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)

Vitamin C was shown to be an essential requirement for the growth of mouse myeloma cells in an in vitro colony assay. Human leukemia (acute nonlymphocytic leukemia) cell colonies grow well in a similar in vitro culture system, and vitamin C has been shown to enhance the growth of leukemic cell colonies in 77 (35%) of 219 leukemic patients while none of 34 normal bone marrows tested simultaneously shows growth enhancement by this vitamin. This vitamin C effect is reproducible in repeated experiments in same patients, specific to this vitamin, selective for leukemic cells, and is proven to be biological in nature. Further, leukemic cells are mobilized back and forth between cycling and resting states with vitamin C supplementation/depletion. Our more recent study indicates that the preleukemia (myelodysplastic syndrome), generally known to be related to acute nonlymphocytic leukemia, has similar pattern in terms of vitamin C sensitivity, with 8 of 25 patients (32%) showing the growth enhancement with this vitamin.
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PMID:Vitamin C in leukemia and preleukemia cell growth. 336 76

Monoclonal antibodies were obtained after fusion of mouse P3X63-AG.8.653 myeloma cells with spleen cells isolated from BALB/cCr mice immunized with denatured DNA modified by 1-nitrosopyrene reduced with sodium ascorbate (AP-d-DNA) and complexed electrostatically to methylated bovine serum albumin. Ten stable hybridoma lines have been isolated and characterized by enzyme-linked immunosorbent assay (ELISA). They all recognize 1-aminopyrene (1-AP)-modified DNA, but not free 1-nitropyrene or 1-aminopyrene. Antibody 11H2 is the most specific for AP-DNA showing no cross-reactivity with unmodified native DNA. It also recognizes 8-nitro-1-AP and 6-nitro-1-AP modified DNA. There was some low cross-reactivity with DNA modified by a benzo[a]pyrene diol epoxide and N-acetoxy-N-2-acetylaminofluorene. Competitive ELISA with antibody 11H2 reliably detected AP-DNA adducts formed when 1-nitropyrene was incubated with Salmonella typhimurium TA1538. By immunological methods, AP-DNA adducts were shown to be unstable to heat denaturation. This suggests that specific monoclonal antibodies to carcinogen-DNA adducts will be useful not only for detecting and quantitating carcinogen-DNA damage but also for probing adduct stability.
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PMID:Monoclonal antibodies to 1-aminopyrene-DNA. 402 27

It is well documented that despite global abnormalities of the immune system in AIDS and other immune deficiency diseases or in immunosuppressed patients, the incidence of only a few kinds of tumor increases, and that the degree of immunosuppression seems not to be a critical factor in the development of even these tumors. The fact that tumors do not develop in the majority of population during their lifetime, despite the ineffectiveness of the known immune system against the majority of tumors, can only be explained by hypothesizing that the living system has an additional defense mechanism against tumors. On the bases of literary data, it can be assumed that the effective agents of this defense mechanism are certain substances of the circulatory system. We proved this hypothesis by being able to select thirteen substances of the circulatory system from 71 compounds tested, using the synergistic tumor cell-killing effect as criteria. The mixture containing the thirteen substances (L-tryptophan, L-tyrosine, L-methionine, L(-)-malate, L-ascorbate, L-arginine, L-phenylalanine, L-histidine, 2-deoxy-D-ribose, d-biotin, pyridoxine, adenine and riboflavin) had a cytotoxic effect against Sp2/0-Ag14 mouse and K562, HEp-2, HeLa and Caco-2 human tumor cell lines in well-controlled conditions, but it was not cytotoxic against Vero normal cell line. The mixture of the above substances increased significantly the survival time of mice (T/C% 148.1) injected i.p. with Sp2/0-Ag14 mouse myeloma cells by killing more than 2 logs (99%) of the cells. Approximately the same 2 logs cell kill was found counting the Sp2/0-Ag14 cells in the ascitic fluid of control and treated animals after finishing treatment. The above mixture slowed down the growth of HeLa solid tumor significantly (T/C%, the least value 35.7). The weight loss of control and treated group during treatment did not differ significantly.
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PMID:Inhibition of the growth of a murine and various human tumor cell lines in culture and in mice by mixture of certain substances of the circulatory system. 766 76

