benzyloxycarbonyl-isoleucyl-glutamyl(o-tert-butyl)-alanyl-leucinal and Multiple-Myeloma

The outcome of multiple myeloma has substantially improved over the past decade, mainly due to recently approved drugs, such as thalidomide, lenalidomide, and bortezomib. Nevertheless, most patients still relapse and, therefore, drugs with new mechanisms of action are urgently needed to overcome this resistance. In this Review, we discuss some of the new targeted therapeutic strategies under assessment in preclinical and clinical studies in multiple myeloma. Unfortunately, the single-agent clinical activity of most of these new drugs has been limited; nevertheless, their effectiveness might be enhanced by their rational combination with each other or with conventional agents.

Topics: Antibodies, Monoclonal; Antigens, Surface; Antineoplastic Agents; Apoptosis; Arsenic Trioxide; Arsenicals; Cell Cycle; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Cysteine Proteinase Inhibitors; Depsipeptides; DNA Methylation; Enzyme Inhibitors; Epigenesis, Genetic; Farnesyl-Diphosphate Farnesyltransferase; Heat-Shock Proteins; Histone Deacetylase Inhibitors; Humans; Mitogen-Activated Protein Kinase Kinases; Multiple Myeloma; NF-kappa B; Oligopeptides; Oxides; Peptides, Cyclic; Phosphoinositide-3 Kinase Inhibitors; Protein Kinases; Receptor Protein-Tyrosine Kinases; Receptors, Cell Surface; Signal Transduction; TOR Serine-Threonine Kinases

Topics: Drug Approval; Humans; Multiple Myeloma; Oligopeptides; United States; United States Food and Drug Administration

Multiple myeloma is a neoplasm of mature and immature plasma cells, it remains an incurable disease using conventional chemotherapy and increasing aggressive approaches. In recent years, due to the better understanding of myeloma biology, genetics and tumor formation, there are lots of new active drugs or combinational chemotherapy regimens having been developed, such as proteasome inhibitors, immunomodulatory agents etc, they are more effective than conventional chemotherapy. This article summarizes the recent advances with the new options for the treatment of multiple myeloma.

Topics: Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Hematopoietic Stem Cell Transplantation; Humans; Multiple Myeloma; Oligopeptides

The proteasome inhibitor PSI is potently cytotoxic in vitro against human chronic myeloid leukemia (CML) and acute myeloid leukemias (AML). Here, we have tested proteasome inhibitor I (PSI) in a panel of 11 human multiple myeloma (MM) cell lines and found that it has antiproliferative activity, with an IC50 between 4.5 and 557 nM at 48 h. PSI potentiated the toxicity of a number of chemotherapeutic agents in myeloid leukemia but not in MM cell lines, while in combination with therapeutic proteasome inhibitor PS-341 (Bortezomib) it had a synergistic effect. PSI suppressed the growth of AML cell lines more effectively than PS-341. CFU-GM colony assays revealed that CD34+ bone marrow progenitors from CML and AML patients were more sensitive to PSI than those from normal subjects (IC50: 5, 15 and 50 nM for AML, CML and normal, respectively). Moreover, the growth of normal primitive progenitors (LTC-IC) was unaffected by 15 nM PSI (P=0.576). PSI-induced cell death required RNA transcription and protein synthesis, but not DNA replication, was accompanied by the upregulation of Bcl-2 and modest reduction of Bax and Bcl-XL proteins, and involved the activation of caspases 2, 3, 7 and 8. These findings lend additional support to preclinical investigations with PSI.

Topics: Antineoplastic Agents; Caspases; Cell Line, Tumor; Cell Proliferation; Cysteine Proteinase Inhibitors; Drug Synergism; Gene Expression Regulation, Neoplastic; Humans; Inhibitory Concentration 50; Leukemia, Myeloid; Multiple Myeloma; Neoplastic Stem Cells; Oligopeptides; Proto-Oncogene Proteins c-bcl-2; Transcription, Genetic; Tumor Cells, Cultured