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Effects of p53-Expressing Adenovirus on the Chemosensitivity and Differentiation of Anaplastic Thyroid Cancer Cells

We investigated the p53 status and the ability of exogenous wild-type (wt) p53 to affect chemosensitivity in three anaplastic thyroid carcinoma cell lines (BHT-101, SW-1736, and KAT-4). All three cell lines had nonfunctional p53. Treatment with mitomycin C or adriamycin did not result in accumulatio...

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Bibliographic Details
Published in:The journal of clinical endocrinology and metabolism 1998-07, Vol.83 (7), p.2516-2522
Main Authors: Blagosklonny, Mikhail V, Giannakakou, Paraskevi, Wojtowicz, Malgorzata, Romanova, Larisa Y, Ain, Kenneth B, Bates, Susan E, Fojo, Tito
Format: Article
Language:English
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Summary:We investigated the p53 status and the ability of exogenous wild-type (wt) p53 to affect chemosensitivity in three anaplastic thyroid carcinoma cell lines (BHT-101, SW-1736, and KAT-4). All three cell lines had nonfunctional p53. Treatment with mitomycin C or adriamycin did not result in accumulation of p53 or induction of p21WAF1/CIP1 or Mdm-2 and did not cause Rb dephosphorylation. BHT-101 and KAT-4 cells had mutant p53. SW-1736 cells were functionally mutant because of marked down-regulation of wt p53 messenger ribonucleic acid, representing a novel mechanism of p53 dysfunction. Infection with a p53-expressing adenovirus (Ad-p53) induced high levels of p21 and Mdm-2 proteins. In BHT-101 cells, induction of p21 and Mdm-2 was evident 10 h after infection. In KAT-4 cells, induction of p21 and Mdm-2 was observed 1 day after infection, and continued to increase over the ensuing 24 h. SW-1736 cells demonstrated intermediate kinetics. Sensitivity to the cytotoxic effect of Ad-p53 paralleled the kinetics of p21/Mdm-2 induction. BHT-101 cells were most sensitive to killing by Ad-p53, with an IC50 of less than 2 multiplicity of infection; SW-1736 cells were intermediate in sensitivity; KAT-4 cells were resistant. All three cell lines became more sensitive to adriamycin after wt p53 expression, with a 10-fold decrease in IC50 values. The latter observation may make a combination of wt p53 and chemotherapeutic drugs an attractive modality for treating anaplastic thyroid cancer.
ISSN:0021-972X
1945-7197
DOI:10.1210/jcem.83.7.4984