Organ toxicity in BMT may in part be due to free radical damage. Therefore the 'Total Radical-trapping Antioxidant Parameter of plasma' (TRAP), individual plasma antioxidants, serum iron and linoleic acid, a main substrate of lipid peroxidation, were monitored before and after BMT, and they were compared with values obtained from healthy controls. Seven patients (3 AML, 3 CML, 1 multiple myeloma) receiving 16 mg/kg busulfan, 30-45 mg VP-16 and 120 mg/kg cyclophosphamide were investigated. TRAP values declined during chemotherapy by about 40% (day -9: 1019 +/- 245 mumol/l, mean +/- s.d.; day 0: 660 +/- 164 mumol/l; P < 0.05). The concentration of uric acid, one of the main antioxidants in plasma, decreased markedly (day -9: 339 +/- 108 mumol/l, day 0: 148 +/- 61 mumol/l; P < 0.05) and paralleled TRAP values. Vitamin E and bilirubin did not change from day -9 to 0 whereas vitamin C increased (day -9: 46 +/- 16 mumol/l, day 0: 89 +/- 44 mumol/l; P < 0.05). Serum iron rapidly increased within the pre-transplantation period, reaching values normally seen only in iron overload (day -9: 11.8 +/- 5.2 mumol/l, day 0: 40.6 +/- 6.5 mumol/l; P < 0.05). Linoleic acid levels were normal at the start and decreased substantially (27.0 +/- 1.6 wt% at day -9; 15.7 +/- 4.9 wt% at day 0; P < 0.05), indicating possible lipid peroxidation during high-dose chemotherapy. In conclusion, complex monitoring of the antioxidant status before and after BMT revealed a breakdown of plasma antioxidant defence and of radical-vulnerable lipids, which was associated with high circulating levels of iron.
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PMID:Deteriorating free radical-trapping capacity and antioxidant status in plasma during bone marrow transplantation. 767 Apr 3

Serum vitamin B(12) radioimmunoassays may give falsely low results in patients with folate deficiency, multiple myeloma, megadose of vitamin C and following radioisotope organ scan. We evaluated 10 consecutive healthy women on oral contraceptives (OC) who had falsely low vitamin B(12) levels, as reflected by normal urine methylmalonic acid and plasma homocysteine. After 1-month cessation of OCs, vitamin B(12) returned to the normal range in all women. Transcobalamin I (TCI) blood level was decreased in 60% of patients. OCs may cause temporary low vitamin B(12) blood levels of no clinical significance that can be associated with low TCI levels
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PMID:Oral contraceptives can cause falsely low vitamin B(12) levels. 1111 Nov 17

There is growing evidence that proteins are early targets of reactive oxygen species, and that the altered proteins can in turn damage other biomolecules. In this study, we measured the effects of proteins on the oxidation of liposome phospholipid membranes, and the formation of protein hydroperoxides in serum and in cultured cells exposed to radiation-generated hydroxyl free radicals. Lysozyme, which did not affect liposome stability, gave 50% protection when present at 0.3 mg/ml, and virtually completely prevented lipid oxidation at 10 mg/ml. When human blood serum was irradiated, lipids were oxidized only after the destruction of ascorbate. In contrast, peroxidation of proteins proceeded immediately. Protein hydroperoxides were also generated without a lag period in hybrid mouse myeloma cells, while at the same time no lipid peroxides formed. These results are consistent with the theory that, under physiological conditions, lipid membranes are likely to be effectively protected from randomly-generated hydroxyl radicals by proteins, and that protein peroxyl radicals and hydroperoxides may constitute an important hazard to biological systems under oxidative stress.
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PMID:Peroxidation of proteins and lipids in suspensions of liposomes, in blood serum, and in mouse myeloma cells. 1199 13

Motexafin gadolinium (MGd), an expanded porphyrin, is a tumor-selective redox-mediator that reacts with many intracellular reducing metabolites. Because redox mechanisms mediate apoptosis in multiple myeloma, we hypothesized that disruption of redox balance by MGd would result in cellular cytotoxicity in myeloma. We examined the effects of MGd on cellular cytotoxicity, apoptosis, reactive oxygen species (ROS) production, and intracellular drug uptake in dexamethasone-sensitive (C2E3), dexamethasone-resistant (1-310 and 1-414) chemotherapy-sensitive (8226-RPMI) and highly chemotherapy-resistant (DOX-10V) myeloma cells. We found complete inhibition of proliferation and cytotoxicity in each sensitive and resistant cell line with 24-hour exposure to clinically relevant concentrations of 50 muM MGd and 50 to 100 microM ascorbate, which was required for the effect. The mechanism of cytotoxicity was related to induction of apoptosis as demonstrated by alteration in mitochondrial membrane potential and elevated annexin V expression. This was accompanied by depletion of intracellular glutathione and increased ROS production. Moreover, catalase substantially abrogated MGd-induced cell death. Using fluorescence microscopy and flow cytometry, we found intracellular uptake of MGd and intracellular ROS production. MGd also induced apoptosis in fresh malignant cells from patients with multiple myeloma. These studies provide a rationale for clinical investigation of this novel redox-mediating agent in patients with multiple myeloma and related disorders.
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PMID:Motexafin gadolinium generates reactive oxygen species and induces apoptosis in sensitive and highly resistant multiple myeloma cells. 1538 78

