title: Effects of p53-expressing adenovirus on the chemosensitivity and differentiation of anaplastic thyroid cancer cells.
abstract: We investigated the p53 status and the ability of exogenous wildtype (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.
authors.affiliation: Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: M V
authors.initials: MV
authors.lastname: Blagosklonny
authors.forename: P
authors.initials: P
authors.lastname: Giannakakou
authors.forename: M
authors.initials: M
authors.lastname: Wojtowicz
authors.forename: L Y
authors.initials: LY
authors.lastname: Romanova
authors.forename: K B
authors.initials: KB
authors.lastname: Ain
authors.forename: S E
authors.initials: SE
authors.lastname: Bates
authors.forename: T
authors.initials: T
authors.lastname: Fojo
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002277:Carcinoma / Q000188:drug therapy* / Q000821:virology; D002454:Cell Differentiation / Q000502:physiology; D002945:Cisplatin / Q000627:therapeutic use; D004249:DNA Damage; D004317:Doxorubicin / Q000627:therapeutic use; D015967:Gene Expression Regulation, Viral / Q000502:physiology*; D016158:Genes, p53; D006801:Humans; D007700:Kinetics; D007763:Lac Operon; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004317:Doxorubicin; D002945:Cisplatin