Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0153690 (bone metastases)
 6,382 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The efficacy of an association of cyclophosphamide (CPM) and 5-fluorouracil was studied in 15 patients with prostate cancer not responding to oestrogen therapy, and more particularly its effect on pain due to bone metastases. No objective improvement was noted with this association, but there was a definitite reduction in bone metastases pain in 5 of the patients, with an average remission time of 4 months. Half of the patients had nausea and vomiting, but in spite of this digestive intolerance those patients who obtained pain relief for 4 months considered the treatment to be of positive value. This therapy is recommended only fater the failure of castration, anti-androgens, and oestrogens, together with nitrogen mustard (Estracyt) and corticotherapy.
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PMID:[Palliative chemotherapy with 5 FU and CPM in cancer of the prostate with bone metastases resistant to oestrogens. A clinical trial (author's transl)]. 9 8

Bisphosphonates are used with increasing frequency in the management of skeletal complications in patients with breast cancer. In this paper, we have investigated whether bisphosphonates, besides their known beneficial effects on tumor-associated osteoclastic resorption, are capable of inhibiting breast cancer cell adhesion to bone matrix. For that we used two in vitro models for bone matrix (cortical bone slices and cryostat sections of trabecular bone from neonatal mouse tails). Four bone matrix-bound nitrogen-containing bisphosphonates (pamidronate, olpadronate, alendronate, and ibandronate) inhibited adhesion and spreading of breast cancer cells to bone dose-dependently, whereas etidronate and clodronate had little or no effect. Strikingly, the relative order of potency of the bisphosphonates in inhibiting the adhesion of cancer cells to cortical and trabecular bone corresponded to their relative antiresorptive potencies in vivo as well as their ranking in in vitro bone resorption assays with predictive value for their clinical efficacy. It appears that nitrogen-containing bisphosphonates alter selectively the adhesive properties of the extracellular bone matrix preventing the attachment of breast cancer cells to it. Besides the beneficial effects of bisphosphonates on tumor-induced osteoclastic resorption, the previously unrecognized effect presented in this paper makes these agents suitable for earlier pharmacologic intervention in patients with breast cancer at risk of developing bone metastases.
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PMID:Bisphosphonates inhibit the adhesion of breast cancer cells to bone matrices in vitro. 869 61

Bisphosphonates (BPs) are used for the treatment of both benign and malignant diseases characterized by increased bone resorption. Because of their potential nephrotoxicity, currently available BPs have to be administered by slow intravenous infusion, with conventional doses requiring an infusion time of at least 2 h. In the present investigation, we evaluated the safety and efficacy of the new BP ibandronate as administered by intravenous bolus injection. On day 0, 15 normocalcemic breast cancer patients with bone metastases were treated with 3 mg of ibandronate injected intravenously over 60-120 s. Ibandronate treatment led to significant decreases in serum levels of calcium (p < 0.0001) and phosphate (p < 0.0001) and to subsequent increases in serum concentrations of parathyroid hormone (p <0.0001) and calcitriol (p <0.0001). Moreover, there was a significant reduction in the urinary excretion of calcium (p <0.0001), pyridinoline (p <0.001), and deoxypyridinoline (p < 0.0001). Three serious adverse events were observed: vomiting (WHO grade 3), pulmonary infection (WHO grade 2), and deterioration of a pre-existing impaired glucose tolerance (WHO grade 3). Only vomiting appeared to be related to administration of the drug. The most frequent nonserious adverse events were 10 cases of transient clinically asymptomatic hypocalcemia and 8 cases of asymptomatic hypophosphatemia. Serum levels of creatinine and urea nitrogen did not increase, nor did creatinine clearance deteriorate. When tested with the dipstick method, proteinuria was present in five (33%) patients prior to ibandronate treatment (median protein concentration, 30 mg/dl). Following the BP injection, seven (47%) patients showed slight (highest protein concentration, 30 mg/dl) transient proteinuria at at least one time point, of which six cases appeared in conjunction with leucocyturia and three with microhematuria. Side effects specific to aminosubstituted BPs (fever, reduction in white blood cell counts, and lymphocyte counts) were not seen in these 15 patients. In conclusion, a single intravenous injection of 3 mg of ibandronate significantly inhibited osteoclast activity as reflected by the decrease in serum calcium and in urinary parameters of bone resorption. Serum creatinine levels and estimates of creatinine clearance were not affected by therapy. However, before repeated bolus injections of ibandronate at this dosage can be recommended for further clinical trials, whether a relationship exists between the transient pathological urinary findings and injected ibandronate needs to be determined.
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PMID:Administration of the bisphosphonate ibandronate (BM 21.0955) by intravenous bolus injection. 915 73

