Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Zoledronic acid (Zometa, Novartis Pharmaceuticals Corp, East Hanover, NJ) is a new, highly potent bisphosphonate that may provide improved management of skeletal complications in cancer patients with bone metastases. A total of 383 cancer patients with osteolytic bone lesions was evaluated in two phase I studies and one phase II study of zoledronic acid. The phase I studies used two dosing regimens, either a 5-minute monthly intravenous infusion of 0.1 to 8 mg administered for 3 or more months or a single 30 to 60 second intravenous bolus of 1 to 16 mg. Zoledronic acid was well tolerated in the two phase I studies and a maximum tolerated dose was not reached in either study. A dose-dependent decrease in urinary markers of bone resorption was observed with the monthly 5-minute infusion. A single intravenous bolus of doses ranging from 2 to 16 mg zoledronic acid suppressed biochemical markers of bone resorption for up to 8 weeks. The phase II study evaluated a 5-minute infusion of 0.4, 2, or 4 mg zoledronic acid and a 2-hour infusion of 90 mg pamidronate in 280 patients with bone metastases and multiple myeloma or breast cancer. Significantly fewer patients receiving the 2 and 4 mg doses of zoledronic acid or 90 mg pamidronate required radiation therapy to bone than those patients receiving a 0.4 mg dose of zoledronic acid. Only 30% to 35% of patients in the 2 and 4 mg zoledronic acid groups or in the pamidronate group experienced any skeletal related event compared with 46% in the 0.4 mg zoledronic acid group. Adverse events consistent with an acute phase reaction were observed with both bisphosphonates. No new, unexpected adverse events were observed with this novel bisphosphonate. These studies support the further evaluation of zoledronic acid in cancer patients with osteolytic metastases. Doses of 0.4 mg or less are ineffective, while rapid infusion of more than 8 mg may increase the risk of renal dysfunction. A 4 mg dose given as a brief infusion appears to offer an excellent benefit/risk ratio for further evaluation in phase III trials.
 ...
PMID:Zoledronic acid in cancer patients with bone metastases: results of Phase I and II trials. 1134 62

The propensity for breast cancer cells to metastasize to bone and to induce osteolysis has long been recognized. Characteristics of both the tumor cells and the bone microenvironment contribute to this phenomenon. The presence of tumor in bone is associated with activation of osteoclasts, resulting in excessive bone resorption and subsequent osteolysis. Breast cancer cells and other tumor types influence osteoclastic bone resorption by increasing the number of osteoclasts and enhancing their resorptive activity. Parathyroid hormone-related peptide, in addition to its role in humorally mediated hypercalcemia, is secreted by metastatic breast cancer cells in bone in which it acts as a paracrine factor to stimulate osteoclasts. As bone matrix is broken down by activated osteoclasts, a rich supply of mitogenic factors is released, including insulin-like growth factors, bone morphogenetic proteins, and fibroblast growth factors. Transforming growth factor (TGF)-beta, one of the most abundant of the bone-derived factors, promotes increased production of parathyroid hormone-related peptide by tumor cells, establishing a "vicious cycle" leading to progressive tumor growth and bone destruction. Bisphosphonates interrupt this cycle by inhibiting osteoclasts, in part by inducing osteoclast apoptosis. In several animal models of breast cancer metastasis to bone, bisphosphonates decrease the number of new bone metastases and inhibit progression of existing lesions. A single 3 microg intravenous injection of zoledronic acid (Zometa; Novartis Pharmaceuticals Corp, East Hanover, NJ), a new highly potent bisphosphonate, prevented destruction of trabecular bone in an orthotopic mouse mammary tumor model. Tumor volume in bone was decreased by zoledronic acid in a dose-dependent manner in the same model, and tumor cell apoptosis was increased by zoledronic acid in bone metastases in the 4T1 murine model of mammary carcinoma metastasis. Zoledronic acid at a dose of 1.0 microg/d for 10 days also reduced bone lesion area in a nude mouse model with existing bone metastases. Although bisphosphonates, including zoledronic acid, are able to induce apoptosis in tumor cells in vitro, studies in animal models to date have generally not shown a reduction in nonosseous tumor. Therefore, bisphosphonate-associated tumor reduction in bone is most likely mediated by osteoclast inhibition or is related to high local concentrations of bisphosphonates in the bone compartment.
 ...
PMID:Preclinical studies with zoledronic acid and other bisphosphonates: impact on the bone microenvironment. 1134 63

