrey Knauf were stably transfected with human RP3 via ligation of RP3 onto the retroviral vector, pMV7 as described previ ously. The RP3 transfected thyrocytes were grown in Coons Modified F12 medium supplemented with 7. 5% fetal bovine serum, 2 mM L glutamine, and 100 U/ml penicillin/strep tomycin.