Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hematological malignancies including acute leukemia, and multiple myeloma are disorders characterized by the accumulation of neoplastic hematopoietic cells, resulting in aggressive clinical manifestations with poor prognosis. The therapeutic approach to these disorders is basically chemotherapy for achieving complete remission based on the concept of total cell kill. However, severe side effects and complications such as serious infection and bleeding due to anti-cancer drugs are major problems in the clinical setting. In addition, repeated episodes of relapse of the disease may lead to refractory or chemotherapy-resistant disorders. These problems are occurred because anti-cancer agents have effects on both cancer cells and normal hematopoietic cells. The clinical evidences thus suggest the limitations of the chemotherapy for hematological malignancies: novel effective therapeutic approaches with less toxicity are therefore actively being sought. Differentiation-inducing therapy employing a physiologically active derivative of vitamin A, all-trans retinoic acid (ATRA), brought remarkably advances in the therapeutic outcome of APL at the end of last century. More recently, the clinical success of imatinib mesylate (STI571), potent competitive inhibitor of the Bcr/Abl protein tyrosine kinase, in the treatment of CML has focused enthusiasm toward molecular targeted therapy for the hematological malignancies. The therapeutic activity of these agents can be explained by their abilities to modify cellular growth, differentiation, and apoptosis in cells by activating unknown gene programs that molecular cellular proliferation. We have actively sought out new agents among natural products and cytokines with the ability to induce cellular differentiation and apoptosis. In this symposium, I will present our recent data of these novel compounds and their molecular mechanisms for inducing differentiation and apoptosis of hematological malignant cells.
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PMID:A novel therapeutic approach for hematological malignancies based on cellular differentiation and apoptosis. 1243 Aug 59

Significant advances have been made in the development of targeted interventions for hematologic malignancies. Progress has been made in defining the molecular pathogenesis of human leukemias. Data indicate that nonrandom, somatically acquired translocations, inversions, and other abnormalities occur in many acute leukemias. In the treatment of acute promyelocytic leukemia (APL), targeted therapy with all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy leads to dramatic improvements in disease-free survival. Imatinib mesylate, a signal transduction inhibitor that inhibits tyrosine kinase activity, the protein product of the ABL proto-oncogene, has remarkable activity in patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (Ph(+)) acute lymphoblastic leukemia (ALL). Farnesyltransferase inhibitors (FTIs), a promising class of agents that target multiple pathways including Ras proteins, are potential anticancer therapy for a wide range of malignancies, including leukemias and myelodysplastic syndromes (MDS). There also is evidence that recombinant human erythropoietin therapy (r-HuEPO) can benefit patients with chronic lymphocytic leukemia (CLL), multiple myeloma, and lymphomas. This supplement will discuss advances in our understanding of human leukemias, including the use of unconjugated monoclonal antibodies such as Campath-1H (Wellcome, Beckenham, UK, and Ilex Oncology, San Antonio, TX) and rituximab and immunoconjugates such as gemtuzumab ozogamicin and BL-22. Although these novel therapies are beginning to fulfill their promise, continued research efforts are needed to determine the optimal role of targeted therapy in acute and chronic leukemias.
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PMID:Advancing the treatment of hematologic malignancies through the development of targeted interventions. 1244 45

The synthetic retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (AHPN/CD437) appears to possess an apoptotic activity superior to classical retinoids in vitro as in vivo. Numerous studies have shown that CD437-induced apoptosis is independent of its nuclear receptor activity, suggesting that CD437 might have a unique mechanism of action. The purpose of this study was to compare CD437- and all-trans retinoic acid (atRA)-induced cell death. CD437 provoked a rapid apoptotic phenotype immediately followed by secondary necrosis in RPMI 8226, U266 and L363 human myeloma cell lines. Nuclear apoptotic features were observed upon both CD437 and atRA treatments. In contrast, membrane blebbing and the subsequent formation of apoptotic bodies, a classical apoptotic event, was only observed upon atRA treatment. In addition, CD437, contrary to atRA, was unable to induce tissue transglutaminase (tTG), an intracellular enzyme involved in the formation of cross-linked protein polymers contributing to apoptotic morphological changes. Taken together, these data suggest that CD437 induces rapid but incomplete apoptotic phenotype in human myeloma cells.
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PMID:The novel retinoid AHPN/CD437 induces a rapid but incomplete apoptotic response in human myeloma cells. 1258 72

