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)

Recent data have renewed the interest for arsenic-containing compounds as anticancer agents. In particular, arsenic trioxide (As2O3) has been demonstrated to be an effective drug in the treatment of acute promyelocytic leukemia by inducing programmed cell death in leukemic cells both in vitro and in vivo. This prompted us to study the in vitro effects of As2O3 and of another arsenical derivative, the organic compound melarsoprol, on human myeloma cells and on the plasma cell differentiation of normal B cells. At pharmacological concentrations (10(-8) to 10(-6) mol/L), As2O3 and melarsoprol caused a dose- and time-dependent inhibition of survival and growth in myeloma cell lines that was, in some, similar to that of acute promyelocytic leukemia cells. Both arsenical compounds induced plasma cell apoptosis, as assessed by 4',6-diamidino-2-phenylindole staining, detection of phosphatidylserine at the cell surface using annexin V, and by the terminal deoxynucleotidyl transferase-mediated nick end labeling assay. As2O3 and melarsoprol also inhibited viability and growth and induced apoptosis in plasma-cell enriched preparations from the bone marrow or blood of myeloma patients. In nonseparated bone marrow samples, both arsenical compounds triggered death in myeloma cells while sparing most myeloid cells, as demonstrated by double staining with annexin V and CD38 or CD15 antibodies. In primary myeloma cells as in cell lines, interleukin 6 did not prevent arsenic-induced cell death or growth inhibition, and no synergistic effect was observed with IFN-alpha. In contrast to As2O3, melarsoprol only slightly reduced the plasma cell differentiation of normal B cells induced by pokeweed mitogen. Both pokeweed mitogen-induced normal plasma cells and malignant plasma cells showed a normal nuclear distribution of PML protein, which was disrupted by As2O3 but not by melarsoprol, suggesting that the two arsenical derivatives acted by different mechanisms. These results point to the use of arsenical derivatives as investigational drugs in the treatment of multiple myeloma.
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PMID:Arsenic trioxide and melarsoprol induce apoptosis in plasma cell lines and in plasma cells from myeloma patients. 1007 Sep 61

All-trans retinoic acid (ATRA) is currently widely used in the therapy of acute promyelocytic leukemia and is being tested in vitro and in vivo on several other malignancies. Previously ATRA has been shown to inhibit the growth in vitro, of established human myeloma cell lines as well as cultured primary myeloma cells from patients. ATRA acts by down-regulating IL-6-receptor-alpha or gp130 on the surface of the myeloma cells. However, despite its in vitro effects on myeloma cells, ATRA therapy on advanced stage multiple myeloma (MM) patients has so far largely been ineffective. In current studies, we have assessed the efficacy of ATRA therapy against primary murine plasma cell tumors, which are an animal model for human MM. These tumors are induced at about 50% incidence in pristane-primed BALB/c mice by injection of v-raf/v-myc- containing retroviruses and are IL-6 dependent. Using this animal model, we assessed the effect of ATRA as a therapeutic agent against primary tumors at two early time points in disease development. ATRA was administered in liposomal vesicles (ATRAGEN), since liposomal-ATRA has been shown to circumvent clearance mechanisms by hepatic microsomes, which normally occur with free ATRA. In addition, ATRAGEN was previously shown to be less toxic in mice than free ATRA. ATRAGEN was administered beginning on day 25 or day 45 after virus injection and continued twice weekly for 8-11 weeks. ATRAGEN administration begun at either time point did not alter the incidence or the latency of plasma cell tumors compared with control animals. These results suggest that ATRA may not be an effective sole therapy against early MM.
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PMID:Assessment of all-trans retinoic acid (ATRA) efficacy as a single agent in primary lymphoid neoplasia. 1045 60

Spicamycin is a potent inducer of differentiation of human myeloid leukemia cells (HL-60) and murine myeloid leukemia cells (M1). One of the spicamycin derivatives, KRN5500, shows a broad spectrum of antitumor activity against human tumor xenografts in nude mice. In this study, we first investigated the differentiation efficacy of spicamycin and KRN5500 in HL-60 and acute promyelocytic leukemia cell line, NB4, and found that low concentrations of both compounds induced differentiation to a small extent in both cell lines, but markedly induced apoptosis in NB4 cells. Further investigation in a myeloid leukemia cell line, NKM-1, a lymphoma cell line, Daudi, and a multiple myeloma cell line, NOP-1, showed that high concentrations of both compounds also induced apoptosis in these cells. The 50% inhibitory concentration (IC(50)) determined by 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that myeloid cells were more sensitive to both compounds than lymphoid cells, and spicamycin was more potent than KRN5500. Western blot analysis of Bcl-2, Bcl-xL and Bax expression and immunofluorescence analysis of promyelocytic leukemia (PML) protein indicated that apoptosis induced by spicamycin and KRN5500 was associated with down-regulation of Bcl-2 expression and modulation of PML protein. Thus, spicamycin and KRN5500 may be useful for the treatment of myeloid and lymphoid neoplasms.
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PMID:Spicamycin and KRN5500 induce apoptosis in myeloid and lymphoid cell lines with down-regulation of bcl-2 expression and modulation of promyelocytic leukemia protein. 1087 12

