Omacetaxine mepesuccinate for the treatment of leukemia.

INTRODUCTION: Omacetaxine mepesuccinate, formerly known as homoharringtonine, is a first-in-class cephalotaxine that has experienced phases of increasing and waning interest since its first use in traditional Chinese medicine. With activity being reported in patients with chronic myeloid leukemia (CML) resistant to currently available tyrosine kinase inhibitors, renewed interest has recently been generated. AREAS COVERED: The development of omacetaxine mepesuccinate, with emphasis on synthesis and mode of administration, is addressed. An overview on current clinical results as a single agent or within combination regimens in patients with acute myeloid leukemia (AML) and CML is given. EXPERT OPINION: Omacetaxine mepesuccinate has a unique mode of action and appreciable activity in AML and CML with generally mild nonhematologic toxicity. In patients with AML, results indicate a role within combination regimens in selected, possibly elderly patient populations. In CML, patients with resistance to tyrosine kinase inhibitors, especially due to the T315I mutation, are the most intensively studied. Despite successful results in some patients, single-agent therapy with omacetaxine mepesuccinate has resulted in modest results. However, upfront combination with tyrosine kinase inhibitor represents an attractive option due their differing mechanisms of action.

The expanding role of nilotinib in chronic myeloid leukemia.

IMPORTANCE OF THE FIELD: Several therapeutic options, including tyrosine kinase inhibitors, exist for the treatment of patients with Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML). Despite impressive results, there is room for improvement for those patients who are either resistant or intolerant to imatinib. AREAS COVERED IN THIS REVIEW: An overview is given on the clinical results with nilotinib, a rationally designed second-generation tyrosine kinase inhibitor, as first- and second-line therapy in patients with Ph-positive CML. Important factors in predicting resistance to nilotinib and guiding therapeutic decisions are addressed. WHAT THE READER WILL GAIN: Knowledge on the clinical efficacy and safety of nilotinib after imatinib failure and as first-line treatment. Point mutations in the kinase domain (KD) of BCR-ABL1 are important determinants of clinical sensitivity to currently available tyrosine kinase inhibitors, including nilotinib. Information on specific BCR-ABL1 KD mutations and safety profiles assist in therapeutic decision making. TAKE HOME MESSAGE: Nilotinib is a highly effective and well-tolerated therapeutic option in patients with Ph-positive CML after imatinib failure. Early evidence demonstrating increased efficacy has allowed expanding nilotinib to previously untreated patients in chronic phase. Insights into mechanisms of resistance to tyrosine kinase inhibitors and predictive factors for response will allow for a more individualized use of these agents.

Nilotinib.

Therapy with imatinib mesylate is a standard of care for most patients with Philadelphia chromosome-positive chronic myeloid leukemia (CML). However, resistance or intolerance to imatinib develops in a considerable number of patients leading to relapse or discontinuation of treatment. Nilotinib is a rationally designed second-generation tyrosine kinase inhibitor (TKI) with improved affinity and specificity against the BCR-ABL kinase, when compared with imatinib. Considerable efficacy after imatinib failure has been demonstrated in clinical trials leading to nilotinib's current approval as second-line therapy for CML in chronic and accelerated phase (AP). The role of nilotinib as first-line treatment for CML, in combinatorial strategies and in the context of specific BCR-ABL mutations, requires future studies.

Expression profiling reveals specific gene expression signatures in gastric MALT lymphomas.

The purpose of this study is to identify genes that are involved in the etiology of Helicobacter pylori induced gastric MALT lymphoma. We compared gene expression profiles of gastric MALT lymphoma with their corresponding gastric MALT (chronic gastritis with formation of follicles and aggregates). cDNA microarrays were used to compare these two tissue types from the same patient (n = 21). Quantitative PCR and immunohistochemical staining were performed to validate the microarray results. Three hundred and fifty eight out of 11,552 genes were differentially expressed between gastric MALT lymphomas and gastric MALT. Thirty eight genes are implicated in immune response, 66 in signal transduction and 36 in cell proliferation. Interestingly, chromosome 6 was the only chromosome which was significantly over-represented with 25 genes (EASE score p = 0.01254). Several surface markers of haematopoietic cells, such as CD1c, CD40, CD44, CD53, CD83, CD86 and members of the HLA-D family were up-regulated in lymphoma tissues, indicating antigen-dependent survival of lymphoma cells. We conclude that gastric MALT lymphoma shows a specific gene expression profile, which allows the differentiation from H. pylori induced lymphoid gastritis.

Nilotinib for the treatment of chronic myeloid leukemia.

The introduction of targeted therapy has revolutionized the treatment of chronic myeloid leukemia (CML). The pivotal role of the Philadelphia chromosome, resulting from the breakpoint cluster region-Abelson (BCR-ABL) translocation, led to the development of imatinib mesylate, a tyrosine kinase inhibitor with significant activity against the BCR-ABL oncoprotein. Unprecedented clinical activity in CML led to rapid approval and established first-line therapy with imatinib mesylate as the standard of care in most patients. However, the occurrence of imatinib resistance or intolerance has sparked the development of newer drugs with increased activity or specificity. Nilotinib is a second-generation tyrosine kinase inhibitor that has been rationally designed on the basis of imatinib. An overview is given on clinical results in imatinib-resistant or -intolerant patients that led to its current approval as second-line therapy for the chronic and accelerated phases of CML. Future studies will address the role of nilotinib as first-line therapy, in combination strategies and in the context of specific BCR-ABL mutations.

Distinct gene expression profile of human mesenchymal stem cells in comparison to skin fibroblasts employing cDNA microarray analysis of 9600 genes.

Broad differentiation capacity has been described for mesenchymal stem cells (MSC) from human bone marrow. We sought to identify genes associated with the immature state and pluripotency of this cell type. To prove the pluripotent state of the MSC, differentiation into osteocytes, adipocytes, and chondrocytes was performed in vitro. In contrast, normal skin cells did not harbor these differentiation abilities. We compared the expression profile of human bone marrow MSC with cDNA from one primary human skin cell line as control, using a cDNA chip providing 9600 genes. The identity of all relevant genes was confirmed by direct sequencing. Data of gene array expression were corroborated employing quantitative PCR analysis. About 80 genes were differently expressed more than threefold in MSC compared to mature skin fibroblasts. Interestingly, primary human MSC were found to upregulate a number of genes important for embryogenesis such as distal-less homeo box 5, Eyes absent homolog 2, inhibitor of DNA binding 3, and LIM protein. In contrast, mesenchymal lineage genes were downregulated in MSC in comparison to skin cells. We also detected expression of some genes involved in neural development, indicating the broad differentiation capabilities of MSC. We conclude that human mesenchymal stem cells harbor an expression profile distinct from mature skin fibroblast, and genes associated with developmental processes and stem cell function are highly expressed in adult mesenchymal stem cells.

Prognostic significance of N-RAS and K-RAS mutations in 232 patients with acute myeloid leukemia.

Reports on the prognostic impact of mutations in the RAS proto-oncogenes in patients with acute myeloid leukemia (AML) are conflicting. A peptide nucleic acid (PNA)-based technique was used on 232 AML samples to detect point mutations of the hotspots in N-RAS and K-RAS. No significant correlations between RAS mutations and clinical features, karyotype or FLT3 were found.