Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0153690 (bone metastases)
 6,382 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

YH529, [1-hydroxy-2-(imidazo [1,2-a] pyridin-3-yl) ethylidene]-bisphosphonic acid monohydrate, is a newly developed third-generation bisphosphonate with a potent inhibitory activity toward osteoclastic bone resorption. The primary cellular mechanism of osteolysis associated with metastatic cancer is osteoclast-mediated. It is likely that bisphosphonates would be efficacious in this situation. In the present study, we examined the effect of YH529 in a nude mice bone metastasis model, in which the intracardiac injection of a human breast cancer cell line, MDA-MB-231 (MDA-231), leads to osteolytic bone metastases. To examine whether YH529 would prevent such bone metastasis, we administered YH529 s.c. to nude mice simultaneously with cancer cell inoculation through the entire experimental period (protocol 1) or performed short-term prophylactic administration before inoculation of the MDA-231 cells (protocol 2). In addition, to examine the possible therapeutic effects of the drug on established bone metastases, we injected YH529 after radiographically small but distinct osteolytic bone metastases had been detected (protocol 3). In all protocols, YH529 (2 microg/mouse/day) markedly inhibited bone metastases as well as the progression of established metastatic foci that were quantified on the radiographs. Histological examination and histomorphometrical analysis revealed that YH529 markedly reduced the number of osteoclasts and the size of the tumor at the metastatic bone sites. Our results suggest that YH529 may suppress metastasis formation and tumor growth in bone through inhibition of osteoclastic bone resorption.
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PMID:Effect of a newly developed bisphosphonate, YH529, on osteolytic bone metastases in nude mice. 965 May 65

Bombesin-like peptides such as gastrin-releasing peptide (GRP) have been shown to play a role in cancer as autocrine growth factors that stimulate tumor growth through specific receptors. To search for potential clinical indications for GRP analogues, it is important to identify human tumor types expressing sufficient amounts of the respective receptors. In the present study, we have evaluated the expression of GRP receptors in human nonneoplastic and neoplastic prostate tissues using in vitro receptor autoradiography on tissue sections with 125I-Tyr4-bombesin as radio-ligand. GRP receptors were detected, often in high density, in 30 of 30 invasive prostatic carcinomas and also in 26 of 26 cases of prostatic intraepithelial proliferative lesions, corresponding mostly to prostatic intraepithelial neoplasias. Well-differentiated carcinomas had a higher receptor density than poorly differentiated ones. Bone metastases of androgen-independent prostate cancers were GRP receptor-positive in 4 of 7 cases. Conversely, GRP receptors were identified in only a few hyperplastic prostates and were localized in very low density in glandular tissue and, focally, in some stromal tissue. In all of the cases, the receptors corresponded to the GRP receptor subtype of bombesin receptors, having high affinity for GRP and bombesin and lower affinity for neuromedin B. These data demonstrate a massive GRP receptor overexpression in prostate tissues that are neoplastically transformed or, like prostatic intraepithelial neoplasias, are in the process of malignant transformation. GRP receptors may be markers for early molecular events in prostate carcinogenesis and useful in differentiating prostate hyperplasia from prostate neoplasia Such data may not only be of biological significance but may also provide a molecular basis for potential clinical applications such as GRP-receptor scintigraphy for early tumor diagnosis, radiotherapy with radiolabeled bombesin-like peptide analogues, and chemotherapy with cytotoxic bombesin analogues.
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PMID:Gastrin-releasing peptide receptors in the human prostate: relation to neoplastic transformation. 1007 Sep 77

In renal cell carcinoma, bone metastases remain a major medical challenge because they are refractory to the antiproliferative effects of immunotherapy. We critically review the biological and clinical data which implicate interleukin-6 in the tumor growth, the pathogenesis of the bone metastases and the response to immunotherapy.
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PMID:[Renal cancer: bone metastases, immunotherapy and interleukin-6]. 1054 48