A novel therapeutic potential for acute promyelocytic leukemia using arsenic trioxide (As(2) O(3) ) has been reported. Recent in vitro studies demonstrated that As(2) O(3) effectively inhibits the growth of some cell lines derived from patients with malignant lymphoma, chronic lymphocytic leukemia and multiple myeloma. Adult T-cell leukemia (ATL) is an aggressive neoplasm of mature T-cell origin caused by human T-cell leukemia virus type-I (HTLV-I) the prognosis of which still remains very poor. A possible role of As(2) O(3) for the treatment of ATL is demonstrated from evidence that As(2) O(3) significantly inhibits the growth of HTLV-I infected T-cell lines and induces apoptosis in fresh ATL cells at clinically achievable concentration of the agent. The growth inhibition of As(2) O(3) treated HTLV-I infected T-cell lines was induced by both apoptosis and G(1) phase accumulation. Cleaved bcl-2 protein and an enhanced expression of bak protein in the cells were coincidentally observed during As(2) O(3) treatment. A broad spectrum caspase inhibitor, z-Val-Ala-DL-Asp-fluoromethylketone inhibited the apoptosis induced by As(2) O(3). Increased expression of p53, Cip1/p21 and Kip1/p27, and dephosphorylation of retinoblastoma protein (pRb) were detected in the As(2) O(3) treated cells. In conclusion, As(2) O(3) might become a new therapeutic tool in the treatment of ATL as As(2) O(3) induces apoptosis by destruction of the bcl-2 protein and enhancement of the bak protein production proceeding to activate caspases, and also induces G(1) phase accumulation by enhancement of p53, Cip1/p21, Kip1/p27 and dephosphorylation of pRb to HTLV-I infected T-cell lines.
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PMID:Arsenic trioxide and the growth of human T-cell leukemia virus type I infected T-cell lines. 1104 29

Arsenic trioxide (AT) has been the object of renewed interest as a therapeutic since studies in China in the late 1980s confirmed its efficacy in the treatment of acute promyelocytic leukemia (APL). These studies have been replicated in the West, with complete remissions achieved in 80% to 90% of patients with refractory or relapsed APL. The drug has been relatively well tolerated. The dose used for treatment of APL (0.15 mg/kg/d) is approximately 50% of the maximum-tolerated dose (MTD). Common side effects have included fatigue, rash, fluid retention, and QTc-interval prolongation on electrocardiogram. A "retinoic acid syndrome," similar in its manifestations to that noted after administration of all-trans retinoic acid (RA), has been observed in APL patients. Recent studies have included dose-ranging trials to determine pharmacokinetics and the optimum schedule of administration, and studies of possible mechanisms of action. Promising future trials include combining AT with RA in the treatment of newly diagnosed APL, and broadening the range of AT therapy to other leukemias, lymphomas, multiple myeloma and some solid tumors.
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PMID:Arsenicals in hematologic cancers. 1104 17

Arsenic trioxide inhibits growth and promotes apoptosis in many different cancer cell lines. The National Cancer Institute is working cooperatively with research centers across the U.S. to evaluate its clinical activity in hematologic malignancies, such as acute promyelocytic leukemia, acute myeloid leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, non-Hodgkin's lymphoma, Hodgkin's disease, chronic lymphocytic leukemia, myelodysplastic syndrome, and multiple myeloma. It is also supporting research in solid tumors, such as advanced hormone-refractory prostate cancer and renal cell cancer and in cervical cancer and refractory transitional cell carcinoma of the bladder. The safety and pharmacokinetics of arsenic trioxide are also being evaluated in pediatric patients with refractory leukemia and lymphoma. The results of these ongoing studies should provide important insights into the clinical utility of arsenic trioxide in these diseases.
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PMID:Clinical trials of arsenic trioxide in hematologic and solid tumors: overview of the National Cancer Institute Cooperative Research and Development Studies. 1133 37

