Full text PDF (3.9MB) - Jurnalul de Chirurgie

Articole de sinteză Jurnalul de Chirurgie, Iaşi, 2008, Vol. 4, Nr. 2 [ISSN 1584 – 9341]
carcinoma in whom an activity of 12,6GBq was delivered, with a 29% response and prolonged
survival [44].
Treatments targeting RET gene or protein
Germ line RET mutation are found in 95% of hereditary MTC and 40-70 of sporadic
MTC. Oncogenic activity of RET may be inhibited by: dominant negative RET mutants that
will create a RET protein without oncogenic activity or tyrosine kinase inhibitors, inhibitors of
RET protein-kinase or inhibition of tumorigenic patways upstream of tyrosine kinase [40].
Dominant negative RET mutants - Adenoviral vectors expressing dominant negative
RET mutants have being used in some studies as gene therapy. Their use results in reduced
quantity of RET protein at cell surface and the oncogenic capacity of RET [40].
Thyrosine kinase inhibitors - Imatinib (Glivec) reduces tumor size in animal model but
the concentration needed to induce clinical efects in humans seems to be too high. Recently
transient stable disease have been reported with Imatinib 600 mg per day in 9 patients [45]. A
phase II study combining tyrosine kinase inhibitor imatinib with chemothrapy (dacarbazine and
capecitabine) is in way. Other tyrosine kinase inhibitors in preclinical and clinical trials are:
vandatanib, sorafenib, motesamib and sunitinib. They act not only on RET protein kinase but
also on other tyrosine kinases associated with VEGFR, EGFR, FGFR being a multitarget
inhibitors [2,41]. Irinotecan a topoisomerase poison in association with tyrosine kinase inhibitor
CEP-751 block in S phase MTC cells [46].
Use of suicide genes - The suicide gene system involves a combination of herpex
simplex virus type thymidine kinase and ganciclovir. Physiologically, intracellular kinases will
convert ganciclovir monophosphate in ganciclovir triphosphate wich in toxic for cells [38].
COX 1 and COX 2 inhibitors – indometacin could induce inhibition of tumor growth
and calcitonin secretion in MTC cell lines [47].
Radioiodine therapy following iodine symporter (NIS) gene expression - NIS may be
transfected into MTC cells which will express the symporter and may be targeted by
radioiodine [38,48].
CONCLUSIONS
Differentiated thyroid cancers arising from follicular epithelium have an excellent
prognosis as long as they are limited and may be treated with surgery and radioiodine. During
evolution some initially differentiated thyroid cancer loses their ability to respond to
radioiodine and this is the cases in which there are a few or none therapeutic options.
Conventional chemotherapeutic agents have shown not significant activity in differentiated
thyroid cancer and MTC. In the last years the new acquisitions regarding the genetics of thyroid
tumors development allowed the use of new therapeutic agents targeting advanced thyroid
carcinomas. Some of them are in preclinical trials and others inter into clinical trials.
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