2-2-bis(hydroxymethyl)-1-azabicyclo(2-2-2-)octan-3-one and Leukemia--Myeloid

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.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Apoptosis; ATP Binding Cassette Transporter, Subfamily B, Member 1; Aza Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cell Survival; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Female; Gene Deletion; Genes, p53; Humans; In Situ Hybridization, Fluorescence; Karyotyping; Leukemia, Myeloid; Male; Middle Aged; Neoplasm Proteins; Tumor Cells, Cultured