The dismal outcome of patients after treatment in ATC has stimulated research investigation to improve outcome results. Exogenous interleukin 6 has been used but unfortunately was ineffective.60 After gene transfection with wild-type p53, three ATC cell lines became more sensitive to doxorubicin (Adriamycin), suggesting that combining wild-type p53 and chemotherapy might improve the results of therapy.61 The transfection of a human thyroperoxidase gene to restore iodine trapping in non-iodide-concentrating tumor cells seen in anaplastic cancer was not effective.62 Bone morpho-genetic protein (BMP-7) resulted in growth inhibition in ATC cells by inhibiting cyclin-dependent kinase activity, shifting the Rb protein to the hypophosphorylated state.63 The compound 1,25-dihydroxy vitamin D3 and several of its non-calciomimetic analogs show dose-dependent inhibition of cell growth in ATC cells in vitro64 and in vivo.65 Growth inhibition of anaplastic cancer cells was also demonstrated by histone deacetylase inhibitors as a result of increased apoptosis, with activation of the caspase cascade and the induction of a cell cycle arrest through reduction of cyclin-dependent kinase activity.66

Bovine seminal ribonuclease has been reported to have beneficial effects for treatment of aggressive thyroid cancer.67 An E1B 55-kDa gene-defective adenovirus (ONYX-O15) worked synergistically with two antineoplastic drugs (doxorubicin and paclitaxel) to increase cell death in ATC.68 Apigenin, a flavonoid, showed promise by inhibiting the signal transduction pathways regulating growth and survival in human ATC cells.69 It has also been documented that levels of (k)alphal tubulin relative to thyroglobulin were greatly increased in anaplastic cancer so that chemotherapy targeted at microtubulin might prove to be useful for ATC treatment.70 Restoration of p53 expression in ATC inhibited proliferation and restored differentiation in human ATC cells as well as responsiveness to physiologic stimuli.46 It has also been reported that CA4P, a tubulin-binding agent derived from the African bush willow, may have antitumor effects in ATC, thought to be due to a combination of primary antineoplastic effects and impairment of tumor vascularity.71 Although investigation into the biologic character of ATC continues, therapeutic innovations are still relatively scanty. Even as prospective trials continue to be limited, it has been noted that ATC arising from papillary or follicular thyroid malignancies have different genetic backgrounds and retain some of the cytogenetic characteristics of the parent problem.72 BRAF mutations have been demonstrated to be restricted to papillary cancer and poorly differentiated and anaplastic cancer arrising from papillary malignancy, with distinct properties that enable them to develop poorly differentiated and anaplastic cancer.73 Also, a panel of tumor suppressor genes has been studied that is associated with thyroid neoplasia. The results demonstrate a pattern of alloleic loss, so that the majority of cases showed mutations in two distinct areas and substantial increases in mutation rates in the anaplastic components of the transformed ATC from preexisting well-differentiated malignancy.74 P107 is thought to play a constitutive role in the progression of papillary cancer to anaplasia, showing a marked decrease in the anaplastic component.75 Efforts have also been made to investigate the expression of cytokeratin 20 (ck20) in differentiated and anaplastic cancer, and the resultant investigation has demonstrated that ck20-positive tumors have a poor prognosis, reinforcing the need for adjuvant treatment in such a selected group.76 Cytogenetic work has also shown that different gene dosage copy sequence and balances are important to pathways of transformation of follicular into anaplastic cancers.77 The transcriptional factor E2F1 controls the RB-E2F signaling pathway, and there is enough regulation of E2F1 in papillary cancer as compared with ATC that may demonstrate a role in carcinogenesis.78 Gene therapy of ATC has been investigated using the interleukin-12 gene in BALB/C (nu/nu) mice, and initial results suggest a clinical application may be considered.79 Other investigation has demonstrated that the radiosensitivity of transformed thyroid cells is due in part to the elevated basal activity in the induction of the active form of nuclear transcription factor kappa B, prompting investigators to theorize that inhibition of NF-kappa B could enhance radiation therapy of ATC.80 Workers have also looked at imatineb mesylate monotherapy in treatment of ATC only to find that future clinical studies are futile and not to be encouraged.81 It has also been demonstrated that experimental in vitro incorporation of gemcitabine into liposomes enhances the drug's cytotoxic effect, indicating a more effective drug intake inside the cell, which may permit lower dosage of this drug in the treatment of ATC.82 Etiology and more complex treatment programs may be investigated, but surgical investigators are still left with the rather simplistic feeling that, although there is no successful treatment for ATC, patients who have undergone liberal surgery for thyroid neoplasia or early surgery with complete resection of ATC have the best chance of response and survival.83

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