Bisphosphonates (BPs) are pyrophosphate analogues in which the oxygen in P-O-P has been replaced by a carbon, resulting in a metabolically stable P-C-P structure. Pamidronate (1b, Novartis), a second-generation BP, was the starting point for extensive SAR studies. Small changes of the structure of pamidronate lead to marked improvements of the inhibition of osteoclastic resorption potency. Alendronate (1c, MSD), with an extra methylene group in the N-alkyl chain, and olpadronate (1h, Gador), the N,N-dimethyl analogue, are about 10 times more potent than pamidronate. Extending one of the N-methyl groups of olpadronate to a pentyl substituent leads to ibandronate (1k, Roche, Boehringer-Mannheim), which is the most potent close analogue of pamidronate. Even slightly better antiresorptive potency is achieved with derivatives having a phenyl group linked via a short aliphatic tether of three to four atoms to nitrogen, the second substituent being preferentially a methyl group (e.g., 4g, 4j, 5d, or 5r). The most potent BPs are found in the series containing a heteroaromatic moiety (with at least one nitrogen atom), which is linked via a single methylene group to the geminal bisphosphonate unit. Zoledronic acid (6i), the most potent derivative, has an ED(50) of 0.07 mg/kg in the TPTX in vivo assay after sc administration. It not only shows by far the highest therapeutic ratio when comparing resorption inhibition with undesired inhibition of bone mineralization but also exhibits superior renal tolerability. Zoledronic acid (6i) has thus been selected for clinical development under the registered trade name Zometa. The results of the clinical trials indicate that low doses are both efficacious and safe for the treatment of tumor-induced hypercalcemia, Paget's disease of bone, osteolytic metastases, and postmenopausal osteoporosis.
 ...
PMID:Highly potent geminal bisphosphonates. From pamidronate disodium (Aredia) to zoledronic acid (Zometa). 1216 45

Inoculation of syngeneic MRMT-1 mammary tumour cells into one tibia of female rats produced tumour growth within the bone associated with a reduction in bone mineral density (BMD) and bone mineral content (BMC), severe radiological signs of bone destruction, together with the development of behavioural mechanical allodynia and hyperalgesia. Histological and radiological examination showed that chronic treatment with the bisphosphonate, zoledronic acid (30 microg/kg, s.c.), for 19 days significantly inhibited tumour proliferation and preserved the cortical and trabecular bone structure. In addition, BMD and BMC were preserved and a dramatic reduction of tartrate resistant acid phosphatase-positive polykaryocytes (osteoclasts) was observed. In behavioural tests, chronic treatment with zoledronic acid but not the significantly less effective bisphosphonate, pamidronate, or the selective COX-2 inhibitor, celebrex, attenuated mechanical allodynia and hyperalgesia in the affected hind paw. Zoledronic acid also attenuated mechanical hyperalgesia associated with chronic peripheral neuropathy and inflammation in the rat. In contrast, pamidronate or clodronate did not have any anti-hyperalgesic effect on mechanical hyperalgesia in the neuropathic and inflammatory pain models. We conclude that zoledronic acid, in addition to, or independent from, its anti-metastatic and bone preserving therapeutic effects, is an anti-nociceptive agent in a rat model of metastatic cancer pain. This unique property of zoledronic acid amongst the bisphosphonate class of compounds could make this drug a preferred choice for the treatment of painful bone metastases in the clinic.
 ...
PMID:Disease modifying and anti-nociceptive effects of the bisphosphonate, zoledronic acid in a model of bone cancer pain. 1246 93

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.
 ...
PMID:Pathophysiology of bone metastases from prostate cancer and the role of bisphosphonates in treatment. 1278 13

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.
 ...
PMID:The use of zoledronic acid in the management of metastatic bone disease and hypercalcaemia. 1452 88