Prostate stem-cell antigen (PSCA) is a cell-surface antigen expressed in normal prostate and overexpressed in prostate cancer tissues. PSCA expression is detected in over 80% of patients with local disease, and elevated levels of PSCA are correlated with increased tumor stage, grade, and androgen independence, including high expression in bone metastases. We evaluated the therapeutic efficacy of anti-PSCA mAbs in human prostate cancer xenograft mouse models by using the androgen-dependent LAPC-9 xenograft and the androgen-independent recombinant cell line PC3-PSCA. Two different anti-PSCA mAbs, 1G8 (IgG1kappa) and 3C5 (IgG2akappa), inhibited formation of s.c. and orthotopic xenograft tumors in a dose-dependent manner. Furthermore, administration of anti-PSCA mAbs led to retardation of established orthotopic tumor growth and inhibition of metastasis to distant sites, resulting in a significant prolongation in the survival of tumor-bearing mice. These studies suggest PSCA as an attractive target for immunotherapy and demonstrate the therapeutic potential of anti-PSCA mAbs for the treatment of local and metastatic prostate cancer.
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PMID:Anti-PSCA mAbs inhibit tumor growth and metastasis formation and prolong the survival of mice bearing human prostate cancer xenografts. 1122 95

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.
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PMID:Preclinical studies with zoledronic acid and other bisphosphonates: impact on the bone microenvironment. 1134 63

Parathyroid hormone-related peptide (PTHrP) has a high homology with the N-terminal portion of the parathyroid hormone (PTH). The gene of PTHrP is complex and can generate by alternative splicing at least three mature peptides containing 139, 141 and 173 amino acids. PTHrP acts via a common receptor with PTH but also via specific receptors. In physiological circumstances, PTHrP is produced locally in many normal tissues where it has autocrine/paracrine functions, particularly during embryonic development, growth regulation and differentiation of many cellular types. PTHrP has endocrine action on bone and kidney. The humoral hypercalcemia of malignancy is mainly mediated by PTHrP. Most hypercalcemic patients with solid tumors have increased plasma PTHrP, whereas PTHrP is not detectable in healthy subjects. During treatment with bisphosphonates, elevated plasma levels of PTHrP are associated with a weak response. PTHrP has also a significant role in the pathophysiology of bone metastases. PTHrP can induce a local osteolysis near the bone metastases, which favours their progression and thus participates in the autocrine regulation of tumor growth. In breast cancer, PTHrP is detected in about 60% of primary tumors and in more than 70% of bone metastases, whereas only 17% of nonbone metastases express PTHrP. A higher expression of PTHrP and its mRNA 1-139, is positively correlated with an invasive tumor phenotype and the development of bone metastases. PTHrP is an effector of transforming growth factor (TGFbeta) in the development and progression of osteolytic bone metastases. TGFbeta, which is released in bone matrix during osteolytic resorption, enhances tumor cells PTHrP production. Then, PTHrP stimulates bone resorption and develops tumor cells metastatic potential. Thus a feedback loop exists between carcinoma cells and the bone microenvironment, leading to a vicious circle.
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PMID:[PTHrP and breast cancer]. 1174 1

Bone metastases are one of the most common problematic complications of advanced cancers. In addition to causing significant pain, bone metastases often result in fractures and debilitation. Stimulation of osteoclast activity by factors secreted by tumor cells is believed be the primary mechanism of bone destruction. Bisphosphonates inhibit osteoclast-related bone resorption, and have become standard therapy in the treatment of hypercalcemia of malignancy and postmenopausal osteoporosis. More recently, bisphosphonates have been shown to decrease pain and skeletal fractures associated with bone metastases. Structural changes in bisphosphonates influence their relative potency as well as other potentially beneficial effects such as inhibition of tumor growth factors, alteration of adhesion molecules, and apoptosis of tumor cells.
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PMID:Bisphosphonates in the treatment of bone metastases. 1189 24

Common cancers frequently develop bone metastases, which are often osteolytic in nature due to activation of osteoclast differentiation and bone resorption. This may result from direct stimulation of these cells by the metastasis, or may be due to indirect enhancement of osteoclast activity by osteoblasts. A further feature of the bone metastasis is an extensive medullary angiogenesis which supports tumor growth. The alphaVbeta3 integrin is highly expressed in bone metastatic cells, as well as in osteoclasts and in the activated endothelium, where it plays a major role in cell function. In contrast, this receptor is barely expressed in other cell types. Our hypothesis is that inhibition of this mechanism, which is not widespread in most tissues and at the same time is common to several steps of cancer-induced osteolysis (i.e., homing, growth, and survival of metastatic cells, osteoclast bone resorption, and angiogenesis), should represent a suitable target to block the development of bone spreading of metastatic tumors. We extend this hypothesis to downstream signalling molecules activated by ligation of the alphaVbeta3 integrin, some of which (i.e., Src, PYK2, and Shc) could have similar specific roles in tumor cells, activated endothelium and osteoclasts, but not in other cell types.
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PMID:The role of the alphaVbeta3 integrin in the development of osteolytic bone metastases: a pharmacological target for alternative therapy? 1215 91

