Epidermal growth factor receptor 1 expression is upregulated in undifferentiated thyroid carcinomas in humans.

Background: Epidermal growth factor receptor 1 (EGFR1) signaling is involved in human cancer cell progression and is responsible for aggressive biological behavior and poor clinical outcome in several human malignancies. Activation of the EGFR1 pathway has been proposed, among others, as being involved in the progression of thyroid cancer toward a thyroid-stimulating hormone (TSH)-independent phenotype. We have previously observed that undifferentiated thyroid carcinoma cells are hyper-sensitive to EGF signaling of downstream intracellular pathways, and this correlated both with the loss of TSH-dependency and increase in EGF-dependent proliferation and migration.

Erlotinib enhances the proapoptotic activity of cytotoxic agents and synergizes with paclitaxel in poorly-differentiated thyroid carcinoma cells.

Background: The therapeutic role of EGFR inhibitors in thyroid malignancies is still controversial even though the full activation of EGF signaling has recently been proposed as involved in the dedifferentiation of human thyroid cancers.

Materials And Methods: Agents which target EGFR signaling (erlotinib, cetuximab and panitumumab) were evaluated at preclinical level in a panel of thyroid tumor cell lines.

Results: Erlotinib induced a dose-dependent inhibition of cell proliferation together with inhibition of EGF-induced AKT and ERK1/2 signaling only in poorly-differentiated thyroid carcinoma FRO cells.

Targeting epidermal growth factor receptor 1 signaling in human thyroid-stimulating hormone-independent thyroid carcinoma FRO cells results in a more chemosensitive and less angiogenic phenotype.

Background: Poorly differentiated and anaplastic thyroid cancers are aggressive malignancies unresponsive to standard treatments. The mechanisms responsible for the progression of thyroid tumors toward a thyroid-stimulating hormone (TSH)-independent phenotype are still under discussion, and a better understanding of them may provide novel molecular targets for the treatment of this disease. We evaluated the hypothesis that epithelial growth factor (EGF) signaling may play a role in favoring the loss of TSH dependency in human differentiated thyroid tumor cells.

Nevirapine restores androgen signaling in hormone-refractory human prostate carcinoma cells both in vitro and in vivo.

Background: Prostate carcinomas are androgen-dependent neoplasms which progress toward a hormone-independent phenotype during hormone-deprivation therapy. We evaluated nevirapine, a reverse transcriptase inhibitor, as a new treatment in hormone-refractory prostate carcinoma cells with the aim of restoring the androgen-dependency of tumor cells, the rationale being that endogenous reverse transcriptase is up-regulated in transformed cells and reverse transcriptase inhibitors exert a differentiating activity in human tumors.

Methods And Results: Nevirapine induced extensive reprogramming of gene expression in vitro with up-regulation of genes that might be silenced during prostate tumor progression (i.

Nevirapine toxicity in non-HIV cancer patients.

Background: Nevirapine (NVP) is a nonnucleoside reverse transcriptase inhibitor used in HIV patients and recently evaluated as a differentiating and antiproliferative agent in human malignancies. However, while NVP is a safe treatment in immunocompromised patients, NVP-containing regimens have been associated with severe immune-mediated toxicities in non-HIV individuals.

Methods And Results: We describe the toxicity profile of single-agent NVP in 6 non-HIV cancer patients treated for a median period of 7.

Reinduction of cell differentiation and 131I uptake in a poorly differentiated thyroid tumor in response to the reverse transcriptase (RT) inhibitor nevirapine.

Our recent findings have shown that the reverse transcriptase (RT) inhibitors, nevirapine and efavirenz, used for 10 years in human immunodeficiency virus (HIV) disease, act as cytostatic and differentiating agents by modulating gene expression in several human tumor cell models. In dedifferentiated thyroid cancer, they reestablish thyroid-stimulating hormone (TSH) signaling, Na/I symporter (NIS), thyroglobulin peroxidase (TPO) expression, and even radioiodine uptake (RIU). In this paper, we describe the case of a 76-year-old woman who was affected by thyroid papillary carcinoma and who underwent a total thyroidectomy and a debulking of the right laterocervical region for lymph-node metastases, vessel infiltration, and neoplastic thrombosis of the internal jugular vein, followed by 3 radioiodine treatments.

The Nrf2 transcription factor contributes to the induction of alpha-class GST isoenzymes in liver of acute cadmium or manganese intoxicated rats: comparison with the toxic effect on NAD(P)H:quinone reductase.

In rat liver, in addition to their intrinsic transferase activity, alpha-class GSTs have Se-independent glutathione peroxidase activity toward fatty acid hydroperoxides, cumene hydroperoxide and phospholipids hydroperoxides but not toward H(2)O(2.) We have previously shown that hepatic GST activity by these isoenzymes is significantly increased 24h after cadmium or manganese administration (Casalino et al., 2004).

Reverse transcriptase inhibitors down-regulate cell proliferation in vitro and in vivo and restore thyrotropin signaling and iodine uptake in human thyroid anaplastic carcinoma.

Context: Two classes of repeated genomic elements, retrotransposons and endogenous retroviruses, encode for endogenous nontelomeric reverse transcriptase (RT), a gene that is down-regulated in differentiated cells but is highly expressed in embryonic and transformed tissues. Two nonnucleosidic RT inhibitors, efavirenz and nevirapine, currently used in HIV treatment, reversibly down-regulate tumor growth and induce differentiation in several human tumor cell models.

Objectives: Aggressive biological behavior and loss of specific thyroid cell functions, such as thyroglobulin, thyroid peroxidase, TSH receptor, Na/I symporter expression, and iodine uptake are features of anaplastic thyroid cancer.