The role of p53 in death of IL-3-dependent cells in response to cytotoxic drugs

This report examines the cytotoxicity of chemotherapeutic agents to primary bone marrow-derived IL-3-dependent cells. Such cells derived from p53-null mice were resistant to almost 100-fold higher concentrations of the inhibi tors of deoxyribonucleotide synthesis FUdR, methotrexate and hydroxyurea th an cells with wild-type p53, In contrast, the cytotoxicity of the DNA damag ing agents X-irradiation, cisplatin or bleomycin was p53-independent. The t opoisomerase II inhibitor etoposide induced p53-dependent death, which sugg ests that DNA damage may not be its primary mechanism of cytotoxicity in th is cell type. An IL3-dependent cell line which expresses wild-type p53 was used to demonstrate that the ability of cytotoxic drugs to increase p53 exp ression level does not control their ability to induce p53-dependent loss o f clonigenicity. Finally, comparison with a p53-null IL3-dependent cell lin e was used to show that absence of p53 delays the rate of entry into apopto sis following treatment with either DNA damaging agents or inhibitors of de oxyribonucleotide synthesis. This distinguishes short-term effects of p53 o n rate of entry into apoptosis from its role in controlling ultimate cell s urvival.