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)

Bone-targeted Src tyrosine kinase (STK) inhibitors have recently been developed for the treatment of osteoporosis and cancer-related bone diseases. The concept of bone targeting derives from bisphosphonates, and from the evolution of such molecules in terms of therapeutic efficacy for the treatment of bone disorders. Interestingly, some of the earliest bisphosphonates were recognized for their ability to inhibit calcium carbonate precipitation (scaling) by virtue of their affinity to chelate calcium. This chelating property was subsequently exploited in the development of bisphosphonate analogs as inhibitors of the bone-resorbing cells known as osteoclasts, giving rise to breakthrough medicines, such as Fosamax (for the treatment of osteoporosis) and Zometa (for the treatment of osteoporosis and bone metastases). Relative to these milestone achievements, there is a tremendous opportunity to explore beyond the limited chemical space (functional group diversity) of such bisphosphonates to design novel bone-targeting moieties, which may be used to develop other classes of promising small-molecule drugs affecting different biological pathways. Here, we review studies focused on bone-targeted inhibitors of STK, a key enzyme in osteoclast-dependent bone resorption. Two strategies are described relative to bone-targeted STK inhibitor drug discovery: (i) the development of novel Src homology (SH)-2 inhibitors incorporating non-hydrolyzable phosphotyrosine mimics and exhibiting molecular recognition and bone-targeting properties, leading to the in vivo-effective lead compound AP-22408; and (ii) the development of novel ATP-based Src kinase inhibitors incorporating bone-targeting moieties, leading to the in vivo-effective lead compound AP-23236. In summary, AP-22408 and AP-23236, which differ mechanistically by virtue of blocking Src-dependent non-catalytic or catalytic activities in osteoclasts, exemplify ARIAD Pharmaceuticals' structure-based design of novel bone-targeted lead compounds, successfully achieving in vivo proof-of-concept and providing the framework for the next-generation molecules that have further advanced, in terms of preclinical studies, for the treatment of osteoporosis and related bone diseases, including osteolytic bone metastases.
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PMID:Novel bone-targeted Src tyrosine kinase inhibitor drug discovery. 1457 23

Painful and life-threatening skeletal complications are common in patients with advanced cancer metastatic to bone. Patients with breast cancer and multiple myeloma who survive for 2 or more years after developing bone metastases/lesions are at chronic risk for skeletal complications. Patients with prostate cancer and other solid tumors are also at high risk for skeletal complications, and, until recently, no effective treatment had been identified. Zoledronic acid, a new-generation bisphosphonate, was recently shown to be safe and effective as treatment for the prevention of skeletal complications in three randomized, phase III trials involving more than 3000 patients with multiple myeloma, breast, prostate, and lung cancers, and other solid tumors. Zoledronic acid (4 mg) was at least as effective as pamidronate (90 mg) in preventing skeletal complications in the overall study population of patients with breast cancer and multiple myeloma and was superior to pamidronate in the subset of over 1000 patients with breast cancer. In patients with solid tumors, including prostate cancer and lung cancer, zoledronic acid significantly reduced the incidence and delayed the onset of skeletal complications compared with placebo. Zoledronic acid is the first bisphosphonate with broad clinical utility and may become the preferred bisphosphonate for the treatment of bone metastases in patients with advanced cancers.
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PMID:Zoledronic acid for the treatment of bone metastases in patients with breast cancer and other solid tumors. 1461 36

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.
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PMID:Rationale for the use of bisphosphonates in osteoblastic and osteolytic bone lesions. 1465 42

