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)

Somatomedin C, also called insulin-like growth factor I (Sm-C/IGF-I), is a highly conserved polypeptide required for the proliferation of many cell types. Since several attempts in our laboratory to recover monoclonal antibody-secreting hybrids to this peptide by the direct fusion of hyperimmunized splenocytes with myeloma cells had been unsuccessful, we modified our approach by coculturing hyperimmunized BALB/c splenocytes and a small amount of the antigen for 5 days prior to fusion with the P3X63Ag.8.653 myeloma cell line. Of 88 microcultures at risk, specific antibody was detected in 24. Two clones were expanded in ascites fluid and characterized as to isotype, affinity, and specificity. Both were IgG1,kappa and bound human Sm-C/IGF-I with affinity constants of 1.09 and 1.01 X 10(10) liter/mol, respectively. Both clones were quite specific for Sm-C/IGF-I with inconsequential binding to insulin-like growth factor II, multiplication-stimulating activity, any of the chymotryptic fragments of Sm-C/IGF-I, insulin preparations, hGH, hTSH, mEGF, or mouse albumin. In vitro boosting after primary in vivo immunization appears to provide monoclones of an IgG isotype in contrast to primary in vitro immunization, which reportedly favors an IgM isotype. The antibodies produced in this study have proved to be extraordinarily useful in defining the physiologic role of Sm-I/IGF-I with immunoneutralization techniques and in the purification of human Sm-C/IGF-I by affinity chromatography.
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PMID:Derivation of monoclonal antibodies to human somatomedin C/insulin-like growth factor I. 368 3

We report the sudden and dramatic reversal of maturity onset diabetes in a 57-year-old woman in association with relapse of IgA myeloma diagnosed 3 years earlier. Prior to the relapse of the myeloma, twice daily insulin had been administered at a dose which had been stable for 3 years. However, the same dose produced hypoglycaemic coma at the time of relapse and, subsequently, blood glucose was controlled by diet alone. There had been no significant change in weight or renal function prior to the hypoglycaemic episode. Investigations showed a suppressed fasting serum insulin level in association with an inappropriately high serum level of IGF-II compared with IGF-I and a 'big' IGF-II concentration at the upper end of the normal range. Pituitary, adrenal and liver disease, as well as the autoimmune insulin syndrome, were excluded. The findings are consistent with the hypothesis that the plasma cell tumour was associated with excessive production of insulin-like peptides with consequent reduction in the blood glucose level.
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PMID:Reversal of diabetes associated with escape of myeloma: evidence for inappropriate IGF-II secretion. 794 48

Multiple myeloma cell lines express functional receptors for insulin-like growth factors (IGFs) and several cell types that make up the bone marrow microenvironment produce these cytokines. This suggests that IGFs may play a role in survival and/or expansion of the malignant clone within the marrow in patients with multiple myeloma. We tested the effects of these growth factors on myeloma cells challenged with dexamethasone. Dye exclusion and MTT assays demonstrated that both IGF-I and IGF-II protected the 8226 and dox-40 myeloma cell lines and three primary myeloma cultures from dexamethasone-induced cytotoxicity in a dose-dependent fashion. Morphologic studies of target cells and their nuclei as well as DNA electrophoresis confirmed the IGFs afforded protection against dexamethasone-induced apoptosis. Insulin also protected but was less impressive and required much higher concentrations. IGFs also protected against cycloheximide-induced apoptosis but were ineffective against serum starvation, topoisomerase II inhibitors, or anti-fas antibodies. IGF-induced protection against dexamethasone was not associated with any alteration in quantitative or qualitative expression of BCL-2, BAX or BCL-X proteins. These data indicate that insulin-like growth factors may play a role in maintenance of the malignant clone in patients with myeloma by protecting tumour cells from apoptotic death.
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PMID:Multiple myeloma cells are protected against dexamethasone-induced apoptosis by insulin-like growth factors. 916 10

