TY - JOUR T1 - Modulation of Cisplatinum Cytotoxicity by p53: Effect of p53-Mediated Apoptosis and DNA Repair JF - Molecular Pharmacology JO - Mol Pharmacol SP - 966 LP - 972 DO - 10.1124/mol.56.5.966 VL - 56 IS - 5 AU - Jianguo Fan AU - Joseph R. Bertino Y1 - 1999/11/01 UR - http://molpharm.aspetjournals.org/content/56/5/966.abstract N2 - A stable transfectant (S2SN7) of p53-null SaOS-2 (human osteosarcoma) cells expressing wild-type p53 under the tight control of a tetracycline-responsive promoter was used to study the functional roles of p53 in cellular response to cisplatinum (CP). When cells were grown in media containing normal concentrations (10%) of serum, induction of p53 by tetracycline withdrawal resulted in an 8-fold decrease in sensitivity to CP. In contrast, when cells were grown in lower serum (1%) media, induction of p53 led to a 10-fold increase in sensitivity to CP. The p53-mediated sensitivity to CP under lower serum conditions was attributed, at least in part, to increased susceptibility of p53-mediated apoptosis. Under lower serum (0.1–1%) but not normal serum conditions, p53 induction correlated with selective down-regulation of bcl-2, an inhibitor of apoptosis. In addition, a host-cell reactivation assay showed that induction of p53 caused a significant increase in repair of CP-induced DNA damage under normal serum but not low serum conditions. These data suggest that growth conditions may modulate and possibly reverse p53-mediated CP sensitivity by altering p53-mediated gene regulation and, as a result, susceptibility to apoptosis. They also suggest that a combined effect of p53-mediated apoptosis and DNA repair may be the ultimate determinant in p53-mediated cellular resistance or sensitivity to chemotherapeutic drugs. ER -