Bisphosphonates (BPs) used as inhibitors of bone resorption all contain two phosphonate groups attached to a single carbon atom, forming a "P-C-P" structure. The bisphosphonates are therefore stable analogues of naturally occuring pyrophosphate-containing compounds, which now helps to explain their intracellular as well as their extracellular modes of action. Bisphosphonates adsorb to bone mineral and inhibit bone resorption. The mode of action of bisphosphonates was originally ascribed to physico-chemical effects on hydroxyapatite crystals, but it has gradually become clear that cellular effects must also be involved. The marked structure-activity relationships observed among more complex compounds indicate that the pharmacophore required for maximal activity not only depends upon the bisphosphonate moiety but also on key features, e.g., nitrogen substitution in alkyl or heterocyclic side chains. Several bisphosphonates (e.g., etidronate, clodronate, pamidronate, alendronate, tiludronate, risedronate, and ibandronate) are established as effective treatments in clinical disorders such as Paget's disease of bone, myeloma, and bone metastases. Bisphosphonates are also now well established as successful antiresorptive agents for the prevention and treatment of osteoporosis. In particular, etidronate and alendronate are approved as therapies in many countries, and both can increase bone mass and produce a reduction in fracture rates to approximately half of control rates at the spine, hip, and other sites in postmenopausal women. In addition to inhibition of osteoclasts, the ability of bisphosphonates to reduce the activation frequency and birth rates of new bone remodeling units, and possibly to enhance osteon mineralisation, may also contribute to the reduction in fractures. The clinical pharmacology of bisphosphonates is characterized by low intestinal absorption, but highly selective localization and retention in bone. Significant side effects are minimal. Current issues with bisphosphonates include the introduction of new compounds, the choice of therapeutic regimen (e.g., the use of intermittent dosing rather than continuous), intravenous vs. oral therapy, the optimal duration of therapy, the combination with other drugs, and extension of their use to other conditions, including steroid-associated osteoporosis, male osteoporosis, arthritis, and osteopenic disorders in childhood. Bisphosphonates inhibit bone resorption by being selectively taken up and adsorbed to mineral surfaces in bone, where they interfere with the action of osteoclasts. It is likely that bisphosphonates are internalized by osteoclasts and interfere with specific biochemical processes and induce apoptosis. The molecular mechanisms by which these effects are brought about are becoming clearer. Recent studies show that bisphosphonates can be classified into at least two groups with different modes of action. Bisphosphonates that closely resemble pyrophosphate (such as clodronate and etidronate) can be metabolically incorporated into nonhydrolysable analogues of ATP that may inhibit ATP-dependent intracellular enzymes. The more potent, nitrogen-containing bisphosphonates (such as pamidronate, alendronate, risedronate, and ibandronate) are not metabolized in this way but can inhibit enzymes of the mevalonate pathway, thereby preventing the biosynthesis of isoprenoid compounds that are essential for the posttranslational modification of small GTPases. The inhibition of protein prenylation and the disruption of the function of these key regulatory proteins explains the loss of osteoclast activity and induction of apoptosis. These different modes of action might account for subtle differences between compounds in terms of their clinical effects. In conclusion, bisphosphonates are now established as an important class of drugs for the treatment of bone diseases, and their mode of action is being unravelled. As a result, their full therapeutic potential is gradual
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PMID:Bisphosphonates: from the laboratory to the clinic and back again. 1042 31

In addition to inhibiting bone resorption, bisphosphonates also exert anti-tumor effects. The most potent compounds are the newer, nitrogen-containing bisphosphonates such as zoledronic acid. In vitro, bisphosphonates inhibit proliferation and induce apoptosis in human tumor cell lines, and interfere with cell adhesion, invasion and growth factor secretion. The combination of bisphosphonates with other anti-cancer drugs such as paclitaxel or tamoxifen markedly enhances these effects. In vivo, zoledronic acid has recently been shown to inhibit angiogenesis. Although bisphosphonates are very effective against bone metastases, their in vivo anti-tumor potential against visceral metastases remains to be explored.
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PMID:Anti-tumor potential of bisphosphonates. 1108 84

Bisphosphonates are potent inhibitors of bone resorption and provide a therapeutic benefit for patients with bone metastases. Zoledronic acid is a highly potent, nitrogen-containing bisphosphonate. In the present trial, we assessed the safety and tolerability of increasing doses of zoledronic acid and its effects on urinary markers of bone resorption in cancer patients with bone metastases. Fifty-nine cancer patients with bone metastases were enrolled sequentially into one of 8 treatment groups in the core protocol. Each patient received a 5-min i.v. infusion of 0.1, 0.2, 0.4, 0.8, 1.5, 2, 4, or 8 mg zoledronic acid monthly for 3 months. Patients were monitored for clinical findings, adverse events, electrocardiograms, markers of bone resorption, as well as routine hematology, blood chemistries, and urinalysis. Thirty patients who demonstrated a radiographic response to treatment or stable disease in the core protocol were enrolled in a humanitarian extension protocol and continued to receive monthly infusions. Zoledronic acid was well tolerated at all dose levels. Adverse events reported by >10% of patients included skeletal pain, nausea, fatigue, upper respiratory tract infection, constipation, headache, diarrhea, and fever. Three patients in the core protocol and one patient in the extension protocol experienced grade 3 skeletal pain, "flu-like" symptoms, or hypophosphatemia, which were possibly related to treatment; all recovered completely. Adverse events were reported with similar frequency across all of the dosage groups. Zoledronic acid resulted in sustained, dose-dependent decreases in urinary markers of bone resorption. Zoledronic acid was safe and well tolerated and demonstrated potent inhibition of bone resorption.
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PMID:A phase I dose-ranging trial of monthly infusions of zoledronic acid for the treatment of osteolytic bone metastases. 1129 37

