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 introduction of zoledronic acid, a new-generation bisphosphonate, has greatly extended the use of bisphosphonates in the treatment of patients with bone metastases. On the basis of results from three large, randomized, phase III clinical trials enrolling more than 3,000 patients, zoledronic acid (4 mg via 15-minute infusion) was approved in the United States for the treatment of patients with documented bone metastases from solid tumors in conjunction with standard antineoplastic therapy and patients with multiple myeloma. Zoledronic acid is also approved in Europe for the prevention of skeletal-related events in patients with advanced malignancies involving bone. Current treatment guidelines published by the American Society of Clinical Oncology recommend the use of intravenous bisphosphonates at first radiographic evidence of osteopenia in patients with multiple myeloma or osteolytic bone lesions in patients with breast cancer to significantly reduce the occurrence and delay the onset of skeletal complications. Zoledronic acid has also demonstrated efficacy in the treatment of bone metastases in patients with prostate cancer, lung cancer, and other solid tumors. Bisphosphonate therapy is generally well tolerated but can be associated with increases in serum creatinine. Therefore, monitoring renal function is required for all patients receiving bisphosphonate therapy. Serum creatinine should be monitored before each dose and treatment withheld until any serum creatinine elevations have resolved to baseline levels. Caution should be exercised when treating patients who are receiving other potentially nephrotoxic therapies. With these simple precautions, intravenous bisphosphonate therapy is safe for long-term use and provides durable treatment benefits.
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PMID:Recommendations for zoledronic acid treatment of patients with bone metastases. 1585 80

Bone metastases commonly occur in the course of malignant tumor disease. For many years, attempts have been made to identify factors for the management of cancer-induced skeletal complications. Nowadays, synthetic antiresorptive agents are considered to be indispensable for the treatment of cancer-related skeletal events, such as bone metastasis. The most common of these drugs are the bisphosphonates, which represent one of the most significant advances over the last 10 years in the field of supportive care and cancer. They are used for the treatment of cancer-induced hypercalcemia, for the prevention and treatment of postmenopausal osteoporosis, for patients with bone metastases secondary to breast cancer and multiple myeloma. A third-generation bisphosphonate, zolendronate, has been shown to minimize the destructive consequences of bone metastases and to exert a profound effect on tumor-induced osteolysis and tumor growth in bone. Zoledronate is already used for the treatment of hypercalcemia of malignancy, multiple myeloma-related osteolytic events and for patients with documented bone metastases from solid tumors in conjunction with standard antineoplastic therapy. The structure-function activity of the three generations of bisphosphonates developed to date, the in vitro models used for studying their effects on osteoclasts and osteoblasts, as well as the results of clinical trials obtained by the third generation bisphosphonate, zoledronic acid, are presented.
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PMID:In vitro and in vivo antiresorptive effects of bisphosphonates in metastatic bone disease. 1579 91

Breast cancer is the leading type of cancer among women, and bone metastases are common in patients with breast cancer, affecting more than half of all patients with advanced disease. Bisphosphonates are the current standard of care for preventing skeletal complications associated with bone metastases. Clinical trials investigating the benefit of bisphosphonate therapy have used a composite end point defined as a skeletal-related event (SRE) or bone event, which typically includes pathologic fracture, spinal cord compression, radiation or surgery to bone, and hypercalcaemia of malignancy. Bisphosphonates significantly reduced the incidence of these events. Zoledronic acid, pamidronate, clodronate and ibandronate have demonstrated efficacy compared with placebo. Zoledronic acid has also been compared with another active bisphosphonate (i.e. pamidronate) and shown by multiple event analysis to be significantly more effective at reducing the risk of SREs. Bisphosphonates effectively reduce and prevent skeletal complications in patients with bone metastases from breast cancer. Preclinical data suggest that bisphosphonates have antitumour effects. Bisphosphonates may also be of use in the adjuvant setting.
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PMID:Bisphosphonates in breast cancer. 1580 76

Prostate cancer cells metastasize to the bone where their interaction with osteoclasts and osteoblasts can lead to alterations in the structure of the bone. We determined whether the systemic administration of the bisphosphonate, zoledronate, could prevent bone lysis and halt the proliferation of human prostate cancer cells injected into the tibia of nude mice. Zoledronate did not affect the in vitro proliferation of human prostate cancer PC-3MM2 cells. The in vivo administration of zoledronate produced significant bone preservation but did not inhibit the progressive growth of PC-3MM2 cells. The systemic administration of STI571 (imatinib mesylate, Gleevec), an inhibitor of phosphorylation of the platelet-derived growth factor receptor, in combination with paclitaxel, produced apoptosis of tumor cells and bone- and tumor-associated endothelial cells. The systemic administration of zoledronate with STI571 and paclitaxel produced a significant preservation of bone structure, a decrease in tumor incidence and weight, and a decrease in incidence of lymph node metastasis. This therapeutic activity was correlated with inhibition of osteoclast function, inhibition of tumor cell proliferation, and induction of apoptosis in tumor-associated endothelial cells and tumor cells. Cancer is a heterogeneous disease that requires multimodality therapy. The present data recommend the combination of a bisphosphonate agent with protein tyrosine kinase inhibitor and an anticycling drug for the treatment of prostate cancer bone metastasis.
Cancer Res 2005 May 01
PMID:Modulation of bone microenvironment with zoledronate enhances the therapeutic effects of STI571 and paclitaxel against experimental bone metastasis of human prostate cancer. 1586 66