Insulin-like growth factors (IGF-I, IGF-II) have long been recognized as important mitogens in many types of malignancies. Because the role of IGFs in growth control of myeloma cells has not been extensively examined, we have used a panel of IL-6-responsive myeloma cell lines to address this issue. Initial studies demonstrated that IGF-I and IGF-II significantly enhanced DNA synthesis by each of the four cell lines, even when assayed in the absence of IL-6. The specificity of the IGF response was confirmed using an IGF-I receptor Ab, and additional studies demonstrated that IGF responsiveness did not result from induction of autocrine IL-6 expression. When IL-6 responsiveness was assayed, three of four cell lines synthesized DNA in response to IL-6 alone; however, the magnitude of responsiveness was greatly enhanced by addition of IGFs. Similar results were obtained when proliferation and cell cycle progression were analyzed. By contrast, the KP-6 cell line was responsive to IL-6 only when IGF was present. Finally, we analyzed the effects of IGF-I on normal B lymphocytes. IGF, however, did not stimulate B cell DNA synthesis, suggesting that IGF responsiveness may represent a key difference between normal and malignant B cells. In summary, these studies suggest that IGFs may play an important role in multiple myeloma by virtue of their ability to directly stimulate tumor cell growth as well as modulate the magnitude of IL-6-driven growth.
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PMID:A role for insulin-like growth factor in the regulation of IL-6-responsive human myeloma cell line growth. 920 Apr 90

The physiology of cultured animal cells, in particular hybridoma, myeloma and insect cells, with respect to growth and proliferation, amino acid metabolism, energy metabolism and cellular responses to environmental stress is discussed in this paper. The rate of proliferation of hybridoma cells in serum-containing media is limited by growth factors at a surprisingly early stage of growth. To maintain exponential growth in a batch culture, it is necessary to stimulate cell proliferation with repeated additions of serum or pure growth factor. It is further suggested that proliferation of Spodoptera frugiperda (Sf9 insect cells), a normal cell line able to grow in a serum-free medium without any added growth factors, is regulated by autocrine growth factors and possibly by other regulatory mechanisms, as Sf9 cells secrete a growth factor (IGF-I) and the medium still appears nutritionally sufficient at the time of cessation of growth. The uptake and metabolism of amino acids is one of the determinants of growth and production. Wasteful overproduction of amino acids in myeloma and hybridoma cells is a result of excess glutamine, and can be avoided by glutamine limitation. Synthesis of amino acids may be conditional, as in Sf9 cells which synthesise glutamine provided that ammonium is supplied to the medium; and cysteine (from methionine) provided that a sufficiently young inoculum is used. Uptake of amino acids in Sf9 cells appears regulated in relation to the proliferative status as there is a distinct cessation of uptake even before growth ceases. The energy metabolism in myeloma, hybridoma and insect cells is a typically substrate-concentration-dependent overflow metabolism. Substrate limitation (glucose and glutamine) decreases by-product formation and increases metabolic efficiency in all these cell lines. However, glutamine limitation, as used in fed-batch cultures (or chemostat cultures) provokes cell death (in parallel to growth) in hybridoma cells in the concentration range below 0.05 mM.
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PMID:Physiology of cultured animal cells. 948 19

