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)

Bisphosphonates (BPs), such as pamidronate and clodronate, are an important class of drugs for the treatment of bone diseases. It is widely recognized that they inhibit bone resorption by suppressing the action of osteoclasts through antagonizing the mevalonate pathway, thereby reducing osteolytic bone metastases derived from different cancers, i.e. breast carcinoma and multiple myeloma. In contrast, the effects of BPs on primary bone tumors is an issue still to be resolved. Therefore, a systematic approach was set up to test the hypothesis that BPs could act directly on osteosarcoma cells. The effects of pamidronate and clodronate on seven osteosarcoma cell lines (HOS, MG-63, OST, SaOS-2, SJSA-1, U(2)OS and ZK-58) were studied. Pamidronate inhibited cell growth in a time- and dose-dependent manner, and decreased proliferation for up to 73% at 50 microM after 72 h, whereas its monophosphonate analog 3-aminopropyl phosphonate did not reduce cell viability at concentrations up to 2 mM. Clodronate showed less inhibitory effects (maximally 38% reduction at 1 mM after 72 h). Importantly, cell growth of fibroblasts was only very weakly affected by treatment with pamidronate. These results suggest that pamidronate may be a useful agent for the treatment of patients with osteosarcoma.
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PMID:The bisphosphonate pamidronate is a potent inhibitor of human osteosarcoma cell growth in vitro. 1139 74

Metastatic bone disease develops as a result of the many interactions between tumour cells and bone cells. This leads to disruption of normal bone metabolism, with the increased osteoclast activity seen in most, if not all, tumour types providing a rational target for treatment. The clinical course of metastatic bone disease in multiple myeloma, breast and prostate cancers is relatively long, with patients experiencing sequential skeletal complications over a period of several years. These include bone pain, fractures, hypercalcaemia and spinal cord compression, all of which may profoundly impair a patient's quality of life. External beam radiotherapy and systemic endocrine and cytotoxic treatments are the mainstay of treatment in advanced cancers. However, it is now clear that the bisphosphonates provide an additional treatment strategy, which reduces both the symptoms and complications of bone involvement. Ongoing research is aimed at trying to define the optimum route, dose, schedule and type of bisphosphonate in metastatic bone disease and in the prevention and treatment of osteoporosis in cancer patients. In vitro suggestions of direct anticancer activity and some promising clinical data in early breast cancer have resulted in considerable interest in the possible adjuvant use of bisphosphonates to inhibit the development of bone metastases.
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PMID:Metastatic bone disease: clinical features, pathophysiology and treatment strategies. 1141 67

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

Aminobisphosphonates, potent derivatives of bisphosphonates, are frequently used for the treatment of conditions such as osteoporosis and bone metastases that are characterized by excessive osteoclastic bone resorption. Using T-cell receptor (TCR) transfer studies, we show that recognition of antigenic aminobisphosphonates that are known to stimulate human gammadelta T cells in vitro and in vivo (potency: risedronate > alendronate > pamidronate) requires expression of the Vgamma2Vdelta2 TCR and is thus Vgamma2Vdelta2 TCR-dependent. Myeloma cells or monocytes pulsed with risedronate and then washed rendered these target cells sensitive to lysis by a Vgamma2Vdelta2 T-cell clone or cell line. These results suggest that Vgamma2Vdelta2 TCR-dependent recognition leading to direct cytolysis of aminobisphosphonate-sensitized osteoclast or tumor targets may be a mechanism whereby aminobisphosphonate treatment of cancers metastatic to bone decreases osteoclastic activity and tumor burden and also may account for the decreased osteoclastic activity associated with successful treatment of osteoporosis.
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PMID:Vgamma2Vdelta2 T-cell receptor-mediated recognition of aminobisphosphonates. 1152 Aug 16

The clinical use of bisphosphonates for the management of bone metastases in malignant disease is well established, though the precise pathophysiology of metastasis and the mechanism of action of bisphosphonates is not fully understood. In addition, recent clinical studies indicate that bisphosphonates may have an anticancer effect. Animal models can contribute to further development of these drugs, and a number of improved models have been developed in the past few years. The mouse heart injection model represents the late stages in osteolytic metastasis but the newer orthotopic model has advantages because it better represents the whole process of metastasis. The process of osteoblastic metastasis has been more difficult to study but models have been created in mice by using intracardiac inoculation of certain types of human breast cancer cells. Research in myeloma in the past has been hampered by the lack of good animal models but two promising models have been recently developed. These different models should enable mechanisms to be elucidated and contribute background information for the design of further clinical trials.
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PMID:Preclinical models of bone metastases. 1154 69

Paget's disease and bone metastases in cancer patients share many common properties. Both are characterized by a localized increase in osteoclast (OCL) formation leading to bone resorption. In both Paget's disease and bone metastases the increased OCL formation and the increased osteoclastogenic nature of the bone microenvironment are mediated by common factors, namely interleukin (IL)-6 and RANK ligand (RANKL). Available data suggest that in the case of Paget's disease there is increased RANKL and IL-6 production, and IL-6 enhances the responsivity of the OCL precursors to RANKL, contributing to the elevated numbers of OCLs. In patients with multiple myeloma, 95% to 100% of whom develop bone lesions, both IL-6 and RANKL levels are increased. Bisphosphonates bind locally to the surfaces of the bone undergoing osteoclastic resorption to inhibit this process. Paget's disease has in the past and will continue in the future to provide a model to test the efficacy of bisphosphonates in inhibiting bone resorption. Paget's disease provides an ideal model in which to investigate the efficacy of the new third-generation bisphosphonates in the treatment of bone metastases as well as nonmalignant bone disease.
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PMID:Studies in Paget's disease and their relevance to oncology. 1154 71