Chromosomal band 1p34-36 is a commonly rearranged locus in many types of cancers. We cloned the breakpoint region of a chromosomal translocation, t(1;14)(p34;q32), found in the human multiple myeloma (MM) cell line, ODA. This rearrangement occurred between the nearby switch region of the immunoglobulin heavy chain (IgH) gene (Sgamma3) at 14q32 and the first intron of the human retinoic acid-inducible E3 protein (E3)/lysosome-associated protein, transmembrane-5 (LAPTm5) gene at the 1p34 locus. Consequently, the E3 gene, which is a hematopoietic cell-specific transcript induced by retinoic acid and located at the rearranged allele, was interrupted within its coding region and was not expressed in the ODA cell line in spite of the other allele still being intact. The expression derived from the remaining intact allele in ODA cells was silenced by DNA methylation at sequences within the first intron around a GC-rich EagI site. Interestingly, the silenced expression of E3 mRNA due to DNA methylation of intron 1 sequences was frequently encountered in MM cells [6/10 (60%) of MM cell lines tested], while E3 is expressed in normal plasma cells and in most other hematopoietic cell lines including those of B-cell lineage. Thus, as the E3 protein has been suggested to be involved in cellular differentiation and apoptotic pathways in certain cell types, our results suggest that loss of E3 gene expression might be a crucial event during the progression of human MM.
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PMID:Inactivation of the E3/LAPTm5 gene by chromosomal rearrangement and DNA methylation in human multiple myeloma. 1288 55

All-trans retinoic acid (ATRA) is a natural oxidative metabolite of Vitamin A (retinol) and is known to be a regulator of cell proliferation differentiation, especially in various malignant cells. The cyto-differentiating action of ATRA has led to its usage in the treatment of several malignancies, particularly acute promyelocytic leukemia (APL). There have been many reports regarding the cell biological effects of ATRA on human myeloma cells and a few clinical trials. Most of these reports have revealed growth inhibition by ATRA mediated by down-regulation of the IL-6/IL-6R auto/paracrine loop, and upregulation of p21/Cip1. Here, we review previous reports and introduce experimental results obtained using various myeloma cell lines established in our laboratory.
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PMID:Effects of all-trans retinoic acid (ATRA) on human myeloma cells. 1469 15

We previously showed that HIV-1 protease inhibitors slowed the proliferation of human myeloid leukemia cells and enhanced their differentiation in the presence of all-trans retinoic acid (ATRA). In this study, we found that protease inhibitors, including ritonavir, saquinavir, and nelfinavir, but not indinavir, induced growth arrest and apoptosis of U266, RPMI8226, and ARH77 human multiple myeloma (MM) cells in association with down-regulation of antiapoptotic protein Mcl-1. Also, protease inhibitors inhibited the survival of freshly isolated MM cells from patients. In contrast, these protease inhibitors did not affect survival of normal B cells and colony formation of myeloid committed stem cells (CFU-GM) from healthy volunteers. In addition, we found that all of the protease inhibitors, except for indinavir, blocked interleukin-6 (IL-6)-stimulated phosphorylation of both signal transducer and activator of transcription 3 (STAT 3) and extracellular signal-regulated kinase 1/2 in U266 and RPMI8226 MM cells. Moreover, the protease inhibitors inhibited both the basal and IL-6-stimulated STAT 3/DNA binding activity in U266 cells as measured by an ELISA-based assay. Furthermore, ritonavir inhibited production of vascular endothelial growth factor one of the targets of STAT 3, in U266 and RPMI8226 cells as measured by ELISA. Taken together, protease inhibitors might be useful for treatment of individuals with MM.
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PMID:HIV-1 protease inhibitor induces growth arrest and apoptosis of human multiple myeloma cells via inactivation of signal transducer and activator of transcription 3 and extracellular signal-regulated kinase 1/2. 1507 91

All-trans retinoic acid (ATRA) is a derivative of vitamin A. ATRA inhibits the growth of human myeloma cell lines and freshly isolated myeloma cells in vitro mainly by down-regulating interleukin-6 receptor. Clinically, however, ATRA alone has not been efficacious and adverse events, notably hypercalcemia, have been common. In the present study 10 patients with stable multiple myeloma after conventional chemotherapy received ATRA alone for 2 months, followed by a combination of ATRA and the chemotherapy regimen during which no further reduction of the paraprotein had occurred. The purpose of the combination therapy was to sensitize the myeloma cells with ATRA to chemotherapy by blocking the growth-promoting effect of IL-6. Although ATRA was well tolerated, ATRA alone lacked clinical efficacy. The combination therapy resulted minimal responses in 4 patients and relatively long progression-free survival in 4 patients was achieved. In 3 of these responding patients serum concentrations of interleukin-6 and/or soluble interleukin-6 receptor were elevated prior to the study. The bone marrow cells of responding patients were sensitive to ATRA in vitro. These results show that ATRA alone is not effective to treat multiple myeloma. There may be some beneficial effect of ATRA in combination chemotherapy in selected patients who have activated IL-6 signaling.
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PMID:Treatment of multiple myeloma with all-trans retinoic acid alone and in combination with chemotherapy: a phase I/II trial. 1516 Sep 51