Patients with bone metastases from breast cancer often experience substantial skeletal complications -- including debilitating bone pain -- which negatively affect quality of life. Zoledronic acid (4 mg) has been demonstrated to reduce significantly the risk of skeletal complications in these patients and is administered via a short, 15-min infusion every 3 weeks, allowing the possibility for home administration. This study compared the efficacy and safety of zoledronic acid administered in the community setting vs the hospital setting in breast cancer patients with > or =1 bone metastasis receiving hormonal therapy. After a lead-in phase of three infusions of 4 mg zoledronic acid in the hospital setting, 101 patients were randomized to receive three open-label infusions in the community or hospital setting, followed by three infusions in the opposite venue (a total of nine infusions). The Brief Pain Inventory (BPI) and the European Organisation for Research and Treatment of Cancer Quality of Life Core Questionnaire 30 (EORTC QLQ-C30) were used to assess potential benefits of zoledronic acid therapy. At study end, analysis of the BPI showed significant reductions in worst pain (P=0.008) and average pain in the last 7 days (P=0.039), and interference with general activity (P=0.012). In each case, there were significantly greater improvements in pain scores after treatment in the community setting compared with the hospital crossover setting for worst pain (P=0.021), average pain (P=0.003), and interference with general activity (P=0.001). Overall global health status showed a significant median improvement of 8.3% (P=0.013) at study end. Physical, emotional, and social functioning also showed significant overall improvement (P=0.013, 0.005, and 0.043, respectively). Furthermore, physical, role, and social functioning showed significantly greater improvements after treatment in the community setting compared with the hospital crossover setting (P=0.018, 0.001, and 0.026, respectively). There was no difference between hospital and community administration in renal or other toxicity, with zoledronic acid being well tolerated in both treatment settings. These data confirm the safety and quality-of-life benefits of zoledronic acid in breast cancer patients with bone metastases, particularly when administered in the community setting.
Br J Cancer 2005 May 23
PMID:Zoledronic acid significantly improves pain scores and quality of life in breast cancer patients with bone metastases: a randomised, crossover study of community vs hospital bisphosphonate administration. 1587 Jul 21

Jaw bone necrosis is a clinical condition associated with defects in vascularization of the maxilla or the mandibular bone, usually present following head and neck radiotherapy and/or oral surgical interventions. Bisphosphonates are synthetic analogues of pyrophosphate used in the treatment of patients with hypercalcemia as a result of malignancy, bone metastasis and for the treatment of other disorders such as metabolic bone diseases, Paget's disease and osteoporosis. Over last 10 years, cases of jaw bone necrosis have been associated with the use of bisphosphonate therapy. In particular, Ruggiero et al. (J Oral Maxillofac Surg 2004; 62: 527-534) in 2004 described a large group of patients (63) with jaw bone necrosis probably related to the use of these drugs. It should be noted that all the patients in the group described either underwent head and neck radiotherapy or had a dental extraction while taking bisphosphonates. In the present study, we reported four cases of jawbone necrosis in patients taking pamidronate (Aredia) and zoledronate (Zometa) without having undergone any kind of radiotherapy or dental surgery. All the patients were females between the ages of 56 and 71 years; three were treated with bisphosphonates for bone metastasis and one for multiple myeloma. All the patients received surgical treatment with bone curettage, with partial and/or temporary improvement of the lesions. Although a treatment for bisphosphonate-induced bone lesions has not yet been established, we suggest careful evaluation of the patients' oral health before prescribing bisphosphonate treatment.
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PMID:Jaw bone necrosis without previous dental extractions associated with the use of bisphosphonates (pamidronate and zoledronate): a four-case report. 1620 82

Bisphosphonates are proven to be effective in the treatment of benign or malignant skeletal diseases characterized by enhanced osteoclastic bone resorption. Nitrogen-containing bisphosphonates (N-BPs) have also been demonstrated to exhibit direct anti-tumour effects. They not only inhibit proliferation and induce apoptosis in cultured cancer cells, but additionally interfere with adhesion of cancer cells to the bone matrix and inhibit cell migration and invasion. These effects are potentiated when N-BPs are combined with anticancer drugs like taxoids, doxorubicin or imatinib. Zoledronic acid is a highly potent N-BP that has been particularly well investigated, preclinically and in clinical practice. Growing preclinical evidence shows that zoledronic acid also exhibits direct anti-tumour activity. The overall effects on tumour cells appear to be mediated via diverse pathways, such as apoptosis, angiostasis, cell-cell-interactions and immunomodulation. The current insights and fronts of ongoing research are reviewed. Higher doses of zoledronic acid or more frequent applications than currently approved may be required to achieve clinically meaningful anti-tumour effects. The future challenge is to focus on optimizing dosing regimens and drug combinations to maximize the anti-tumour potential of zoledronic acid and to take advantage of the observed synergy with standard neoplastic agents.
Cancer Treat Rev 2005
PMID:Anti-tumour activity of zoledronic acid. 1622 95

