Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006826 (cancer)
 1,092,456 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The two main therapeutic applications of bisphosphonates are tumour bone disease and osteoporosis. They constitute the standard treatment for cancer hypercalcaemia, and placebo-controlled trials have shown that the prolonged administration of bisphosphonates, such as pamidronate or clodronate, can reduce the frequency of complications from tumour bone disease due to metastatic breast cancer or myeloma by a quarter to one-half. The results obtained with the intravenous route appear to be more impressive and more rapidly obtained than with oral compounds. Both agents can reduce the risk of vertebral, wrist and hip fractures by 30 - 50%, whereas other antiresorptive agents, such as raloxifene (Eli Lilly & Co.) or calcitonin (Unigene Laboratories Inc.), have only been demonstrated to reduce the incidence of vertebral fractures. The short infusion time (4 mg over 15 min) offers a convenient therapy and constitutes the most evident advantage of zoledronic acid, which will improve patients' quality of life. Zoledronic acid has the potential to change the treatment of osteoporosis dramatically.
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PMID:Zoledronic acid: an advance in tumour bone disease therapy and a new hope for osteoporosis. 1266 19

Zoledronic acid (Zometa) is the most recent addition to the clinically available bisphosphonates. Clinical benefits in metabolic, as well as cancer-related bone disease have been observed. In addition to its profound antiosteoclast effects, it has demonstrated anticancer effects in preclinical models. Zoledronic acid has been evaluated in randomized, double-blind clinical trials of osteoporosis, Paget's disease of bone, and metastatic, osteolytic and osteoblastic bone disease. Antiosteoclast activity has been demonstrated by reductions in the bone breakdown products N-telopeptide, C-telopeptide and deoxypyridinoline. Bone mineral density, measured by dual energy x-ray absorptometry, is increased with administration of zoledronic acid in postmenopausal osteoporosis. Clinical benefit in cancer includes improvement in bone pain, reductions in skeletal events and delay in time-to-first-skeletal-events. These zoledronic acid treatment benefits have been demonstrated in patients with multiple myeloma, breast, prostate and lung cancer, and other solid tumors.
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PMID:Zoledronic acid (Zometa) use in bone disease. 1272 75

Less than 25 years ago, tumor-induced hypercalcemia was often a lethal complication of cancer. Nowadays, it can be successfully and easily treated in at least 90% of the cases by rehydration and potent antiosteoclastic bisphosphonates. The standard therapy consists of the administration of 90 mg of pamidronate (Aredia Dry Powder) or more recently, 4 mg of zoledronic acid (Zometa)], which is even more efficient, at least in patients without bone metastases. Recurrent hypercalcemia is nevertheless difficult to control and antibodies against parathyroid-hormone-related protein may prove to be a useful treatment.
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PMID:Treatment of tumor-induced hypercalcemia: a solved problem? 1272 83

Zoledronic acid (ZOL) is a nitrogen-containing bisphosphonate and its use in reducing osteoporosis and cancer-induced osteolysis is increasing. Recent findings indicated that ZOL has a direct effect on cancer cells. In this study, the effect of ZOL was examined on the aggressive MDA-MB-231 breast cancer cell line. ZOL induces an important inhibition of cell invasion at low concentrations (1 microM). This is not explained by modifications of proteases involved in cell invasiveness (matrix metalloproteinases and urokinase-type plasminogen activator), but by a disorganisation of actin cytoskeleton due to RhoA inhibition related to its defective prenylation as it was reversed by geranylgeraniol (GGOH) and mimicked by the Rho selective inhibitor C3 exoenzyme. In addition, ZOL inhibits the chemotactic effect induced by stromal cell-derived factor 1(SDF-1), a chemokine greatly involved in cancer metastasis to bone. This effect is related to both reduction of cell motility induced by RhoA inhibition and to a decreased expression of CXCR-4, the SDF-1 receptor. Finally, ZOL reduces Cox-2 expression and, consequently, the secretion of prostaglandins E2 (PGE2) in a RhoA-independent manner. This inhibition could contribute to bone protection in breast cancers because PGE2 stimulates osteoclast-mediated bone resorption. In summary, new insights in the mechanism of ZOL action on aggressive breast cancer cells are demonstrated and could explain its beneficial action in both the reduction of osteolysis and prevention of metastasis.
Br J Cancer 2003 May 19
PMID:New insights into the actions of bisphosphonate zoledronic acid in breast cancer cells by dual RhoA-dependent and -independent effects. 1277 33