Imexon is a cyanoaziridine derivative that has antitumor activity in multiple myeloma. Previous studies have shown that imexon induces oxidative stress and apoptosis in the RPMI 8226 myeloma cell line. This study reports that imexon has cytotoxic activity in other malignant cell lines including NCI-H929 myeloma cells and NB-4 acute promyelocytic leukemia cells, whereas normal lymphocytes and U266 myeloma cells are substantially less sensitive. Flow cytometric experiments have shown that imexon treatment is associated with the formation of reactive oxygen species (ROS) and the loss of mitochondrial membrane potential (Deltapsi(m)) in imexon-sensitive myeloma cell lines and NB-4 cells. In contrast, reduction of Deltapsi(m) and increased levels of ROS were not observed in imexon-resistant U266 cells. Treatment of imexon-sensitive RPMI 8226 cells with the antioxidant N-acetyl-L-cysteine (NAC) protects cells against these effects of imexon. Mitochondrial swelling was observed by electron microscopy in RPMI 8226 myeloma cells treated with 180 microM imexon as early as 4 hours. Damage to mitochondrial DNA was detected by a semiquantitative polymerase chain reaction assay in imexon-treated RPMI 8226 cells; however, nuclear DNA was not affected. Finally, partial protection of RPMI 8226 cells against the imexon effects was achieved by treatment with theonyltrifluoroacetone, an inhibitor of superoxide production at mitochondrial complex II. These changes are consistent with mitochondrial oxidation and apoptotic signaling as mediators of the growth inhibitory effects of imexon. Interestingly, oxidative damage and decrease of Deltapsi(m) induced by imexon highly correlates with sensitivity to imexon in several myeloma cell lines and an acute promyelocytic leukemia cell line. (Blood. 2001;97:3544-3551)
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PMID:Induction of mitochondrial changes in myeloma cells by imexon. 1136 49

Multiple myeloma (MM) is a clonal B-cell malignancy characterized by slow-growing plasma cells in the bone marrow (BM). Patients with MM typically respond to initial chemotherapies; however, essentially all progress to a chemoresistant state. Factors that contribute to the chemorefractory phenotype include modulation of free radical scavenging, increased expression of drug efflux pumps, and changes in gene expression that allow escape from apoptotic signaling. Recent data indicate that arsenic trioxide (As(2)O(3)) induces remission of refractory acute promyelocytic leukemia and apoptosis of cell lines overexpressing Bcl-2 family members; therefore, it was hypothesized that chemorefractory MM cells would be sensitive to As(2)O(3). As(2)O(3) induced apoptosis in 4 human MM cell lines: 8226/S, 8226/Dox40, U266, and U266/Bcl-x(L). The addition of interleukin-6 had no effect on cell death. Glutathione (GSH) has been implicated as an inhibitor of As(2)O(3)-induced cell death either through conjugating As(2)O(3) or by sequestering reactive oxygen induced by As(2)O(3). Consistent with this possibility, increasing GSH levels with N-acetylcysteine attenuated As(2)O(3) cytotoxicity. Decreases in GSH have been associated with ascorbic acid (AA) metabolism. Clinically relevant doses of AA decreased GSH levels and potentiated As(2)O(3)-mediated cell death of all 4 MM cell lines. Similar results were obtained in freshly isolated human MM cells. In contrast, normal BM cells displayed little sensitivity to As(2)O(3) alone or in combination with AA. Together, these data suggest that As(2)O(3) and AA may be effective antineoplastic agents in refractory MM and that AA might be a useful adjuvant in GSH-sensitive therapies. (Blood. 2001;98:805-813)
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PMID:Ascorbic acid enhances arsenic trioxide-induced cytotoxicity in multiple myeloma cells. 1146 82

The cytotoxic activity of the non-steroidal anti-inflammatory agent ibuprofen to human promyelocytic leukemia cell line HL-60, its multidrug-resistant subline HL-60/VCR (MDR-1 gene coded P-glycoprotein), as well as myeloma U266 and B-lymphoblastoid ARH-77 cell lines was demonstrated with the aid of flow cytometric analysis. Ibuprofen inhibited proliferation and induced apoptosis (detected as sub-G0 nuclei, fluorescein diacetate staining, Annexin-V binding cells and agarose electrophoretic detection of nucleosomal DNA fragmentation) in promyelocytic cells and, to a lesser extent, in U266 and ARH-77 cells.
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PMID:Non-steroidal anti-inflammatory agent ibuprofen-induced apoptosis, cell necrosis and cell cycle alterations in human leukemic cells in vitro. 1158 91

In this paper the use of arsenic compounds as anticancer agents in clinical trials and in in vitro investigations is reviewed, including the experience at our institute. Treatment of newly diagnosed and relapsed patients with acute promyelocytic leukemia (APL) with arsenic trioxide (As2O3) has been found to result in complete remission (CR) rates of 85-93% when given by intravenous infusion for 2-3 h at a dose of 10 mg/day diluted in 5% glucose saline solution. Patients exhibit a response in 28-42 days. CR rates after administration of Composite Indigo Naturalis tablets containing arsenic sulfide and of pure tetraarsenic tetrasulfide reached 98% and 84.9%, respectively. At higher concentrations (1-2 microM), arsenic induced apoptosis, while at lower concentrations (0.1-0.5 microM), it triggered cell differentiation in vitro. As2O3-induced apoptosis has been observed in many cancer cell lines, including esophageal carcinoma, gastric cancer, neuroblastoma, lymphoid malignancies, and multiple myeloma. Its effectiveness was confirmed in the treatment of multiple myeloma. Arsenic compounds are effective agents in the treatment of APL and their activity against other types of cancer requires further investigation.
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PMID:Arsenic compounds as anticancer agents. 1158 71


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