Zoledronic acid (ZOL), a nitrogen-containing bisphosphonate, exerts anti-tumor effects by inhibiting the prenylation of small GTPases. We have also reported that ZOL shows an anti-leukemic effect by inducing apoptosis throughout the S phase to the G(2) / M boundary. Here, we studied the effects of ZOL on various cell cycle regulators, including p53, cyclin-dependent kinases (CDKs), CDK inhibitors and cyclins, using BV173 leukemia and HCT116 colorectal carcinoma cell lines, harboring wild-type (wt-) p53. ZOL induced the accumulation of neither p53 nor p21(WAF1/CIP1) during the execution of apoptosis in BV173 cells. Therefore, we investigated the dependence of ZOL-induced apoptosis on intact p53 by using wt-p53 HCT116 and a p53-degraded HCT116 subline, and observed no significant difference. p57(KIP2) was upregulated by ZOL in BV173 cells, but not in HCT116 cells. Flow cytometric analyses showed that ZOL also impaired the cell cycle-dependent expression patterns of cyclins A, B and D3 in BV173. In conclusion, the p53-independent anti-tumor activities of ZOL suggest that it may be an attractive agent for treating cancers, including those with chemoresistance resulting from the loss of p53 function. ZOL also affected the coordinate expression patterns of several cell cycle regulators during the execution of anti-tumor activity.
Cancer Sci 2004 Feb
PMID:p53-independent anti-tumor effects of the nitrogen-containing bisphosphonate zoledronic acid. 1496 71

Prostate cancer patients are at risk for developing bone loss and bone metastases. Clinicians prescribing ADT should appreciate the potential effects of ADT on BMD as well as the morbidity and mortality that can result from osteoporotic fractures. Measures to address the evaluation of patients and when to treat patients with significant bone loss have been discussed. Bisphosphonates effectively prevent loss of BMD in prostate cancer patients. Treatment of prostate cancer patients with established bone metastases with zoledronic acid should be considered strongly based on the results of the Saad study and other studies of patients with bone metastases with other malignancies. Zoledronic acid is approved by the US FDA for use in men with metastatic hormone-refractory prostate cancer and in the European Union for any patient with bone metastases, including prostate cancer patients,because of the beneficial impact of zoledronic acid on skeletal-related events. There is no validated method to determine which patients might benefit most from bisphosphonate therapy in this setting. Many questions about the use of bisphosphonate therapy in men with prostate cancer must be addressed, both in terms of the use in bone loss and bone metastases. These questions include: What is the optimal timing of therapy? Which bisphosphonate is best? What is the best dose and dose schedule? Do bisphosphonates effectively decrease skeletal fracture rates in patients with osteoporosis? How long should patients receive therapy? Are bisphosphonate "holidays" warranted? What are the long-term skeletal and renal toxicities? Is there a role for sequencing bisphosphonate therapy either before or after chemotherapy? Is bisphosphonate therapy synergistic with certain chemotherapy or other bone-targeted therapies? Which patients are the most likely to benefit from bisphosphonate therapy? What are clinically significant endpoints of bisphosphonate trials in patients with metastatic disease? Does inhibiting bone turnover also inhibit formation of bone metastases? Preliminary work in these areas has been completed, but more questions than answers are available. Given the rising costs of health care, it is imperative that these questions be addressed to best use the health care dollar while offering high-risk patients the best available therapy. At present, no data suggest that bisphosphonates should be used routinely to prevent BMD loss in men with normal BMD or to prevent the development of bone metastases in men with biochemical relapse. Continuing trials may give us guidance in the future.
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PMID:Understanding treatments for bone loss and bone metastases in patients with prostate cancer: a practical review and guide for the clinician. 1512 12

