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)

Bisphosphonates may induce direct anti-tumor effects in breast cancer cells in vitro. In this study, six bisphosphonates were administered to three breast cancer cell lines. Cell proliferation was measured by quantification of the expression of Cyclin D1 mRNA. Apoptosis was determined by flow cytometry of a DNA fragmentation assay. We demonstrated that bisphosphonates have direct effects on cell proliferation and apoptosis in different breast cancer cell lines. However, not all bisphosphonates act equally on breast cancer cells in vitro. Zoledronate seems to be the most potent of the six bisphosphonates. This in vitro study showed that bisphosphonates possess promising anti-tumor potential.
Cancer Lett 2007 Feb 08
PMID:Differential effects of bisphosphonates on breast cancer cell lines. 1662 Dec 45

The prevention of cancer-treatment-induced bone loss (CTIBL) in long-term adjuvant breast cancer therapy is a high priority. Postmenopausal women with cancer, already at increased risk of bone loss because of age-related estrogen deficiency, face accelerated bone loss with the use of estrogen-depleting therapies such as third-generation aromatase inhibitors (AIs). Although effective in reducing cancer recurrence rates in the adjuvant setting, AIs are associated with bone loss and an increased risk of fractures. Bisphosphonates, which act by inhibiting osteoclastic bone resorption, have been shown to increase bone mineral density (BMD) and reduce fracture risk in postmenopausal women with established osteoporosis. Furthermore, the potent bisphosphonate zoledronic acid has been shown to be efficacious in reducing bone loss in premenopausal women receiving combination adjuvant hormone therapy (goserelin, a gonadotropin-releasing hormone agonist, plus either an AI or tamoxifen). The use of zoledronic acid to prevent CTIBL in postmenopausal women receiving adjuvant AI therapy with letrozole is currently being investigated in the Zometa/Femara Adjuvant Synergy Trial (Z-FAST). Postmenopausal women with stage I-IIIa estrogen-receptor-positive and/or progesterone-receptor-positive breast cancer starting letrozole are randomized to receive either upfront zoledronic acid or delayed zoledronic acid. At 6 months, assessable women in the upfront group showed a mean increase of 1.55% in lumbar spine (L1 - L4) BMD, compared with a mean decrease of 1.78% in women in the delayed group, resulting in a difference of 3.33% between groups; moreover, women in the former group showed a mean increase of 1.02% in total hip BMD, compared with a mean decrease of 1.40% in those in the latter group, resulting in a significant difference of 2.42% between groups (P <.001). Thus, the Z-FAST BMD results show that upfront zoledronic acid prevents CTIBL in postmenopausal women receiving adjuvant letrozole therapy for early breast cancer. Combining the anticancer efficacy of letrozole with the bone-protective effect of zoledronic acid may be a successful treatment in this setting.
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PMID:Management of cancer-treatment-induced bone loss in postmenopausal women undergoing adjuvant breast cancer therapy: a Z-FAST update. 1673 Feb 72

Multiple myeloma is the malignant proliferation of plasma cells involving more than 10% of the bone marrow. The bone complications associated with multiple myeloma include bone pain, pathologic fractures, hypercalcemia of malignancy and cord compressions. The principal pathophysiology of bone disease in multiple myeloma is a shift in the balance of bone remodeling toward bone resorption. In recent years, bisphosphonates have become an important treatment for the bone complications of multiple myeloma. Potent inhibitors of osteoclast activity, bisphosphonates interfere with biochemical pathways and induce osteoclast apoptosis. Bisphosphonates also antagonize osteoclastogenesis and promote differentiation of osteoblasts, as well as inhibiting other aspects of osteoclast homeostasis and metabolism. Several studies have evaluated treatment with bisphosphonates in patients with multiple myeloma, and have demonstrated the efficacy of clodronate (Bonefos; Anthra Pharmaceuticals; Princeton, NJ; www.bonefos.com), pamidronate (Aredia; Novartis Pharmaceuticals Corp; East Hanover, NJ; www.pamidronate.com) and zoledronic acid (Zometa; Novartis Pharmaceuticals Corp; East Hanover, NJ; www.us.zometa.com) in reduction of pain, reduction of SREs and survival. Moreover, recent data suggest direct and indirect antimyeloma activity of pamidronate and zoledronic acid.
Cancer Biol Ther 2006 Sep
PMID:Bone complications in multiple myeloma. 1696 19

