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)

A complementary DNA expression library derived from marrow samples from myeloma patients was recently screened and human macrophage inflammatory protein-1alpha (hMIP-1alpha) was identified as an osteoclastogenic factor expressed in these samples. hMIP-1alpha enhanced osteoclast (OCL) formation in human marrow cultures and by highly purified OCL precursors in a dose-dependent manner (5-200 pg/mL). Furthermore, hMIP-1alpha enhanced OCL formation induced by human interleukin-6 (IL-6), which is produced by marrow stromal cells when they interact with myeloma cells. hMIP-1alpha also enhanced OCL formation induced by parathyroid hormone-related protein (PTHrP) and receptor activator of nuclear factor kappaB ligand (RANKL), factors also implicated in myeloma bone disease. Time-course studies revealed that the hMIP-1alpha acted during the last 2 weeks of the 3-week culture period. Reverse transcription-polymerase chain reaction analysis showed that the chemokine receptors for hMIP-1alpha (CCR1 and CCR5) were expressed by human bone marrow and highly purified early OCL precursors. Furthermore, hMIP-1alpha did not increase expression of RANKL. These data demonstrate that hMIP-1alpha is an osteoclastogenic factor that appears to act directly on human OCL progenitors and acts at the later stages of OCL differentiation. These data further suggest that in patients with myeloma, MIP-1alpha produced by myeloma cells, in combination with RANKL and IL-6 that are produced by marrow stromal cells in response to myeloma cells, enhances OCL formation through their combined effects on OCL precursors. (Blood. 2001;97:3349-3353)
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PMID:Macrophage inflammatory protein-1alpha is an osteoclastogenic factor in myeloma that is independent of receptor activator of nuclear factor kappaB ligand. 1136 23

To elucidate the role of PTHrP in myeloma, we examined the expression levels of PTHrP and its receptor in human myeloma cell lines and clinical specimens from 13 myeloma cases. In vitro modification of PTHrP expression and production induced by TGF-beta and PMA in PTHrP expressing myeloma cell lines was also investigated. PTHrP expression was detected in six out of seven myeloma cell lines with an inverse correlation with the expression of its receptor, and in 10 out of 13 clinical specimens in varying degrees. The PTHrP expression and secretion into culture medium were enhanced by supplemental TGF-beta and PMA. PMA also seemed to affect PTHrP upregulation via TGF-beta activation. The fundamental role of PTHrP in bone lesions and hypercalcemia in myeloma may be important to consider even during the initial phase of the disease and particularly in the progression of bone complications with hypercalcemia.
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PMID:Expression and in vitro modification of parathyroid hormone-related protein (PTHrP) and PTH/PTHrP-receptor in human myeloma cells. 1137 53

Bone is a frequent site of cancer metastasis. Bone metastases can result in bone destruction or new bone formation. Bone destruction is mediated by factors produced or induced by tumor cells that stimulate formation and activation of osteoclasts, the normal bone-resorbing cells. Local bone destruction also occurs in patients with osteoblastic metastases and may precede or occur simultaneously with increased bone formation. Several factors, including interleukin (IL)-1, IL-6, receptor activator of NF-kappaB (RANK) ligand, parathyroid hormone-related protein (PTHrP), and macrophage inflammatory protein-1-alpha (MIP-1alpha), have been implicated as factors that enhance osteoclast formation and bone destruction in patients with neoplasia. PTHrP seems to be the major factor produced by breast cancer cells that induces osteoclast formation through upregulation of RANK ligand. Enhanced RANK ligand expression also plays an important role in bone destruction in patients with myeloma. RANK ligand can act to enhance the effects of other factors produced by myeloma cells or in response to myeloma cells, such as MIP-1alpha and/or IL-6, to induce osteoclast formation. Understanding of the molecular mechanisms responsible for osteoclast activation in osteolytic metastases should lead to development of novel therapeutic approaches for this highly morbid and potentially fatal complication of cancer.
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PMID:Biology of osteoclast activation in cancer. 1177 96