Metastasis to bone is a common feature in advanced prostate cancer patients. Current treatments, while effective in suppressing tumour growth and relieving tumour associated bone pain, do not provide long term remission or 'cure' for the disease. A greater understanding of prostate cancer metastasis is required if new treatment strategies are to be developed. Growth of tumour foci in skeletal sites is a major cause of morbidity in advanced prostate cancer and has required the development of specialised approaches to treatment, including the use of bisphosphonates. These drugs inhibit tumour induced osteoclastic bone resorption, thereby preventing skeletal related events and treatment induced bone loss. Zoledronic acid is currently the only bisphosphonate with proven benefit in prostate cancer. Bisphosphonates may also modify the bone microenvironment so that it becomes less favourable for the growth and survival of metastases. The most recent developments in our understanding of the advantages for growth and survival gained by metastatic prostate cancer cells in the skeleton are reviewed, along with the clinical evidence supporting the use of bisphosphonates in advanced prostate cancer.
Cancer Treat Rev 2003 Jun
PMID:Pathophysiology of bone metastases from prostate cancer and the role of bisphosphonates in treatment. 1278 13

Osteoporosis is an important and preventable adverse effect of androgen deprivation therapy for prostate cancer. Androgen deprivation therapy by either bilateral orchiectomies or administration of a gonadotropin-releasing hormone agonist decreases bone mineral density and increases fracture risk. Treatment-related osteoporosis can be prevented by intermittent administration of either intravenous pamidronate or zoledronic acid. Pamidronate (60 mg intravenously every 3 months) prevents bone loss during androgen deprivation therapy. Zoledronic acid (4 mg intravenously every 3 months) not only prevents bone loss but also increases bone mineral density. Alendronate and other oral bisphosphonates may be effective but have not been evaluated in men with castrate testosterone levels. Oestrogen replacement therapy and treatment with selective ooestrogen receptor modulators may prevent bone loss during androgen deprivation therapy. Bicalutamide (150 mg daily) monotherapy increases serum ooestrogen levels and maintains bone mineral density.
Cancer Treat Rev 2003 Jun
PMID:Management of treatment-related osteoporosis in men with prostate cancer. 1278 15

Bisphosphonates (BPs) constitute a major advance in the treatment of malignancy-associated hypercalcemia(MAH). BPs correct MAH through the mechanisms of inhibition of osteoclastic bone resorption. Although BPs are more potent agents than calcitonin in the treatment of MAH, anti-hypercalcemic effect of BPs appears more slowly than that of calcitonin. Therefore, combination therapy with BP and calcitonin is favorable in the treatment of MAH showing hypercalcemic crisis. Zoledronate, most potent bisphosphonate, is apparently superior to pamidronate, standard bisphosphonate, in the treatment of MAH. BP therapy develops no serious adverse effects (i.e. acute renal failure) in clinical practice. However, attention should be paid to BP-induced pyrexia and transient pain increase.
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PMID:[Malignancy-associated hypercalcemia]. 1280 51