Bone metastases are a major cause of cancer morbidity. Bone metastases are associated with pain, fractures, spinal cord compression, ineffective haematopoiesis, and hypocalcaemia of malignancy. The goals of treatment for bone metastases are to prevent disease-related skeletal complications, palliate pain, and maintain quality of life. Bisphosphonates are a standard part of supportive care for patients with bone metastases. Zoledronic acid, a nitrogen containing third generation bisphosphonate, is the most active and is the most thoroughly investigated bisphosphonate for metastatic bone disease. The efficacy and safety of zoledronic acid has been established in three pivotal prospective, randomized controlled trials involving more than 3000 subjects. The evidence is reviewed here with a focus on clinical relevance. Across a broad array of tumour types, zoledronic acid (4 mg intravenously over 15 min every 3-4 weeks) decreased the frequency of skeletal-related events, delayed the time to a first skeletal-related event, and reduced pain. Zoledronic acid is more effective than pamidronate in breast cancer and the only bisphosphonate proven effective for metastatic prostate cancer, lung cancer, renal cell carcinoma and other solid tumours.
Cancer Treat Rev 2005
PMID:Zoledronic acid to prevent skeletal complications in cancer: corroborating the evidence. 1622 55

In various common cancers, the skeleton is a preferred site of metastasis. It is also threatened by bone loss resulting from anti-cancer therapy. Like bone metastases in advanced cancer, cancer treatment induced bone loss (CTIBL) substantially increases fracture risk and dramatically decreases quality of life and patient autonomy. Both chemotherapy and endocrine deprivation therapy (EDT) can significantly decrease bone mineral density (BMD). This is aggravated by the often long duration of EDT, particularly in the adjuvant setting. Cumulative bone loss can put patients at risk of osteopenia and osteoporosis. With their known efficacy in preventing skeletal complications in metastatic disease, bisphosphonates (BP) lend themselves to exploring their extended use, notably in preventing CTIBL. Clinical trials have shown BPs to effectively prevent and treat CTIBL, for which they are recommended by ASCO guidelines. Whether BPs also have the potential to prevent metastatic dissemination to bone remains to be determined. Zoledronic acid, a third-generation BP with a favourable efficacy/safety record, was shown by ongoing large clinical trials to not only prevent or reduce CTIBL in early stage cancer, but to actually increase BMD. The current evidence of the potential of zoledronic acid in addressing CTIBL and preventing bone metastases is reviewed.
Cancer Treat Rev 2005
PMID:Moving into the future: treatment of bone metastases and beyond. 1624 57

Zoledronic acid (Zometa, ZOL) is increasingly used to treat tumour-induced bone disease, and is also reported to have antiangiogenic properties in vivo. In this study, we have investigated the correlations between changes in the proangiogenic cytokine, vascular endothelial growth factor (VEGF), and markers of bone resorption in a cohort of patients with metastatic bone disease, following a single infusion of ZOL. Twenty-four consecutive selected cancer patients with scintigraphic and radiographic evidence of bone metastases were treated for the first time with a single infusion of 4 mg ZOL. Patients were considered ineligible if they had received any steroid therapy, radiotherapy, chemotherapy, immunotherapy or haemopoietic growth factors in the 4 weeks before or during the study period. Circulating levels of VEGF and beta crosslinked type I collagen C-telopeptide (betaCTX) were measured at base-line and at 1, 2, 7 and 21 days following ZOL infusion. The majority of our patients (23/24) developed a significant reduction in circulating levels of betaCTX at just 1 day after the single zoledronic acid infusion, median percentage decrease 67.05% (95% CI, 52.39%; 76.27%). This reduction persisted at all following time points in almost all subjects in our patient population (day 2, 95.8%; day 7, 100%; day 21, 91.7%). The median decrease at day 2 was 85.67% (95% CI, 78.23%; 90.16%); at day 7, 67.38% (95% CI, 67.38%; 86.98); and at day 21, 76.89% (95% CI, 35.00%; 83.16%). Moreover, a linear regression model with variance analysis demonstrated a statistically significant correlation between median VEGF and betaCTX circulating levels at each of the time points (1, 2, 7 and 21 days after ZOL infusion). The present work demonstrates that a single infusion of ZOL was able to induce a rapid and long lasting decrease of betaCTX plasma levels in the majority (23/24) of the included cancer patients. Furthermore, we found that there is a correlation between the levels of VEGF and betaCTX following ZOL treatment. Future clinical trials should be designed to prospectively evaluate the prognostic role of reduction of betaCTX and VEGF in response to ZOL to predict clinical and skeletal outcome.
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PMID:Changes in bone resorption and vascular endothelial growth factor after a single zoledronic acid infusion in cancer patients with bone metastases from solid tumours. 1659 10


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