Zoledronic acid (Zometa), a parenteral bisphosphonate, is an inhibitor of osteoclast-mediated bone resorption and is used in the management of patients with cancer. Zoledronic acid 4 mg is administered as an intravenous infusion over 15 minutes. In the treatment of bone metastases, zoledronic acid is the first and only bisphosphonate to demonstrate efficacy in patients with a broad range of tumour types and in multiple myeloma. In well-designed trials, a single 4 mg dose of zoledronic acid showed good efficacy in the treatment of patients with hypercalcaemia of malignancy. Zoledronic acid 4 mg was superior to pamidronic acid 90 mg, administered as a 2-hour infusion, as assessed by normalised serum calcium concentrations 10 days after administration. In conjunction with antineoplastic therapy, zoledronic acid was an effective long-term (up to 25 months) treatment for skeletal-related events in patients with bone metastases associated with multiple myeloma or solid tumours. In patients with bone metastases secondary to breast cancer or bone lesions from myeloma, zoledronic acid was at least as effective as pamidronic acid, based on assessments of skeletal-related events 25 months after the start of treatment. In addition, compared with pamidronic acid, the overall risk of developing skeletal complications, including hypercalcaemia of malignancy, was significantly reduced in recipients of zoledronic acid. Compared with pamidronic acid, zoledronic acid reduced the risk of patients with breast cancer developing a skeletal-related event by an additional 20%. Zoledronic acid was significantly more effective than placebo on most efficacy measures in patients with bone metastases secondary to other solid tumours (e.g. lung, prostate) and showed sustained efficacy for up to 15 months. Preliminary data indicate that its efficacy in these patients is sustained for up to 24 months. Estimates of the cost effectiveness of zoledronic acid in the treatment of prostate cancer were consistent with those of other bisphosphonates, and cost-effectiveness ratios were within limits considered acceptable economic value. Zoledronic acid was generally well tolerated, with a tolerability profile similar to that of pamidronic acid and placebo. As with other bisphosphonates, deterioration of renal function has occasionally been reported in patients receiving zoledronic acid and monitoring of serum creatinine is recommended during treatment. The efficacy of zoledronic acid is therefore well established in patients with hypercalcaemia of malignancy and, for up to 25 months, in the treatment of complications arising from metastatic bone disease in patients with multiple myeloma or solid tumours. The clinical profile of zoledronic acid compares favourably with that of pamidronic acid in patients with cancer and zoledronic acid has a more convenient administration schedule with the potential for better compliance. Thus, zoledronic acid is an effective bisphosphonate and is positioned to play an important role in the management of advanced cancer patients with bone metastases.
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PMID:Zoledronic acid: a review of its use in patients with advanced cancer. 1516 27

Skeletal morbidity, including hypercalcemia of malignancy (HCM), places a severe burden on patients with advanced cancers. Bisphosphonates effectively correct HCM and reduce skeletal morbidity in patients with bone metastases. However, with the widespread use of bisphosphonates, the safety and convenience of therapy are emerging concerns. The delivery of effective doses of early bisphosphonates required a lengthy 24-hour i.v. infusion protocol because of renal tolerability issues. The introduction of more potent bisphosphonates with superior tolerability profiles has allowed therapy to be safely delivered via shorter i.v. infusions. Intravenous therapy with etidronate, clodronate, pamidronate, ibandronate, and zoledronic acid has been used to treat HCM and skeletal complications in cancer patients. Of these therapies, zoledronic acid (which can be safely administered via a 15-minute i.v. infusion) is the most convenient and effective and has demonstrated an excellent safety profile with long-term use. Zoledronic acid has also received the broadest regulatory approval of any bisphosphonate and can be used to treat HCM or bone lesions secondary to multiple myeloma and a wide variety of solid tumors, including breast, prostate, and lung cancers. In addition to the patient preference for shorter infusion times, the 15-minute i.v. infusion protocol of zoledronic acid can provide benefits for infusion centers by potentially increasing patient throughput.
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PMID:Safety and convenience of a 15-minute infusion of zoledronic acid. 1585 82

