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Clinical Implications and Impact of Discovery of the Thyroid Hormone Receptor on Integrin αvβ3 (T3 therapy may be safer than T4 for cancer patients)

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  • Clinical Implications and Impact of Discovery of the Thyroid Hormone Receptor on Integrin αvβ3 (T3 therapy may be safer than T4 for cancer patients)

    https://www.frontiersin.org/articles...019.00565/full

    Front. Endocrinol., 23 August 2019 | https://doi.org/10.3389/fendo.2019.00565
    Clinical Implications and Impact of Discovery of the Thyroid Hormone Receptor on Integrin αvβ3–A Review
    Aleck Hercbergs*
    • Department of Radiation Oncology, Cleveland Clinic, Cleveland, OH, United States
    T4 and Cancer Biology

    T4 in physiological free hormone concentrations stimulates proliferation of cancer cells in vitro and in xenografts (13, 3945). Preclinical studies of tetrac, which blocks thyroid hormone action at integrin αvβ3, have shown arrested tumor growth (7, 11) in a variety of tumor xenografts including xenografts of renal cell carcinoma (13), non-small cell lung carcinoma (46), medullary carcinoma of the thyroid (41), pancreatic carcinoma (43), and multi-drug resistant breast cancer (47).
    Euthyroid Hypothyroxinemia and Divergence of Action Between T4 and T3

    This is a eumetabolic state maintained in the total absence of blood thyroxine by providing exogenous T3. The individual can therefore live and perform all normal daily activities and functions as prior to removal of the source of T4 or post total thyroidectomy. Preclinical evidence (12) indicates that T3, bound with a lower affinity by αvβ3 (9), is of low activity at physiological levels at the receptor (5, 39). The clinical ramifications of these effects on cancer cells are supported by the results of induction of the state of euthyroid hypothyroxinemia in patients with advanced cancers and with normal thyroid function (1).

    In a compassionate-need study of terminal patients with a variety of incurable solid tumors, extended survival was observed in a majority of patients using exogenous T3 to induce and maintain hypothyroxinemia. T3 administration prevented symptomatic hypothyroidism. Low odds of survival were surmounted in 19 of 23 patients (83%) who exceeded the expected median survival of literature-reported series used as controls (1). An additional approach is to terminate exogenous T4 supplementation to allow the T4 level to decline and supplement with T3 titrated individually to the patient's functional needs. Examples of the outcomes of this strategy on advanced disease (glioblastoma and sarcoma) are shown in Figures 35.
    Conclusion
    Identification of the integrin αvβ3 receptor pathway promises a paradigm changing approach to manage and treat cancer more effectively than currently available modalities.
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    “‘i love myself.’ the quietest. simplest. most powerful. revolution ever.” ---- nayyirah waheed
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