Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bone is a favorable microenvironment for tumor cell colonization because of abundant growth factors released during active bone resorption. Bisphosphonates can dramatically affect the ability of tumor cells to grow in bone by inhibiting osteoclast-mediated bone resorption and by depriving tumors of growth-promoting signals. Moreover, bisphosphonates have direct anti-tumor effects in vitro via induction of apoptosis. Zoledronic acid is a nitrogen-containing bisphosphonate that has demonstrated potent anti-tumor activity in vitro and in vivo. In vitro studies have provided important clues as to the molecular mechanisms by which zoledronic acid induces apoptosis of human breast cancer cell lines. Studies in multiple myeloma and breast cancer models have shed further light on the possible mechanisms underlying the in vivo anti-tumor effects of zoledronic acid. These studies have led to the development of novel strategies to target specific molecular pathways involved in osteoclast maturation and activity, tumor cell metastasis, and tumor growth and survival. The clinical application of these strategies may ultimately prevent bone metastasis.
 ...
PMID:The anti-tumor potential of zoledronic acid. 1465 41

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

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.
 ...
PMID:p53-independent anti-tumor effects of the nitrogen-containing bisphosphonate zoledronic acid. 1496 71

Bisphosphonates effectively inhibit osteoclast-mediated bone resorption and are integral in the treatment of benign and malignant bone diseases. The evolution of bisphosphonates over the past 30 years has led to the development of nitrogen-containing bisphosphonates (N-BPs), which have a mechanism of action different from that of the nonnitrogen-containing bisphosphonates. Studies conducted over the past decade have elucidated the mechanism of action and pharmacologic properties of the N-BPs. N-BPs exert their effects on osteoclasts and tumor cells by inhibiting a key enzyme in the mevalonate pathway, farnesyl diphosphate synthase, thus preventing protein prenylation and activation of intracellular signaling proteins such as Ras. Recent evidence suggests that N-BPs also induce production of a unique adenosine triphosphate analogue (Apppi) that can directly induce apoptosis. Our increased understanding of the pharmacologic effects of bisphosphonates is shedding light on the mechanisms by which they exert antitumor effects. As a result of their biochemical effects on protein prenylation, N-BPs induce caspase-dependent apoptosis, inhibit matrix metalloproteinase activity, and downregulate alpha(v)beta(3) and alpha(v)beta(5) integrins. In addition, zoledronic acid (Zometa; Novartis Pharmaceuticals Corp.; East Hanover, NJ and Basel, Switzerland) exerts synergistic antitumor activity when combined with other anticancer agents. Zoledronic acid also inhibits tumor cell adhesion to the extracellular matrix and invasion through Matrigel trade mark and has antiangiogenic activity. A growing body of evidence from animal models demonstrates that zoledronic acid and other bisphosphonates can reduce skeletal tumor burden and prevent metastasis to bone. Further studies are needed to fully elucidate these biochemical mechanisms and to determine if the antitumor potential of bisphosphonates translates to the clinical setting.
 ...
PMID:Bisphosphonates: preclinical review. 1545 25

Bone is a preferred site of metastasis for many solid tumors, and the complications associated with bone metastases can result in significant skeletal morbidity including severe bone pain, pathologic fracture, spinal cord compression, and hypercalcemia of malignancy (HCM). 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 HCM. Bisphosphonates have been shown to significantly reduce the incidence of these events in patients with bone metastases. Zoledronic acid (Zometa; Novartis Pharmaceuticals Corp.; East Hanover, NJ), pamidronate (Aredia; Novartis Pharmaceuticals Corp.), clodronate (Bonefos; Anthra Pharmaceuticals; Princeton, NJ), and ibandronate (Bondronat; Hoffmann-La Roche Inc.; Nutley, NJ) all have demonstrated efficacy superior to that of placebo in patients with breast cancer. Zoledronic acid is the only bisphosphonate that has been compared directly with pamidronate, and it was shown by multiple event analysis to be significantly more effective at reducing the risk of an SRE. In patients with prostate cancer, clodronate, etidronate (Didronel; Procter and Gamble Pharmaceuticals, Inc.; Cincinnati, OH), and pamidronate have demonstrated transient palliation of bone pain. However, zoledronic acid is the only bisphosphonate to demonstrate both significant and sustained pain reduction and a significantly lower incidence and longer time to onset of SREs compared with placebo. Zoledronic acid is also the only bisphosphonate to demonstrate efficacy in patients with bone metastases from a variety of other solid tumors, including lung cancer and renal cell carcinoma. In conclusion, bisphosphonates effectively reduce skeletal complications in patients with bone metastases from breast cancer, and zoledronic acid has demonstrated the broadest clinical activity in patients with a wide variety of tumor types.
 ...
PMID:Bisphosphonates: clinical experience. 1545 26