Decreased bone formation plays an important role in the development of lytic lesions during the late stage of multiple myeloma (MM). Release of insulin-like growth factor binding protein-4 (IGFBP4) by tumour cells adjacent to bone may inhibit IGF-I-stimulated osteoblast growth and contribute to decreased bone formation. The present study demonstrates that the human MM cell line, ARH-77, expresses IGFBP4 and, to a lesser extent, IGFBP6 mRNA and protein. IGFBP4 expression in myeloma cells may be modulated by cytokines released by stromal cells and T cells in the microenvironment. We tested the effect of recombinant interferon-gamma (INF) on IGFBP4 expression in ARH-77. INF increased IGFBP4 mRNA and protein levels at 12 h, with a decline to baseline by 24 h. In contrast, IGFBP4 was not regulated in response to IL-6, TNF-alpha, PDGF BB, bFGF, TGF-beta or the cAMP agonist, forskolin. In other systems. IGFBP4 may also be regulated post-transcriptionally by a protease that is activated by IGF-I or -II. Conditioned medium from ARH-77 cultures incubated with IGF-I or -II for up to 24 h failed to demonstrate proteolytic activity. Proteolysis was also not observed when conditioned medium containing exogenous rhIGFBP4 was incubated with IGF-I or -II under cell-free conditions. To determine if human myeloma tumours also express IGFBP4, total RNA was isolated from four tumour biopsies. All samples expressed detectable levels of IGFBP4 mRNA. These findings indicate that interferon-gamma may indirectly modulate bone formation via the the release of tumour-derived IGFBP4. suggesting that the immune system may influence bone turnover in MM. Failure of myeloma cells to release protease activity may promote IGFBP4 accumulation in the microenvironment during tumour growth.
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PMID:Potential role of insulin-like growth factor binding protein-4 in the uncoupling of bone turnover in multiple myeloma. 1019 30

One of the main characteristics of multiple myeloma (MM) cells is their specific homing and growth in the bone marrow (BM). Differences between stroma-dependent and -independent MM cell lines may reveal key molecules that play important roles in their homing to the BM. We addressed this topic with a murine MM model, including the in vivo 5T33MM (5T33MMvv) stroma-dependent cell line and its in vitro stroma-independent variant (5T33MMvt). Fluorescence-activated cell-sorting analysis showed expression of insulin-like growth factor (IGF)-I receptor and CD44v6 on all 5T33MMvv cells but not on 5T33MMvt cells. Checkerboard analysis and adhesion assays revealed IGF-I-dependent chemotaxis toward BM-conditioned medium and involvement of CD44v6 in the adhesion to BM stroma of only 5T33MMvv cells. However, when 5T33MMvt cells were injected in vivo (5T33MMvt-vv), after 18 h the MM cells harvested from BM were IGF-I receptor and CD44v6 positive. This up-regulation was confirmed in 5T33MMvt-vv cells isolated from terminally diseased animals. These ST33MMvt-vv cells exhibited IGF-I-dependent chemotaxis and CD44v6-dependent adhesion to BM stroma. In vitro culture of the 5T33MMvt-vv cells could completely down-regulate IGF-I receptor and CD44v6. In fact, we could show that direct contact of 5T33MMvt cells with BM endothelial cells is a prerequisite for IGF-I receptor and CD44v6 up-regulation. These data indicate that the BM microenvironment is capable of up-regulating molecules such as IGF-I receptor and CD44v6, which facilitate homing of MM cells to the BM and support their adhesion to BM stroma.
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PMID:In vivo induction of insulin-like growth factor-I receptor and CD44v6 confers homing and adhesion to murine multiple myeloma cells. 1085 Apr 62

Plasma cell neoplasia in humans generally occurs as multiple myeloma, an incurable form of cancer. Tumors with marked similarity can be induced in mice by a variety of agents, including chemicals, silicone, and oncogene-containing retroviruses, suggesting the use of murine tumors as an informative model to study plasma cell disease. Herein, we have focused on the role of insulin-like growth factor I receptor (IGF-IR) signaling in the development of plasma cell disease. The insulin receptor substrate 2/phosphatidylinositol 3'-kinase/p70S6K pathway was found to be either constitutively or IGF-I-dependently activated in all plasma cell tumors. Biological relevance was demonstrated in that plasma cell lines with up-regulated IGF-IR expression levels exhibited mitogenic responses to IGF-I. More importantly, expression of a dominant-negative mutant of IGF-IR in these lines strongly suppressed tumorigenesis in vivo. Taken together, these results demonstrate that up-regulation and activation of IGF-IR and the downstream signaling pathway involving insulin receptor substrate 2, phosphatidylinositol 3'-kinase, and p70S6K may play an important role in the development of a broad spectrum of plasma cell tumors.
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PMID:Activation of insulin-like growth factor I receptor signaling pathway is critical for mouse plasma cell tumor growth. 1091 68