Bone destruction is a hallmark of myeloma, with 70% to 80% of patients manifesting bone involvement. Destruction is mediated through normal osteoclasts (OCLs), which respond to local osteoclast-activating factors (OAFs) produced by myeloma cells or by other cells in the local microenvironment. OAFs implicated in myeloma bone disease include tumor necrosis factor-beta (TNFbeta), RANK ligand (RANKL), interleukin-1 (IL-1), parathyroid hormone-related protein (PTHrP), hepatocyte growth factor (HGH), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNFalpha), and macrophage inflammatory protein-1-alpha (MIP-1alpha). To date, the leading candidates for OAFs are MIP-1alpha and RANKL. Adhesive interactions between marrow stromal cells and myeloma cells induce marrow stromal cells to secrete IL-6, a potent myeloma growth/survival factor that may contribute to the bone disease. Evaluation of myeloma bone disease includes plain radiographs, and newer methods, such as magnetic resonance imaging (MRI), positron emission tomography (PET) scans, technetium-99m-sestamibi (Mibi) scanning, and dual-energy x-ray absorptiometry (DEXA) scanning, may provide more complete information. In addition, biochemical markers of bone resorption are being evaluated, although the limited availability of these assays and lack of extensive testing in patients make their routine use premature. Treatment of myeloma bone disease includes radiation therapy, vertebroplasty, surgery, and bisphosphonates. New developments on the pathogenesis and treatment of myeloma bone disease present great opportunities to combat bone disease.
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PMID:Myeloma bone disease. 1148 16

Multiple myeloma is a plasma cell neoplasia often associated with multiple skeletal lesions and hypercalcemia. Several cytokines, including interleukin (IL)-1, IL-6 and tumor necrosis factor-beta (TNF-beta), derived from myeloma cells are thought to accelerate osteoclastic bone resorption and cause hypercalcemia through a paracrine mechanism. We report on a case of a 69-year-old man with multiple myeloma associated with hypercalcemia and advanced osteolytic lesions. After bisphosphonate treatment and MP (melphalan and prednisolone) therapy, the patient's serum calcium level was successfully but transiently recovered to the normal range. Biochemical analysis showed a remarkable increase in serum parathyroid hormone-related protein (PTHrP; 3.7 pmol/L) and IL-6 (22.0 pg/mL). On the other hand, parathyroid hormone and 1alpha,25(OH)2 vitamin D3 were suppressed. By immunohistochemistry and in situ hybridization on aspiration-biopsied bone marrow clot sections, PTHrP mRNA and protein were detected in the cytoplasm of myeloma cells. The rate of PTHrP-positive myeloma cells was estimated to be at least one-third. Since PTHrP can, as an endocrine factor, systemically act on bone and kidney, hypercalcemia in this case might have been caused through both local osteolytic hypercalcemia and humoral hypercalcemia of malignancy mechanisms.
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PMID:Expression of parathyroid hormone-related protein (PTHrP) in multiple myeloma. 1194 Feb 9

The skeleton is the most common site of metastatic disease in breast cancer and the most common site of first distant relapse. Bone metastases in breast cancer are the source of considerable morbidity, including severe pain, pathological fractures, need for radiotherapy or surgery, and hypercalcemia. Bisphosphonates are potent inhibitors of osteoclast-mediated bone resorption, and it is well known that breast cancer cells in bone can stimulate osteoclast formation and activity leading to the release of growth factors and cytokines, which will further stimulate cancer cell growth and their secretion of osteolytic factors. We are thus typically dealing with a vicious cycle, as the bone resorption-induced release of growth factors from the bone matrix will stimulate breast cancer cell growth (probably mainly by IGFs) and the production of the osteolytic factor PTHrP (probably mainly by TGF-beta but also by extracellular calcium). Clodronate, but not the aminobisphosphonates, can be metabolized to an ATP analog that is toxic for osteoclasts. Nitrogen-containing bisphosphonates, such as pamidronate, ibandronate, and zoledronate, interfere with the mevalonate pathway that is crucial to maintain cell membrane integrity. The net result, regardless of the mechanism, is osteoclast apoptosis, notably through the induction of caspase-3. Bisphosphonates are now the standard treatment for cancer hypercalcemia. Repeated bisphosphonate infusions also exert clinically relevant analgesic effects in at least one half of the patients with metastatic bone pain. Most importantly, prolonged administration of bisphosphonates (for at least 1 year) reduces the frequency of morbid skeletal events by 30-40% in breast cancer metastatic to bone and in up to 50% in patients with multiple myeloma. Newer bisphosphonates, such as ibandronate and zoledronate, will simplify the current therapeutic schemes and improve the cost-effectiveness ratio, and they have the potential to improve the therapeutic efficacy, at least in patients with aggressive osteolytic disease or in the adjuvant setting.
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PMID:Bisphosphonates in the treatment of metastatic breast cancer. 1201 36