The aromatase inhibitors (AIs) anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin) are significantly more effective than the selective estrogen-receptor modulator (SERM) tamoxifen in preventing recurrence in estrogen receptor-positive early breast cancer. Aromatase inhibitors are likely to replace SERMs as first-line adjuvant therapy for many patients. However, AIs are associated with significantly more osteoporotic fractures and greater bone mineral loss. As antiresorptive agents, oral and intravenous bisphosphonates such as alendronate (Fosamax), risedronate (Actonel), ibandronate (Boniva), pamidronate (Aredia), and zoledronic acid (Zometa) have efficacy in preventing postmenopausal osteoporosis, cancer treatment-related bone loss, or skeletal complications of metastatic disease. Clinical practice guidelines recommend baseline and annual follow-up bone density monitoring for all patients initiating AI therapy. Bisphosphonate therapy should be prescribed for patients with osteoporosis (T score < -2.5) and considered on an individual basis for those with osteopenia (T score < -1). Modifiable lifestyle behaviors including adequate calcium and vitamin D intake, weight-bearing exercise, and smoking cessation should be addressed. Adverse events associated with bisphosphonates include gastrointestinal toxicity, renal toxicity, and osteonecrosis of the jaw. These safety concerns should be balanced with the potential of bisphosphonates to minimize or prevent the debilitating effects of AI-associated bone loss in patients with early, hormone receptor-positive breast cancer.
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PMID:Aromatase inhibitors and bone loss. 1698 48

Bisphosphonates are used as potent inhibitors in metastatic bone lesions. They can reduce skeletal burden and prevent bony metastases. They are integral in the treatment of some tumours like breast cancer, prostate cancer and multiple myeloma. As a side effect, these drugs also may cause severe jaw necrosis. Twenty-four patients with bisphosphonate-related jaw necrosis were analyzed in a clinical study. These necroses mostly appeared after administration of aminobisphosphonates. Recurrent avascular necroses were found after changing from Pramidronate to Zoledronate. All patients were treated by resection of necrotic bone. Repeated surgical interventions were required with about 25% of the patients. The management of patients with bisphosphonate-related jaw necrosis remains extremely difficult and includes surgical procedures as well as the eradicating of the necrotic bone including antibiotic therapy. The prevention of such complications consists in a minimization of dental surgical interventions and an avoidance of ulcers by dental prosthesis.
Cancer Treat Rev 2007 Feb
PMID:Bisphosphonate-related jaw necrosis--severe complication in maxillofacial surgery. 1708 33

Since osteosarcoma is a drug-resistant disease, the aim of the present study was to explore the possible interest of therapeutic approaches including nitrogen-containing biphosphonate zoledronic acid using osteosarcoma cell lines with different genetic backgrounds. Parental p53+/pRb+ U2-OS, p53-mutant U2-OS (U2-OS/175) and p53-/pRb- SAOS were sensitive to zoledronic acid with no significant differences in IC50 values. Analysis of cell cycle distribution revealed a time-dependent shifting of U2-OS cells towards G2 phase with cell cycle arrest in G2 phase at 96 h of exposure to the compound. Conversely, U2-OS/175 and SAOS cells responded to treatment with transient cell accumulation in S phase up to 48-72 h, respectively. Cell lines were exposed to increasing concentrations of cisplatin alone or combined with sub-toxic doses of zoledronic acid. A growth inhibitory effect was seen after combined treatment in U2-OS, otherwise resistant to cisplatin up to 100 ng/ml. Zoledronic acid did not efficiently sensitized U2-OS/175 and SAOS to cisplatin, thereby suggesting that different behavior may depend on p53 mutation. This data was confirmed in U2-OS cells where p53 expression was downregulated by RNA interference. Present findings indicate occurrence of sensitization to cisplatin by zoledronic acid in wild-type p53 osteosarcoma cells but not in p53-null cells nor in cells expressing a dominant-negative form of p53, supporting that wild-type p53 is required for synergistic interaction of cisplatin and zoledronic acid.
Cancer Lett 2007 Jun 08
PMID:Growth inhibition and sensitization to cisplatin by zoledronic acid in osteosarcoma cells. 1711 7

Zoledronic acid is a potent bisphosphonate licensed for the treatment of myeloma and bone metastases from solid tumors. Renal deterioration is the most significant toxicity associated with zoledronic acid. We attempted to define the incidence and clinical significance of renal deterioration in patients receiving zoledronic acid and to develop a risk-factor profile for this treatment sequela. This study is a retrospective analysis of all patients who received zoledronic acid at Fox Chase Cancer Center, Philadelphia, Pa, between 1/10/02 and 1/30/04. Data recorded included patient demographics, tumor characteristics, comorbid illnesses, concomitant medications, cancer therapy, number of zoledronic acid doses administered, and serial creatinine measurements. In total, 3,115 evaluable doses of zoledronic acid were administered to 446 patients (median, 4 doses; mean, 6.98 doses; range, 1-28 doses) at a dose of 4 mg over 15 minutes every 3-4 weeks. Of these 446 patients, 42 experienced renal deterioration (median rise in creatinine level, 1.0 mg/dL; range, 0.5-4.4 mg/dL), requiring discontinuation of zoledronic acid therapy in 8 cases. No patient required dialysis and no patient died as a result of zoledronic acid-induced renal dysfunction. On multivariable analysis, predictive factors for the development of renal deterioration were patient age, a diagnosis of myeloma or renal cell cancer, cumulative number of doses, concomitant therapy with a nonsteroidal anti-inflammatory drug, and current or prior therapy with cisplatin. Using these factors, we constructed a predictive model with an area under the receiver operating characteristic curve of 0.75. The incidence of clinically significant renal deterioration in patients treated with zoledronic acid is low.We present a predictive model for decision support when estimating this risk.
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PMID:Impact of zoledronic acid on renal function in patients with cancer: Clinical significance and development of a predictive model. 1713 70