The incidence of bone metastasis was around 13% in 404 patients with hepatocellular carcinoma (HCC) who underwent treatment at the National Kyushu Cancer Center between 1988-97, which is a high value among various cancers. This is, in part, due to the prolonged survival time of HCC patients in recent years. Serum vascular endothelial growth factor (VEGF) levels were significantly elevated in HCC patients with bone metastases as compared to those in patients with liver cirrhosis/chronic hepatitis and HCC patients without bone metastasis. VEGF was positively stained in both the primary lesion and bone metastasis of HCC by immunohistochemistry. In the process of bone metastasis, an increase in bone resorption is a crucial step prior to invasion of the bone. VEGF, the most important angiogenic factor, has been shown to stimulate bone resorption through its effects on osteoclasts. Thus, HCC cells reach the bone marrow space, and then secrete VEGF which facilitates osteolytic bone metastasis. VEGF may also facilitate tumor growth in the bone by acting as an angiogenic factor once invasion of the bone is complete. This might be another reason for the high incidence of bone metastasis in HCC.
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PMID:A possible role of VEGF in osteolytic bone metastasis of hepatocellular carcinoma. 1238 70

In this paper we compare two innovative models of movement-related pain: tumor-induced nociception following implantation of fibrosarcoma cells into bone and muscle inflammation-induced nociception following injection of the irritant carrageenan into muscle. Importantly, using the grip force test, an assay of movement-related hyperalgesia, both non-malignant and malignant pain are examined in parallel. Movement-related hyperalgesia, known clinically as a specific type of 'breakthrough pain', is a common feature of bone cancer and is thought to be a predictor of poor response to conventional analgesic pharmacotherapy (Bruera et al., 1995, J. Pain Symptom. Manage. 10 (1995) 348; Mercadaute et al., 1992, Pain 50 (1992) 151; Pain 81 (1999) 129). Implantation of NCTC 2472 sarcoma cells in both humeri or injection of carrageenan (4%) in both triceps of C3H/He mice produced apparent forelimb hyperalgesia that was not associated with mechanical hyperalgesia in the forepaw, whereas carrageenan at 6 and 8% did evoke significant cutaneous hyperalgesia of the forepaw as well. Control groups receiving implants of vehicle or no treatment at all did not manifest this forelimb hyperalgesia. B6C3/F1 mice implanted with non-lysis-inducing G3.26 melanoma cells or vehicle did not manifest significant hyperalgesia when compared to B6C3/F1 mice receiving fibrosarcoma cells, indicating a dependence on bone involvement for induction of hyperalgesia in this model. Histological examination at days 3, 7, and 10 post-implantation showed a clear correlation of tumor growth-induced bone destruction with behavioral hyperalgesia. Morphine was more potent in decreasing the maximal hyperalgesia induced by carrageenan than that induced by tumor implantation. Acutely administered morphine (3-100mg/kg, i.p.) attenuated peak hyperalgesia of carrageenan-injected mice (ED(50) 6.9 mg/kg) and tumor-bearing mice (ED(50) 23.9 mg/kg) in a dose-related manner with a difference in potency of 3.5. Tumor-implanted mice with a level of hyperalgesia comparable to that induced by carrageenan required almost three times more morphine (ED(50) 18.5mg/kg) for equivalent attenuation of forelimb hyperalgesia. These animal models of movement-related hyperalgesia may aid in discerning the peripheral and central mechanisms underlying pain that accompanies bone metastases and distinguishing it from the pain associated with muscular inflammation. Importantly, they may also aid in predicting differences in analgesic efficacy in different types of musculoskeletal pain.
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PMID:Tumor implantation in mouse humerus evokes movement-related hyperalgesia exceeding that evoked by intramuscular carrageenan. 1250 12


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