midostaurin and Leukemia--Myelogenous--Chronic--BCR-ABL-Positive

The 60th American Society of Hematology (ASH) held in San Diego in December 2018 was followed by the 13th Post-ASH chronic myeloproliferative neoplasms (MPNs) workshop on December 4 and 5, 2018. This closed annual workshop, first introduced in 2006 by Goldman and Mughal, was organized in collaboration with Alpine Oncology Foundation and allowed experts in preclinical and clinical research in the chronic MPNs to discuss the current scenario, including relevant presentations at ASH, and address pivotal open questions that impact translational research and clinical management. This review is based on the presentations and deliberations at this workshop, and rather than provide a resume of the proceedings, we have selected some of the important translational science and treatment issues that require clarity. We discuss the experimental and observational evidence to support the intimate interaction between aging, inflammation, and clonal evolution of MPNs, the clinical impact of the unfolding mutational landscape on the emerging targets and treatment of MPNs, new methods to detect clonal heterogeneity, the challenges in managing childhood and adolescent MPN, and reflect on the treatment of systemic mastocytosis (SM) following the licensing of midostaurin.

Topics: Aging; Animals; Congresses as Topic; DNA Mutational Analysis; Humans; Inflammation; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Mastocytosis; Medical Oncology; Mice; Mutation; Myeloproliferative Disorders; Prognosis; Societies, Medical; Staurosporine; Translational Research, Biomedical; United States

The efficacy and side-effects of drugs do not just reflect the biochemical and pharmacodynamic properties of the parent compound, but often comprise of cooperative effects between the properties of the parent and active metabolites. Metabolites of imatinib, nilotinib and midostaurin have been synthesised and evaluated in assays to compare their properties as protein kinase inhibitors with the parent drugs. The

Topics: Antineoplastic Agents; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Protein Kinase Inhibitors; Pyrimidines; Staurosporine

The protein kinase C inhibitor, staurosporine derivative CGP 41 251, was more efficient than staurosporine in the reversal of decreased anthracycline uptake in the anthracycline-resistant cell subline (A2780/ADR) of ovarian carcinoma. Staurosporine was more efficient than CGP 41 251 in the induction of cytometrically determined DNA fragmentation (cytofluorometric equivalent of apoptosis) in A2780 parental human ovarian carcinoma cells compared with the drug-resistant A2780/ADR subline and in both human leukemia K-562 cells as well as mouse leukemia L1210 compared with the araC-resistant L1210 cells. Staurosporine was a more potent inhibitor than CGP 41 251 of DNA synthesis in both araC-sensitive and -resistant mouse leukemia L1210 cells. CGP 41 251 was a slightly more efficient inhibitor of thymidine incorporation than staurosporine in human leukemia K-562 cells and its combination with araC had a higher inhibitory effect on the DNA synthesis in this cell line than staurosporine. CGP 41 251 exerted DNA synthesis inhibitory effects on both araC-sensitive and -resistant L1210 cells. Staurosporine-induced DNA synthesis inhibition in both araC-resistant and -sensitive L1210 mouse leukemia cells was decreased after combined administration with araC.

Topics: Alkaloids; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Transport; Cell Cycle; Cytarabine; DNA Replication; DNA, Neoplasm; Drug Resistance, Multiple; Drug Synergism; Female; Humans; Leukemia L1210; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Mice; Mice, Inbred DBA; Neoplasm Proteins; Ovarian Neoplasms; Protein Kinase C; Staurosporine; Tumor Cells, Cultured