PRIMA-1 induces apoptosis in acute myeloid leukaemia cells with p53 gene deletion

Abstract

The p53 tumour suppressor gene located on chromosome 17p13 is the most frequently mutated gene in human tumours. About 5-8% of cases with acute myeloid leukaemia (AML) carry the p53 mutation. Recently, the compound p53-dependent reactivation and induction of massive apoptosis (PRIMA-1) has been shown to induce cytotoxic effects and apoptosis in human tumour cells by restoration of the transcriptional activity of mutated p53. This is believed to be mediated by a change in the conformation of mutated p53 protein, restoring DNA binding and activation of p53 target genes. We studied the effects of PRIMA-1 and commonly used antileukaemic drugs on AML cells from 62 patients. Cells were obtained from peripheral blood or bone marrow and were exposed to PRIMA-1, cytarabine, daunorubicin, chlorodeoxyadenosine and fludarabine. This study showed that PRIMA-1 had cytotoxic effects on AML cells. Conventional AML drugs were less effective in cells with hemizygous p53 deletion. Interestingly, our data indicated that PRIMA-1 was more effective in this subgroup of patients compared with patients with normal chromosome 17. Our data suggest that the concept of restoration of p53 protein by PRIMA-1 or a PRIMA-1-based new drug may increase the efficacy of AML treatment in patients with p53 mutations. © 2005 Blackwell Publishing Ltd.