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 wildtype ( wt) p53 to affect chemosensitivity in three anaplastic thyroid carcino ma cell lines (BHT-101, SW-1736, and KAT-4). All three cell lines had nonfunctional p53. Treatment with mitomycin C or adriamycin did not re sult in accumulation of p53 or induction of p21(WAF1/CIP1) or Mdm-2 an d did not cause Rb dephosphorylation. BHT-101 and KAT-4 cells had muta nt 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 adenovir us (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 infe ction, and continued to increase over the ensuing 24 h. SW-1736 cells demonstrated intermediate kinetics. Sensitivity to the cytotoxic effec t of Ad-p53 paralleled the kinetics of p21/Mdm-2 induction. BHT-101 ce lls were most sensitive to killing by Ad-p53, with an IC,, of less tha n 2 multiplicity of infection; SW-1736 cells were intermediate in sens itivity; KAT-B cells were resistant. All three cell lines became more sensitive to adriamycin after wt p53 expression, with a 10-fold decrea se in IC,, values. The latter observation may make a combination of wt p53 and chemotherapeutic drugs an attractive modality for treating an aplastic thyroid cancer.