Although there is no compelling evidence that vitamin C has antitumor activity in humans, clinical trials are testing the hypothesis that ascorbic acid (AA) will enhance the efficacy of arsenic trioxide (As2O3) in myeloma. In vitro, AA cytotoxicity depends on its interaction with free transition metal ions in culture media leading to the generation of H2O2 and other reactive oxygen species (ROSs). Therefore, to circumvent the extracellular in vitro pro-oxidant effects of AA, we loaded HL60, U266, and RPMI-8226 cells with vitamin C by incubation with dehydroascorbic acid (DHA). Loading cells in this manner resulted in prominent, dose-dependent protection of As2O3-treated cells as measured by viability, colony formation, and apoptosis assays. Glutathione depletion enhanced cell sensitivity to the cytotoxic effects of As2O3 and vitamin C loading provided protection. AA was found to generate cytotoxic concentrations of H2O2 in culture medium without cells and copper/iron chelators inhibited this reaction. However, AA did not generate H2O2 in simple buffer or human plasma. Direct incubation with AA resulted in increased intracellular ROSs, whereas DHA incubation decreased it. These results clarify an apparent paradox and indicate that vitamin C loading in HL60, U266, and RPMI-8226 cells ameliorates As2O3 cytotoxicity.
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PMID:Vitamin C protects HL60 and U266 cells from arsenic toxicity. 1567 71

Redox mechanisms have been shown to be important in malignant cell survival and are a system that may be modified for the treatment of hematologic malignancies. Motexafin gadolinium (MGd) is a synthetic expanded porphyrin that selectively accumulates in tumor cells and oxidizes various intracellular metabolites, including ascorbate, nicotinamide adenine dinucleotide phosphate, glutathione, and protein thiols, to generate reactive oxygen species in a process known as futile redox cycling. The rationale for its use in hematologic malignancies is that, like naturally occurring porphyrins, it tends to concentrate selectively in cancer cells, and it has a novel mechanism of action of inducing redox stress and triggering apoptosis in a broad range of malignancies. MGd induces apoptosis in B-cell non-Hodgkin's lymphoma, chronic lymphocytic leukemia, and highly resistant myeloma cell lines. Furthermore, MGd is additive or synergistic with ionizing radiation, several chemotherapy agents, and rituximab in vitro and in vivo tumor models. Through gene expression profiling, various stress-related genes are upregulated in response to MGd, including genes encoding metallothioneins, heat shock proteins, and heme oxygenase. Preliminary results from clinical trials with MGd in hematopoietic malignancies have shown that it is well tolerated, with minimal hematologic side effects in both; it has single agent activity in very heavily pretreated chronic lymphocytic leukemia /small lymphocytic lymphoma patients, and it has induced prompt complete remissions in combination with 90Yttrium-ibritumomab (Y-90 Zevalin; Biogen Idec Inc., Cambridge, MA) for relapsed non-Hodgkin's lymphoma in the first two cohorts of patients enrolled. Various clinical trials studying MGd as a single agent and in combination with radiation and/or chemotherapy for the treatment of hematologic malignancies are ongoing.
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PMID:Motexafin gadolinium induces oxidative stress and apoptosis in hematologic malignancies. 1596 82

Arsenic trioxide (As2O3, Trisenox) is used to treat patients with refractory or relapsed acute promyelocytic leukemia (APL). Its ability to induce apoptosis in various malignant cell lines has made it a potential treatment agent for other malignancies and many clinical trials are currently in progress to evaluate its clinical usefulness for multiple myeloma and glioblastoma cancer. In the present study, we investigated the metabolism of As2O3 regarding its cellular biotransformation and interaction with metallothionein (MT) as a possible protective responses of cells to arsenic-induced cytotoxicity. The study was performed on two types of cell treated with As2O3: (1) human astrocytoma (glioblastoma) cell line U87MG treated with 0.6 microM arsenic for 0, 3, 12, 24, and 48 h or 12 microM arsenic for 3, 6, 12, 24, and 48 h and (2) bone marrow cells (BM) from two patients with multiple myeloma (MM) treated with 7 microM arsenic for 0, 43, and 67 h. Cotreatment with vitamin C (1 mg/mL) was tested in longer exposure of MM BM cells. Traces of methylation products (mainly monomethylarsenic acid) were detected in cell lysates of both cell types and in pellets of U87 MG cells, although we found problems with column-sample interactions in cases where methanol pretreatment of the sample was not used. Pentavalent inorganic arsenic (AsV) was identified in both cell types, and up to 80% of total As in MM bone marrow cell lysates was present as AsV. Such an occurrence (generation) of pentavalent arsenic after As2O3 treatment demonstrates the presence of biological oxidation of trivalent arsenic, which could represent an additional protective mechanism of the cell. Vitamin C decreased As cell content and increased the percentage of pentavalent inorganic arsenic (in the growth medium and cells). The presence of metallothionein (MT) and its response to arsenic treatment was checked in all U87 MG cells, in the control, and in one exposed sample of MM BM cells. During 48 h exposure to 0.6 or 12 muM arsenic MTI/II levels increased in U87 MG cells, but with variable Zn levels, increased Cu levels, and As binding observed in traces only. Involvement of the MT-III isoform was negligible. In contrast, 43 h exposure to 7 microMarsenic did not increase MT content in multiple myeloma cells, and the levels even decreased with respect to the control. To evaluate the importance of the observed processes, MTs in U87 and AsIII-AsV conversion in MM BM cells, which could represent a resistance response of cancer cells treated by As2O3, longer-term observation with different arsenic concentrations should be performed.
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PMID:Arsenic metabolism in multiple myeloma and astrocytoma cells. 1763 24


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