Many advanced cancers, particularly breast cancer and prostate cancer, metastasize to the bone, resulting in painful lesions and skeletal complications. Intravenous bisphosphonate therapy is an important component of palliative care for patients with bone metastases, and pamidronate has been the standard of care for patients with breast cancer and multiple myeloma since 1996. However, zoledronic acid is the first bisphosphonate shown to significantly reduce skeletal morbidity in patients with a wide range of primary tumor types. Zoledronic acid has demonstrated efficacy in the management of hypercalcemia and metastatic bone disease. In phase III studies involving more than 3000 patients with multiple myeloma, breast cancer, prostate cancer, lung cancer, and other cancers, 4 mg zoledronic acid demonstrated consistent efficacy across a range of clinical end-points, and was safe and well tolerated when infused over 15 min. Based on these studies, zoledronic acid appears to be active in patients with bone metastases irrespective of tumor type, and should be considered as the standard of care for the treatment of bone metastases.
 ...
PMID:Proven efficacy of zoledronic acid in the treatment of bone metastases in patients with breast cancer and other malignancies. 1465 40

Various primary malignancies develop bone metastases, and the resultant skeletal complications cause significant morbidity/mortality in advanced cancer patients. Bone lesions associated with metastases are traditionally classified radiologically as either osteolytic or osteoblastic, and both types of lesions are associated with elevated levels of specific bone resorption markers. Some common aspects in the pathophysiology of bone lesions have prompted speculation that treatments for osteolytic metastases might also be effective for predominantly osteoblastic metastases, such as in prostate cancer. Potent osteoclast activity inhibitors, bisphosphonates have been successful in the treatment of osteolytic tumor bone disease. Zoledronic acid is the first bisphosphonate shown to have a direct clinical benefit in the treatment of osteoblastic bone metastases, reducing the number and rate of skeletal events in prostate cancer patients with metastatic bone disease. Moreover, the shorter, more convenient infusion time and similar safety profile of 4 mg zoledronic acid compared with 90 mg pamidronate presently make zoledronic acid the preferred therapy for treatment of bone metastases in patients with all types of advanced malignancy.
 ...
PMID:Rationale for the use of bisphosphonates in osteoblastic and osteolytic bone lesions. 1465 42

Skeletal complications are a major cause of morbidity in men with metastatic prostate cancer. Bone metastases cause pain, fractures, spinal-cord compression, and ineffective hematopoiesis. Men without bone metastases are also at risk for skeletal complications. Androgen deprivation therapy (ADT), the mainstay of treatment for metastatic prostate cancer and a routine part of the management for many men with nonmetastatic prostate cancer, decreases bone mineral density, and increases fracture risk. Pathological osteoclast activation plays a central role in both disease and treatment-related skeletal morbidity. Bisphosphonates, potent inhibitors of osteoclast activity, are now an important part of the management for many men with prostate cancer. Zoledronic acid, a potent intravenous bisphosphonate, decreases the risk of skeletal complications in men with hormone-refractory prostate cancer and bone metastases. Zoledronic acid and pamidronate preserve bone mineral density in men receiving ADT for nonmetastatic prostate cancer. Ongoing clinical trials will evaluate the role of osteoclast-targeted therapy in other settings including prevention of treatment-related fractures, prevention of bone metastases in men with high-risk nonmetastatic prostate cancer, and prevention of skeletal complications in men with hormone-sensitive metastatic disease.
 ...
PMID:Osteoclast-targeted therapy for prostate cancer. 1534 75

A 74-year old white man was undergoing treatment with palliative chemotherapy for Stage IV Prostate Adenocarcinoma with multiple osteoblastic metastases. He was started on intravenous Zoledronic acid for reduction of bone pain and prevention of skeletal complication from multiple bone metastases. Four days after intravenous Zoledronic acid, the patient presented to emergency room with complaints of carpopedal spasm and bronchospasm. On admission, serum calcium and albumin was 3.5 mg/dl and 3.7 g/dl respectively. QT interval was more than 500 m sec. The patient was started on intravenous calcium gluconate. He received 174 gm of intravenous calcium for total of 12 days. His serum calcium returned to a normal range in three months with Vitamin D and calcium supplement. Before starting Zoledronic acid therapy, the patient's serum calcium level was 6.9 mg/dl.
 ...
PMID:Zoledronic acid-induced severe hypocalcaemia in a prostate cancer patient with extensive osteoblastic bone metastases. 1577 96


1 2 3 4 5 Next >>