Insulin-like growth factors (IGF) I and II are potent mitogens for a variety of cancer cells. The proliferative and anti-apoptotic actions of IGF are mediated by the IGF-I receptor (IGF-IR), to which both IGF-I and IGF-II bind with high affinity. To investigate the mitogenic and anti-apoptotic activities of IGF-IR and to achieve better inhibition of IGF-IR function, single-chain antibodies against human IGF-IR (alphaIGF-IR scFvs) were constructed and expressed. IgG cDNA encoding variable regions of light and heavy chains (VL and VH) from mouse IgG were cloned from a hybridoma producing the 1H7 alphaIGF-IR monoclonal antibody [Li et al., Biochem Biophys Res Commun 196: 92-98 (1993)]. The splice-overlap extension polymerase chain reaction was used to assemble a gene encoding the alphaIGF-IR scFv, including the N-terminal signal peptide, VL, linker peptide, VH, and C-terminal DYKD tag. Two types of soluble alphaIGF-IR scFvs, a prototype alphaIGF-IR scFv and its alternative type alphaIGF-IR scFv-Fc, were constructed and expressed in murine myeloma cells. alphaIGF-IR scFv-Fc, containing the human IgG1 Fc domain, was stably expressed in NS0 myeloma cells, using a glutamine synthase selection system, and purified from the conditioned medium of stable clones by protein-A--agarose chromatography. Levels of alphaIGF-IR scFv-Fc expression ranged from 40 mg/l to 100 mg/l conditioned medium. Sodium dodecyl sulfate/polyacrylamide gel electrophoresis analysis under reducing and nonreducing conditions indicated that alphaIGF-IR scFv-Fc is a dimeric antibody. alphaIGF-IR scFv-Fc retained general characteristics of the parental 1H7 monoclonal antibody except that its binding affinity for IGF-IR was estimated to be approximately 10(8) M(-1), which was one-order of magnitude lower than that of 1H7 monoclonal antibody. Injection of alphaIGF-IR scFv-Fc (500 microg/mouse, twice a week) significantly suppressed MCF-7 tumor growth in athymic mice. These results suggest that the alphaIGF-IR scFv-Fc is a first-generation recombinant alphaIGF-IR for the potential development of future alphaIGF-IR therapeutics.
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PMID:Single-chain antibodies against human insulin-like growth factor I receptor: expression, purification, and effect on tumor growth. 1094 7

Mouse plasma cell tumor (PCT) and human multiple myeloma (MM) are terminal B-cell malignancies sharing many similarities. Our recent work demonstrated that activation of the insulin-like growth factor receptor (IGF-IR)/insulin receptor substrate (IRS)/phosphatidylinositol 3' kinase (PI 3'K) pathway was evident in the tumor lines derived from both species. Although PI 3'K activity was higher in mouse tumor lines than that in human tumors, activation of Akt serine/threonine kinase was markedly lower in mouse lines. This discrepancy prompted us to test the status of PTEN tumor suppressor gene, as it has been shown to be a negative regulator of PI 3'K activity. Although all the mouse lines expressed intact PTEN, 2 of the 4 human lines (Delta47 and OPM2) possessing the highest Akt activity lost PTEN expression. Sequencing analysis demonstrated that the PTEN gene contains a deletion spacing from exon 3 to exon 5 or 6 in the Delta47 line and from exon 3 to 7 in the OPM2 line. Restoration of PTEN expression suppressed IGF-I-induced Akt activity, suggesting that loss of PTEN is responsible for uncontrolled Akt activity in these 2 lines. Despite the expression of PTEN with the concomitant low Akt activity in all mouse PCT lines, their p70S6K activities were generally higher than those in 3 human MM lines, arguing for specific negative regulation of Akt, but not p70S6K by PTEN. These results suggest that p70S6K and Akt may be differentially used by the plasma cell tumors derived from mice and humans, respectively.
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PMID:Loss of PTEN expression leading to high Akt activation in human multiple myelomas. 1107 55


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