Bone metastases in patients with renal cell carcinoma are associated with a high risk of skeletal complications. Therefore, a subset analysis of a larger clinical trial was performed to determine the efficacy of zoledronic acid in renal cell carcinoma patients. Patients with bone metastases from solid tumors other than breast or prostate cancer (n=773) were randomized to receive zoledronic acid or placebo via 15-minute infusion every 3 weeks for 9 months. Patients were monitored for skeletal-related events, which were defined as pathological fracture, spinal cord compression, radiotherapy, or surgery to bone. Among the subset of 74 patients with renal cell carcinoma, 46 patients were treated with 4 mg of zoledronic acid or placebo. Significantly fewer patients treated with 4 mg zoledronic acid had a skeletal-related event (37% versus 74% for placebo, P=0.015), and zoledronic acid significantly prolonged the time to first skeletal-related event (median not reached at 9 months versus 72 days for placebo; P=0.006). Zoledronic acid significantly reduced the annual incidence of skeletal-related events by approximately 21% (mean 2.68 versus 3.38 events per year for placebo, P=0.014) and significantly reduced the risk of developing a skeletal-related event by 61% compared with placebo (risk ratio=0.394, P=0.008) by multiple event analysis. Median time to progression of bone lesions was also significantly extended with zoledronic acid treatment (P=0.014). Zoledronic acid is the first bisphosphonate to significantly reduce skeletal morbidity and significantly prolong time to bone lesion progression in patients with bone metastases from renal cell carcinoma.
Clin Cancer Res 2004 Sep 15
PMID:Skeletal complications in patients with bone metastases from renal cell carcinoma and therapeutic benefits of zoledronic acid. 1544 38

Bisphosphonate therapy has become a standard of care for patients with malignant bone disease. In addition, preclinical and preliminary clinical data suggest that bisphosphonates may prevent cancer-treatment-induced bone loss (CTIBL) and the development of malignant bone disease in patients with early-stage cancer. Patients who receive adjuvant hormonal therapy for breast cancer or androgen-deprivation therapy for prostate cancer are at an especially high risk for CTIBL because of reduced estrogenic signaling. Oral clodronate (Bonefos; Anthra Pharmaceuticals; Princeton, NJ), oral risedronate (Actonel; Proctor and Gamble Pharmaceuticals, Inc.; Cincinnati, OH), and i.v. zoledronic acid (Zometa; Novartis Pharmaceuticals Corp.; East Hanover, NJ) have all demonstrated promise in preventing CTIBL in patients receiving hormonal therapy for breast cancer. Zoledronic acid has demonstrated efficacy with the longest between-treatment interval (3-6 months) and is currently being investigated in the Zometa/Femara Adjuvant Synergy Trials (Z-FAST and ZO-FAST in the United States and Europe, respectively). In patients receiving androgen-deprivation therapy for prostate cancer, i.v. pamidronate (Aredia; Novartis Pharmaceuticals Corp.) and i.v. zoledronic acid both have demonstrated significant benefits over placebo, but only zoledronic acid produced significant increases in bone mineral density compared with baseline values. Additionally, bisphosphonates have demonstrated antitumor activities in preclinical models, and clinical trials with oral clodronate suggest that bisphosphonates might prevent or delay bone metastasis in patients with early-stage breast cancer. Clinical trials are investigating the effect of zoledronic acid on disease progression in patients with breast cancer, prostate cancer, and non-small cell lung cancer. The results of these clinical trials should further define the clinical benefit of bisphosphonates in the oncology setting.
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PMID:Toward new horizons: the future of bisphosphonate therapy. 1545 28

Glucocorticoids are widely used in the treatment of lupus patients, and adverse effects, which include osteoporosis and associated fractures, are frequent. Treatment of osteoporosis of young patients should be effective and not harmful to bone growth and remodeling. Bisphosphonates are drugs that decrease the incidence of bone fractures, but their use in juvenile patients is still controversial because of their possible side effects on the growing skeleton. However, recently published studies showed that linear growth continued normally after treatment with these drugs, and there was no excessive suppression of bone remodeling or mineralization defects. Zoledronic acid is a new intravenous bisphosphonate that has been approved by the US FDA for use with hypercalcemia of malignancies and might be an effective treatment for postmenopausal osteoporosis. The authors report a case of a young girl with systemic lupus who developed multiple vertebral collapses due to glucocorticoid therapy, and zoledronic acid was used producing significant clinical and densitometric improvement.
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PMID:The effect of intravenous zoledronic acid on glucocorticoid-induced multiple vertebral fractures in juvenile systemic lupus erythematosus. 1554 4


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