A patient with multiple myeloma who developed hypercalcemia during three different stages of his disease, with a different hypercalcemic agent elevated in his serum on each occasion, is described. The initial episode of hypercalcemia was associated with high serum interleukin-6 (IL-6). After treatment for myeloma normocalcemia was achieved. Subsequently, a relapse of hypercalcemia occurred, this time characterized by frankly elevated plasma parathyroid hormone-related protein (PTHrP) but normal IL-6. Monotherapy with pamidronate infusions resulted in remission of the hypercalcemia and a significant fall in PTHrP levels. A third spell of hypercalcemia characterized by an acute rise in serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D to abnormally high levels occurred during the summer season after prolonged and intense exposure to the sun.
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PMID:Hypercalcemia due to sun exposure in a patient with multiple myeloma and elevated parathyroid hormone-related protein. 1261 17

Gallium nitrate, the nitrate salt of the "near-metal" element gallium, is highly effective in the treatment of cancer-related hypercalcemia. Unlike bisphosphonates, gallium nitrate is effective in both parathyroid hormone-related protein-mediated and non-parathyroid hormone-related protein-mediated hypercalcemia. Gallium nitrate's effects on bone are clearly different from those of bisphosphonates. Gallium nitrate enhances calcium and phosphate content of bone and has direct, noncytotoxic effects on osteoclasts at markedly lower doses than those used for the treatment of cancer-related hypercalcemia. The drug may have clinical application in a variety of disorders associated with accelerated bone loss, including multiple myeloma. Gallium nitrate was originally evaluated as an antitumor agent. Its antitumor activity occurs at somewhat higher doses than those used in the treatment of cancer-related hypercalcemia. Gallium nitrate has substantial single-agent activity in the treatment of advanced lymphoma, particularly diffuse large cell lymphoma, small lymphocytic lymphoma, and follicular lymphoma. Because of its profile, including a different mechanism of action and minimal myelosuppression, the drug merits further evaluation in the treatment of advanced lymphoma. Gallium nitrate also has activity in advanced bladder cancer and may be useful in patients with metastatic or unresectable disease failing first-line chemotherapy regimens. Gallium nitrate exhibits a range of dose-dependent pharmacologic actions that provide a basis for its therapeutic potential in a variety of diseases and warrants further investigational evaluation as an antiresorptive and antitumor agent.
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PMID:Gallium nitrate revisited. 1277 53

A 13-year-old gelding was examined because of weight loss, hyperglobulinemia, and hypercalcemia. Possible causes of hypercalcemia that were considered included renal failure, primary hyperparathyroidism, vitamin D toxicosis, and malignancy. There was no history of vitamin D ingestion, and serum creatinine and parathyroid hormone concentrations were normal, making renal failure and primary hyperparathyroidism unlikely. The hypercalcemia was suspected to be a result of malignancy, but thorough testing did not reveal any neoplastic disease. Eight months later, serum parathyroid hormone-related protein (PTHrP) concentration was high, supporting the suggestion that hypercalcemia was a result of malignancy. In addition, radial immunodiffusion confirmed a selective 300-fold increase in serum IgA concentration. The horse was euthanatized, and postmortem examination revealed neoplastic infiltrates in the kidneys, lymph nodes, liver, and bone marrow. Neoplastic cells had morphologic characteristics of plasma cells, and immunohistochemical staining confirmed that neoplastic cells were expressing PTHrP and IgA. The final diagnosis was multiple myeloma with expression of IgA paraprotein.
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PMID:Hypercalcemia and high serum parathyroid hormone-related protein concentration in a horse with multiple myeloma. 1532 17

Among the hematological malignancies, hypercalcemia has often been reported in lymphoid malignancies such as multiple myeloma and adult T cell leukemia/lymphoma, but it has only rarely been described in acute nonlymphocytic leukemia. We describe here a 14-month-old girl with acute monocytic leukemia complicated by severe hypercalcemia (4.6 mmol/l) at presentation. A bone survey showed generalized bone resorption, but no localized osteolytic lesions. A search for the etiology of the hypercalcemia revealed that the serum levels of parathyroid hormone-related protein (PTHrP) and also proinflammatory cytokines with stimulatory effects on osteolytic bone resorption - TNF-alpha, IL-6 and M-CSF - were elevated. The patient achieved complete remission with induction chemotherapy, and the levels of PTHrP and the cytokines became normalized. In this case, PTHrP and cytokines might have acted cooperatively to exacerbate bone resorption, resulting in severe hypercalcemia.
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PMID:Severe hypercalcemia in a child with acute nonlymphocytic leukemia: the role of parathyroid hormone-related protein and proinflammatory cytokines. 1534 99


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