The knowledge and training of nursing staff is essential for the safety and comfort of patients receiving i.v. therapies. The use of i.v. bisphosphonates as an adjunct to standard antineoplastic therapies in patients with advanced cancer is becoming widespread. Zoledronic acid and pamidronate (Zometa and Aredia, Novartis Pharmaceuticals Corporation, East Hanover, NJ) are nitrogen-containing bisphosphonates. Pamidronate has been the standard of care for patients with osteolytic bone lesions from breast cancer or multiple myeloma. However, zoledronic acid, which has demonstrated increased potency and a broad clinical utility, is emerging as the new standard of care. In addition to treating hypercalcemia of malignancy, zoledronic acid is approved for treating patients with bone metastases (osteolytic or osteoblastic) from a wide range of solid tumors, including breast, prostate, and lung cancers, or osteolytic bone lesions from multiple myeloma. Zoledronic acid (4 mg via a 15-minute infusion) has a safety profile comparable with pamidronate (90 mg via a two-hour infusion) and has demonstrated comparable or superior efficacy to that of pamidronate in every patient population tested. The shorter infusion time of zoledronic acid compared with that of pamidronate may provide added convenience, but safety guidelines should be followed for all i.v. bisphosphonate therapies. These guidelines and nursing care of patients receiving i.v. bisphosphonates are reviewed.
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PMID:Advances in supportive care of patients with cancer and bone metastases: nursing implications of zoledronic acid. 1292 73

Bisphosphonates are potent inhibitors of osteoclast function widely used to treat conditions of excessive bone resorption, including tumor bone metastases. Recent evidence indicates that bisphosphonates have direct cytotoxic activity on tumor cells and suppress angiogenesis, but the associated molecular events have not been fully characterized. In this study we investigated the effects of zoledronate, a nitrogen-containing bisphosphonate, and clodronate, a non-nitrogen-containing bisphosphonate, on human umbilical vein endothelial cell (HUVEC) adhesion, migration, and survival, three events essential for angiogenesis. Zoledronate inhibited HUVEC adhesion mediated by integrin alphaVbeta3, but not alpha5beta1, blocked migration and disrupted established focal adhesions and actin stress fibers without modifying cell surface integrin expression level or affinity. Zoledronate treatment slightly decreased HUVEC viability and strongly enhanced tumor necrosis factor (TNF)-induced cell death. HUVEC treated with zoledronate and TNF died without evidence of enhanced annexin-V binding, chromatin condensation, or nuclear fragmentation and caspase dependence. Zoledronate inhibited sustained phosphorylation of focal adhesion kinase (FAK) and in combination with TNF, with and without interferon (IFN) gamma, of protein kinase B (PKB/Akt). Constitutive active PKB/Akt protected HUVEC from death induced by zoledronate and TNF/IFNgamma. Phosphorylation of c-Src and activation of NF-kappaB were not affected by zoledronate. Clodronate had no effect on HUVEC adhesion, migration, and survival nor did it enhanced TNF cytotoxicity. Taken together these data demonstrate that zoledronate sensitizes endothelial cells to TNF-induced, caspase-independent programmed cell death and point to the FAK-PKB/Akt pathway as a novel zoledronate target. These results have potential implications to the clinical use of zoledronate as an anti-angiogenic or anti-cancer agent.
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PMID:Zoledronate sensitizes endothelial cells to tumor necrosis factor-induced programmed cell death: evidence for the suppression of sustained activation of focal adhesion kinase and protein kinase B/Akt. 1293 98

Zoledronic acid is a potent, third generation, nitrogen-containing bisphosphonate, licensed for the management of skeletal metastases and hypercalcaemia of malignancy, both of which cause considerable morbidity. In the preclinical setting, zoledronic acid has demonstrated superior potency regarding inhibition of osteolysis and reduction of hypercalcaemia as compared with other bisphosphonates. Clinical trials have indicated that zoledronic acid is superior to pamidronate in suppressing osteolysis and in reducing hypercalcaemia of malignancy. Its main mechanism of action is induction of osteoclast apoptosis through inhibition of the mevalonate pathway. Zoledronic acid has also demonstrated direct anti-tumour activity both in vitro and in animal models, suggesting it may be of benefit in preventing the formation of bone metastases. Clinical trials are in progress, assessing the benefit of zoledronic acid in the adjuvant setting in both breast and prostate cancer.
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PMID:The use of zoledronic acid in the management of metastatic bone disease and hypercalcaemia. 1452 88


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