Multiple myeloma is essentially an incurable malignancy and it is therefore of great interest to develop new therapeutic approaches. We previously reported that human B cell-lymphomas express the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) and are killed by PPARgamma ligands. Herein, we investigate the therapeutic potential of PPARgamma ligands for multiple myeloma. The human multiple myeloma cell lines ANBL6 and 8226 express PPARgamma mRNA and protein. The PPARgamma ligands, 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) and ciglitazone, induced multiple myeloma cell apoptosis as determined by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay, loss of mitochondrial membrane potential, and caspase activation. Importantly, the ability of PPARgamma ligands to kill both multiple myeloma cell lines was not abrogated by Interleukin-6 (IL-6), a multiple myeloma growth survival factor. Finally, the RXR ligand 9-cis retinoic acid (9-cis RA) in combination with PPARgamma ligands greatly enhanced multiple myeloma cell killing. These new findings support that PPARgamma ligands may represent a novel therapy for multiple myeloma.
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PMID:Human multiple myeloma cells express peroxisome proliferator-activated receptor gamma and undergo apoptosis upon exposure to PPARgamma ligands. 1545 78

The peroxisome proliferator-activated receptor gamma (PPAR gamma) is a member of the nuclear receptor family that forms heterodimers with retinoid X receptor. These heterodimers bind to DNA and activate the transcription of target genes. Here, we report that the PPAR gamma receptor protein is expressed in primary myeloid and lymphoid leukemias and in lymphoma and myeloma cell lines. In this study, we compared the activity of several PPAR gamma ligands including BRL49653 (rosiglitazone), 15-deoxy-Delta 12,14-prostaglandin J(2), and the novel triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid on leukemia cells. Exposure to these PPAR gamma ligands induced apoptosis in myeloid (U937 and HL-60) and lymphoid (Su-DHL, Sup-M2, Ramos, Raji, Hodgkin's cell lines, and primary chronic lymphocytic leukemia) cells. A similar exposure to these PPAR gamma ligands induced the differentiation of myeloid leukemic cells. A combination of PPAR gamma ligands with a retinoid X receptor agonist (i.e., LG100268) or a retinoic acid receptor agonist (i.e., all trans-retinoic acid) enhanced differentiating and growth-inhibitory effects. 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic acid induced differentiation and apoptosis with much greater potency than the other PPAR gamma ligands in established cell lines and primary chronic lymphocytic leukemia samples. Exposure to 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid induced mitochondrial depolarization and caspase activation, which was associated with apoptosis induction. In Bcl-2-overexpressing chronic lymphocytic leukemia cells, the small-molecule Bcl-2 inhibitor HA14-1 sensitized these cells to 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid-induced apoptosis. These results suggest that PPAR gamma ligation alone and in combination with retinoids holds promise as novel therapy for leukemias by activating the transcriptional activity of target genes that control apoptosis and differentiation in leukemias.
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PMID:Peroxisome proliferator-activated receptor gamma and retinoid X receptor ligands are potent inducers of differentiation and apoptosis in leukemias. 1548 92

It is well known that the differentiation of acute promyelocytic leukaemia (APL) cells by all-trans-retinoic acid (ATRA) may be enhanced by myeloid growth factors, but the requirement for growth factors in this process is unclear. Our previous studies in multiple myeloma and non-APL acute myeloid leukaemia demonstrated that lineage-specific growth factors are required for the maximal activity of many pharmacologic differentiating agents in vitro. Thus, we studied whether the differentiation of APL is similarly dependent on growth factors. We found that the myeloid growth factors granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor markedly increased the differentiation of NB4 cells or APL blasts from clinical samples treated with ATRA, arsenic trioxide (ATO), or bryostatin-1 as evidenced by the enhanced expression of myeloid surface antigens and the inhibition of clonogenic growth. Furthermore, myeloid growth factors were necessary for the differentiation of APL cells since the activity of each pharmacologic agent could be blocked by specific growth factor-neutralizing antibodies. Each differentiating agent was active only at concentrations that inhibited cell cycling, suggesting that this property is also required for differentiation. These data demonstrate that both pharmacologic differentiating agents and myeloid growth factors are required, but neither sufficient, for the differentiation of APL cells. The combined use of pharmacologic differentiating agents and growth factors may improve the clinical efficacy of differentiation therapy in APL.
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PMID:Requirement for myeloid growth factors in the differentiation of acute promyelocytic leukaemia. 1575 92


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