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

Pamidronate belongs to the class of nitrogen-containing bisphosphonates that are potent inhibitors of bone resorption frequently used for the treatment of osteoporosis and cancer-induced osteolysis. The inhibition of osteoclasts' growth has been suggested as the main mechanism of the inhibitory effect of pamidronate on bone metastases. Recent findings indicated that bisphosphonates also have a direct apoptotic effect on other types of tumour cells. Nitrogen-containing bisphosphonates were shown to inhibit farnesyl diphosphate synthase, thus blocking the synthesis of higher isoprenoids. By this mechanism they inactivate monomeric G-proteins of the Ras and Rho families for which prenylation is a functional requirement. On the background of the known key role of G-proteins in tumorigenesis, we investigated a possible beneficial use of pamidronate in the treatment of malignant melanoma. Our results indicate that pamidronate inhibits the cell growth and induces apoptosis in human melanoma cells in vitro. Susceptibility to pamidronate did not correlate to CD95 ligand sensitivity or p53 mutational status. Furthermore it is interesting to note that overexpression of bcl-2 did not abolish pamidronate-induced apoptosis. These data suggests that pamidronate has a direct anti-tumour effect on malignant melanoma cells, independently of the Bax/Bcl-2 level.
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PMID:The bisphosphonate pamidronate induces apoptosis in human melanoma cells in vitro. 1217 10

Bone recurrence constitutes one third of initial sites of relapse and one half of distant sites of relapse at 10 years from diagnosis of breast cancer. Bone pain, fracture (including vertebral fracture resulting from increased bone resorption following chemotherapy-induced menopause), and hypercalcemia are components of skeletal morbidity. The pathophysiology of malignant osteopathy occurs because of the secretion of substances (such as parathyroid hormone-related peptide), by the malignant cell, which stimulate osteoclast function; this in turn feeds further growth, which causes a vicious cycle. Interruption of this cycle by bisphosphonates may inhibit the growth of malignant cells. Bisphosphonates are drugs that inhibit bone turnover by decreasing bone resorption. Side effects of bisphosphonates include upper gastrointestinal symptoms (in oral nitrogen-containing bisphosphonates) and diarrhea (in oral non-nitrogen-containing bisphosphonates) and an acute phase-like reaction with intravenous (I.V.) pamidronate. Bisphosphonates have different molecular mechanisms of action: Nitrogen-containing bisphosphonates (eg, pamidronate and alendronate) inhibit the mevalonate-signaling pathway while the non-nitrogen-containing drugs (eg, clodronate) incorporate into adenosine triphosphate analogues. There is in vitro evidence that these drugs also possess anticancer properties. In hypercalcemia patients, treatment with pamidronate and zoledronate produce prompt and efficient normocalcemia. Intravenous pamidronate and zoledronate, oral clodronate, and ibandronate reduce skeletal complications in patients with bone metastases; I.V. pamidronate and clodronate are useful for bone pain relief. Three adjuvant bisphosphonate trials are discussed herein: 2 small open-label studies giving conflicting results and a large placebo-controlled trial of oral clodronate. This latter trial shows a reduction in the incidence of skeletal metastases (while the patients are on therapy) and an improved survival at 5 years.
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PMID:Bisphosphonates: biological response modifiers in breast cancer. 1219 79

Bisphosphonates inhibit osteoclast-mediated bone resorption in metastatic bone disease. A wealth of preclinical data have begun to shed light on the complex mechanisms by which bisphosphonates inhibit bone resorption and interfere with the formation and growth of bone metastases. Nitrogen-containing bisphosphonates inhibit the mevalonate pathway, which results in the inhibition of osteoclast function and the induction of apoptosis in osteoclasts and tumor cells alike. There is now extensive evidence that bisphosphonates have cytostatic activity against tumor cell lines and inhibit tumor cell adhesion and invasion of the extracellular matrix. These data are supported by a growing body of evidence from animal models demonstrating that bisphosphonates can reduce skeletal tumor burden. However, it remains unclear whether this reduction reflects a direct antitumor effect or an indirect effect via osteoclast inhibition and alteration of the bone microenvironment. Further preclinical studies are needed to elucidate these biochemical mechanisms fully; ultimately, well-controlled clinical trials will be required to investigate whether the antitumor potential of bisphosphonates translates into a significant clinical benefit for patients with cancer.
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PMID:Bisphosphonates in cancer therapy. 1240 50


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