Bone necrosis of the jaws is often related to head and neck radiotherapy, to surgical procedures at maxillary or mandibular level but also to various local and systemic factors such as haematological diseases, haemoglobinopathies and systemic lupus eritematosus; its pathogenesis maybe associated with defects of vascularization. Bisphosphonate are synthetic analogues of pyrophosphate used for the treatment of hypercalcemia in patients with malignancies and bone metastasis and for the treatment of many other disorders such as metabolic bone diseases, Paget's disease, and osteoporosis; their pharmacological activity is related to the inhibition of the osteoclastic function which leads to resorption and reduction of bone vascularization. Since the end of 2003 Bisphosphonate-associated Osteonecrosis (BON) has become an increasing problem and the test of that is the increase of the relative published case report and case series. Here we report 29 cases of bone necrosis of the jaws in patients treated with pamidronate (Aredia), zoledronate (Zometa) and alendronate: 15 underwent surgical procedures and 14 occurred spontaneously. Among these patients (21 females, 8 males; mean age between 45 and 83 years); 14 were treated for bone metastasis, 12 for multiple myeloma and 3 for osteoporosis. Bone necrosis involved only maxilla in 7 patients, only mandible in 20 patients and both in 2 patients. Six patients had multiple osteonecrotic lesions, 3 contemporary lesions and 3 non contemporary. In these patients we performed 3 kinds of therapy, associated or not: medical therapy (with antibiotic drugs, antimycotics and antiseptic mouthwashes), surgical therapy with curettage or sequestrectomy and Nd:YAG laser biostimulation.
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PMID:Bone necrosis of the jaws associated with bisphosphonate treatment: a report of twenty-nine cases. 1717 92

Zoledronic acid (ZOL) has proved activity in bone metastases from prostate cancer through inhibition of mevalonate pathway and of prenylation of intracellular proteins. We have reported that ZOL synergizes with R115777 farnesyltransferase inhibitor (FTI, Zarnestra) in inducing apoptosis and growth inhibition on epidermoid cancer cells. Here, we have studied the effects of the combination of these agents in prostate adenocarcinoma models and, specifically, on androgen-independent (PC3 and DU145) and -dependent (LNCaP) prostate cancer cell lines. We have found that ZOL and R115777 were synergistic in inducing both growth inhibition and apoptosis in prostate adenocarcinoma cells. These effects were paralleled by disruption of Ras-->Erk and Akt survival pathways, consequent decreased phosphorylation of both mitochondrial bcl-2 and bad proteins, and caspase activation. Finally, ZOL/R115777 combination induced cooperative effects also in vivo on tumor growth inhibition of prostate cancer xenografts in nude mice with a significant survival increase. These effects were paralleled by enhanced apoptosis and inactivation of both Erk and Akt. In conclusions, the combination between ZOL and FTI leads to enhanced anti-tumor activity in human prostate adenocarcinoma cells likely through a more efficacious inhibition of ras-dependent survival pathways and consequent bcl-related proteins-dependent apoptosis.
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PMID:R115777 (Zarnestra)/Zoledronic acid (Zometa) cooperation on inhibition of prostate cancer proliferation is paralleled by Erk/Akt inactivation and reduced Bcl-2 and bad phosphorylation. 1719 46

Intervenous (IV) bisphosphonates are used for cancer patients with hypercalcemia of malignancy (HCM) and breast cancer bone metastases (BM). Recently, zoledronic acid, the most potent third generation bisphosphonate, has been approved for both HCM and BM of broad tumors. It showed 850-fold stronger activity than pamidronate in bone resorption assay, and clinical efficacy against multiple cancer bone lesion has been confirmed in randomized clinical trials. Zoledronic acid becomes one of the most used bisphosphonate for cancer patients in the world, and the results of clinical trials for cancer treatment-induced bone loss or postmenopausal osteoporosis are now updating.
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PMID:[Therapeutic agents for disorders of bone and calcium metabolism: Zoledronic acid]. 1721 Oct 90


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