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Therapeutic Usefulness of Wild-Type p53 Gene Introduction in a p53-Null Anaplastic Thyroid Carcinoma Cell Line

The Departments of Pharmacology 1 (M.Na., Y.N., M.Ni.), Anatomy 1 (K.A.), and Surgery 1 (M.Na., H.A.), and the Department of Nature Medicine, Atomic Bomb Disease Institute (T.-t.Y., A.O., H.N., S.Y.), Nagasaki University School of Medicine, Nagasaki 852-8523; and the Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Showa University (M.Y., T.Y.), Tokyo 142, Japan

Address all correspondence and requests for reprints to: Yuji Nagayama, M.D., Department of Pharmacology 1, Nagasaki University School of Medicine, 1–12-4 Sakamoto, Nagasaki 852-8523, Japan. E-mail: nagayama{at}net.nagasaki-u.ac.jp

Anaplastic thyroid carcinomas very often harbor the mutations in the tumor suppressor gene p53. We have previously shown that wild-type (wt) p53 gene introduction led to cell growth arrest, but not apoptosis, in p53-null anaplastic thyroid carcinoma cells. The present studies were designed to evaluate other therapeutic effects of wt-p53 gene introduction on p53-null thyroid carcinoma cells, as chemo- and radiosensitization and inhibition of angiogenesis have also been described recently as additional therapeutic advantages of wt-p53 gene introduction in tumor cells with p53 mutations. A p53-null anaplastic thyroid carcinoma cell line, FRO, and a FRO subline stably expressing a temperature-sensitive (ts) mutant of p53 (p53Val138), tsFRO, were used. ts-p53 functions as mutant and wt at nonpermissive (37 C) and permissive (32 C) temperatures, respectively. tsFRO showed a prolonged cell doubling time compared to parental FRO when cultured at 32 C, but the cell growth rate was similar between FRO and tsFRO at 37 C. The cytotoxic and clonogenic assays demonstrated that although the sensitivity to three different anticancer agents (cisplatin, 5-fluorocytosine, and doxorubicin) was unaltered, radiosensitivity was enhanced in tsFRO compared to FRO at 32 C. Unexpectedly, in studies on angiogenesis, expression levels of vascular endothelial growth factor (an angiogenic factor) messenger ribonucleic acid were similar between FRO and tsFRO, and thrombospondin-1 (an antiangiogenic factor) messenger ribonucleic acid and protein levels were about 2.5-fold lower in tsFRO than FRO at 32 C, although any difference could not be detected in their ability to inhibit in vitro angiogenesis with the culture medium conditioned by tsFRO and FRO at 32 C. These results suggest that p53-defective thyroid carcinomas may benefit from the combination of p53 gene therapy and radiotherapy. However, further study will be necessary to clarify the pathological significance of thrombospondin-1 in angiogenesis and thyroid tumor growth.

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