Bone metastases commonly occur in cancer patients, most frequently in patients with breast and prostate cancers, and are associated with considerable morbidity. Cancer cells secrete a number of paracrine factors that stimulate osteoclast function, resulting in osteolysis. Bisphosphonates are potent inhibitors of both normal and pathologic osteolysis, localizing preferentially to sites of active bone formation and resorption. Clinical studies have shown that long-term bisphosphonate treatment in patients with breast cancer and multiple myeloma decreases skeletal morbidity, skeletal-related events, pain, and improves quality of life. On the basis of the available clinical evidence, bisphosphonates should be part of the standard treatment for breast cancer and multiple myeloma. Currently, there is insufficient data to recommend their routine use for other types of tumors. Preliminary evidence indicates that bisphosphonates may prolong survival in cancer patients, but this needs to be confirmed in controlled clinical trials. Bisphosphonate treatment should start as soon as bone metastases have been identified and be continued for as long as they are a significant clinical problem. At present, the adjuvant role of bisphosphonates is unproven. The new third-generation agents in clinical development, ibandronate and zoledronate, should lead to improvements in therapy compared with current treatment regimens. Improvement in treatment could also be provided by better selection of patients for therapy.
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PMID:Should bisphosphonates be the treatment of choice for metastatic bone disease? 1154 74

Metastatic bone disease is a frequent complication of breast and other cancers, resulting in skeletal complications that are a significant cause of morbidity and mortality. Bone metastases can be difficult to diagnose radiologically and it can also be difficult to evaluate patients' response to treatment by using the methods that are currently available (radiography, bone scans, and computed axial tomography scans). These are relatively insensitive procedures, thus, there is a requirement for new methods for assessing bone response to ensure patients benefit from the optimum type and duration of treatment. Biochemical markers of bone turnover, such as N-telopeptide and the pyridinium cross-links pyridinoline and deoxypyridinoline, may provide information on bone dynamics that in turn may reflect disease activity in bone. Several studies have shown bone markers to be elevated in cancer patients who have documented evidence of metastatic bone disease. Increased levels are also observed in some patients without clinical evidence of bone metastases, when compared with normal subjects. Rises in such markers may be the first indication of bone involvement and therefore may potentially be useful in early diagnosis of progression. Preliminary data suggest bone marker level correlates with the extent of metastatic disease and the number of skeletal sites involved. Markers of bone turnover may be helpful in identifying those patients likely to respond to bisphosphonate treatment. Such markers are also potentially useful in monitoring the effectiveness of bisphosphonate therapy in the management of bone metastases, in both patients with metastatic breast disease and multiple myeloma.
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PMID:Use of markers of bone turnover for monitoring bone metastases and the response to therapy. 1154 77

Bisphosphonates are established as a useful component in the treatment of skeletal metastases in breast cancer and multiple myeloma, and may prove to be useful in other cancers that metastasize to bone. Recent attention has focused on possible preventive effects of bisphosphonates, in the adjuvant therapy of patients with operable breast cancer, either by disrupting the interactions between micrometastatic tumor cells and the bone microenvironment or by direct actions on tumor cells. Three adjuvant trials of the oral bisphosphonate clodronate have been completed, but the results have been conflicting. A reduction in bone and visceral metastases and increased survival with adjuvant clodronate was seen in one study of 302 patients with breast cancer. Another open-label study (299 patients) has shown increased visceral metastases and decreased survival, while an interim analysis of a third, larger, placebo-controlled study (1,079 patients) showed a beneficial effect on bone metastases, but no effect on visceral metastases or survival. The final analysis of this trial is expected in 2001. The evidence has been sufficiently encouraging that further randomized trials are planned or in progress with clodronate and other bisphosphonates including intravenous pamidronate, zoledronate, and oral ibandronate. Careful trial design and selection of patients at high risk for bone recurrence are important for studies to detect adjuvant effects. Convenience and cost are likely to be important considerations for the long-term adjuvant use of bisphosphonates. Oral formulations and the introduction of highly potent bisphosphonates may offer advantages, and require clinical assessment.
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PMID:Adjuvant bisphosphonate therapy: the future. 1154 82

The results of simplified method of hemibody irradiation of 23 patients with multiple painful bone metastases are presented. In all cases without proven bone metastases in skull and distal part of limbs, these parts of the body were excluded from irradiated field. The study comprised 25 cases of hemibody irradiation. The degree of pain relief and performance status improvement was assessed one and two months after treatment, depending on clinical and histopathological diagnosis and type of bone metastases. The best symptomatic results were obtained in the cases of multiple myelomas (100% of pain relief), prostate cancers (the average degree of 78%) and lung cancers (88%). Considering histopathological diagnosis, the best answer was found in multiple myeloma and squamous cell cancer (88%). Taking into account type of metastases the best result was obtained in the cases of osteolytic metastases (65%). No difference between upper and lower hemibody irradiation was found. The statistically significant correlation between pain relief, performance status improvement and decrease of analgetics use was found. The obtained results suggest that presented simplified form of hemibody irradiation is an effective symptomatic treatment modality in the cases with multiple painful bone metastases, giving an increase of life quality without significant radiation morbidity.
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PMID:[The evaluation of the effectiveness of half-body irradiation as palliative treatment in patients with multiple bone metastases]. 1160 77


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