Findings from Italy and Japan in leukemia provide new insights

06-15-2006

Reports from Italy and Japan highlight recent research in leukemia.

Study 1: Chronic myeloid leukemia (CML) imatinib treatment could be enhanced by valproate.

According to recent research from Italy, "The objective of this study was to evaluate the ability of the clinically available histone deacetylase (HDAC) inhibitor valproate to enhance the cytotoxicity of the 13cr-AbI inhibitor imatinib in imatinib-resistant cell lines. Interactions between imatinib and valproate have been examined in imatinib-sensitive and -resistant CML cell lines (K562, KCL-22, CML-T1) and in bone marrow mononuclear cells (MNCs) derived from imatinib-resistant CML patients.

"In imatinib-sensitive cell lines, cotreatment with imatinib 0.5 mcM and valproate 5 mcM for 48 hours potently enhanced imatinib-induced growth arrest and apoptosis. In resistant cell lines and in primary MNCs derived from imatinib-resistant patients, valproate restored sensitivity to the cytotoxic effects of imatinib. Coexposure of cells to valproate and imatinib was associated with repression of several genes involved in Bcr-Abl transformation," explained A. Morotti and colleagues, University of Turin.

The researchers concluded, "In particular, the combination valproate-imatinib downregulated the expression of Bcr-Abl and the antiapoptotic protein Bcl-2, which is particularly overexpressed in imatinib-resistant clones. Data from this study suggested that administration of the clinically available HDAC inhibitor valproate may be a powerful strategy to enhance cytotoxic effects of imatinib in those patient resistant to imatinib or in which complete cytogenetic remission has been not reached."

Morotti and colleagues published their study in Cancer (Valproate enhances imatinib-induced growth arrest and apoptosis in chronic myeloid leukemia cells. Cancer, 2006;106(5):1188-1196).

For additional information, contact A. Morotti, University of Turin, San Luigi Hospital, Dept. Clinic & Biology Science, Gonzole 10, I-10043 Turin, Italy.

Study 2: Human leukemic cells were killed by nuclear entrapment of BCR-ABL.

"The BCR-ABL oncoprotein of chronic myelogenous leukemia (CML) localizes to the cell cytoplasm, where it activates proliferative and antiapoptotic signaling pathways. We previously reported that the combination of the ABL kinase inhibitor imatinib mesylate (IM) and the nuclear export inhibitor leptomycin 8 (LMB) traps BCR-ABL inside the nucleus, triggering the death of the leukemic cells," scientists in Italy reported.

"To evaluate the efficacy of the combination of IM and LMB on human cells, we collected CD34-positive cells from 6 healthy donors and myeloid progenitors from 35 patients with CML," explained A. Aloisi and colleagues, University of Catania. "The sequential addition of IM and LMB generated the strongest reduction in the proliferative potential of the leukemic cells, with limited toxicity to normal myeloid precursors.

"Furthermore, nested reverse transcriptase-polymerase chain reaction (RT-PCR) analysis on colonies representative of each experimental condition demonstrated that the combination of IM and LMB was the most effective regimen in reducing the number of BCR-ABL-positive colonies. The efficacy of the 2-drug association was independent of the clinical characteristics of the patients."

The researchers concluded, "Our results indicate that strategies aimed at the nuclear entrapment of BCR-ABL efficiently kill human leukemic cells, suggesting that the clinical development of this approach could be of significant therapeutic value for newly diagnosed and IM-resistant CML patients."

Aloisi and colleagues published their study in Blood (BCR-ABL nuclear entrapment kills human CMIL cells: ex vivo study on 35 patients with the combination of imatinib mesylate and leptomycin B. Blood, 2006;107(4):1591-1598).

For more information, contact P. Vigneri, University of Catania, Dept. Biomedical Science, Sect General Pathology, Via Androne 83, I-95124 Catania, Italy.

Study 3: 3-substituted benzamide derivatives could be used to treat chronic myeloid leukemia (CML).

According to recent research published in the journal Bioorganic & Medicinal Chemistry Letters, "A series of 3-substituted benzamide derivatives structurally related to STI-571 (imatinib mesylate), a Bcr-Abl tyrosine kinase inhibitor used to treat CML, was prepared and evaluated for antiproliferative activity against the Bcr-Abl-positive leukemia cell line K562."

"About ten 3-halogenated and 3-trifluoromethylated benzamide derivatives were identified as highly potent Bcr-Abl kinase inhibitors," explained T. Asaki and colleagues, Nippon Shinyaku Co.

The researchers concluded, "One of these, NS-187 (9b), is a promising new candidate Bcr-Abl inhibitor for the therapy of STI-571-resistant chronic myeloid leukemia."

Asaki and colleagues published their study in Bioorganic & Medicinal Chemistry Letters (Design and synthesis of 3-substituted benzamide derivatives as Bcr-Abl kinase inhibitors. Bioorg Med Chem Lett, 2006;16(5):1421-1425).

For additional information, contact T. Asaki, Nippon Shinyaku Co. Ltd, Discovery Research Laboratories, Minami Ku, 14 Nishinosho Monguchi Cho, Kyoto 6018550, Japan.

Keywords: Kyoto, Japan, Antiproliferative Activity, Bcr Abl, Chronic Myeloid Leukemia, Imatinib, Inhibitor, Oncology, Proteins, Proteomics, Structure Activity, Cancer Therapy, Tyrosine Kinase.

This article was prepared by Clinical Oncology Week editors from staff and other reports. Copyright 2006, Clinical Oncology Week via NewsRx.com.