Zoledronic acid (ZA) has been shown to inhibit prostate tumor growth in vitro and have beneficial effects in patients with advanced prostate cancer (CaP). The aim of this study was to determine whether ZA exhibits direct anti-tumor effects on CaP cells in vivo. To distinguish the effects of inhibition of osteolysis and direct anti-tumor activity of ZA in vivo, we compared the results of treatment with ZA and osteoprotegerin (Fc-OPG), which inhibits osteolysis, but without significant direct anti-tumor effects. In vitro Fc-OPG had no significant effects on C4-2 proliferation, whereas ZA decreased proliferation. However, both agents decreased tumor growth in bone. Moreover, both increased bone volume and prevented the overall decreases in BMD associated with growth of C4-2 cells in bone. Our study provides novel and significant observations that the in vivo effects of ZA are consistent with indirect effects mediated by osteoclasts.
 ...
PMID:Comparison of Fc-osteoprotegerin and zoledronic acid activities suggests that zoledronic acid inhibits prostate cancer in bone by indirect mechanisms. 1599 21

For a long time, hormone-refractory prostate cancer was regarded as a chemoresistant tumor. The introduction of taxanes has prompted a change in this opinion. For the first time treatment with 75 mg/m(2) docetaxel every 3 weeks has evidenced a survival benefit in a phase III trial (median survival of 18.9 months versus 16.5 months with mitoxantrone). Further advantages were improved pain reduction and quality of life. Neutropenia was foremost among the side effects. Docetaxel is currently the standard treatment for hormone-refractory prostate cancer. The morbidity of metastatic hormone-refractory prostate cancer is influenced by bone metastases. Pain is a prominent feature. Skeletal complications are frequent. Therapy with 4 mg zoledronic acid reduced skeletal complications significantly in comparison to placebo. The most pronounced effect is the reduction of pathological fractures. Side effects include flu-like symptoms, muscle pain, and edemas. Zoledronic acid also belongs to the standard treatment of hormone-refractory prostate cancer with bone metastases.
 ...
PMID:[Therapeutic options for hormone-refractory prostate cancer]. 1671 Jun 77

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.
 ...
PMID:Impact of zoledronic acid on renal function in patients with cancer: Clinical significance and development of a predictive model. 1713 70

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.
 ...
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

Beside their use as antiresorptive drug, bisphosphonates are well known to stimulate gammadelta T cells and to have direct effects on tumor growth. We determined the direct cytotoxic potential, induction of apoptosis, and antimigratory effect of zoledronic acid. The susceptibility of pancreatic carcinoma cells pretreated with bisphosphonates against gammadelta T cells was tested and the subgroup involved in killing was determined. Zoledronic acid has a cytotoxic potential even at pharmacologic dosage. Zoledronic acid does not only induce apoptosis by inhibiting the Ras-pathway but has also an antimetastatic effect as shown in migration assays and by down-regulation of urokinase plasminogen activator. Freshly prepared gammadelta T cells consisting mainly of Vdelta2 cells showed increased cytotoxicity against bisphosphonate-treated pancreatic carcinoma cells. Our results demonstrate that zoledronic acid has a direct apoptotic effect on pancreatic carcinoma cells and has antimigratory properties. Tumor cells treated with zoledronic acid are more vulnerable against Vgamma9 Vdelta2 T cell attack. Treatment with zoledronic acid for patients with pancreatic carcinoma might be an option.
 ...
PMID:Zoledronic acid has direct antiproliferative and antimetastatic effect on pancreatic carcinoma cells and acts as an antigen for delta2 gamma/delta T cells. 1745 12


<< Previous 1 2 3 4 5 6 7 8 9 Next >>