Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0029463 (osteosarcoma)
 16,637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The therapeutic efficacy of PTT.119, p-F-Phe-m-bis-(2-chloroethyl)amino-L-Phe-Met-ethoxy HCl, was evaluated using the transplantable L1210 leukemia and Ridgway osteogenic sarcoma tumor lines and the spontaneous C3H/StRos mammary tumor and AKR leukemia tumor models. Given in a single i.p. dose at 5-10 mg/kg on day 2 or in two injections of 5-7 mg each on days 2 and 9 to BDf1 mice with peritoneal L1210 leukemia grafts, PTT.119 increased the life spans (ILS) of the population dying of tumor by 94%-313%. In addition, 10% of the mice receiving 7 mg PTT.119 on days 2 and 9 were free of L1210 leukemic grafts when autopsied at the end of the 70-day observation period. The average life span of AKR mice with Ridgway osteogenic sarcoma grafts was significantly increased from 36-40 days to greater than 79 days following one or two s.c. injections of 5, 7, or 12.5 mg/kg PTT.119. Administration of PTT.119 at 14 or 14 and 21 days after tumor graft not only induced regression of palpable tumors but resulted in the absence of grafts in 60%-70% of the mice in several of the treated groups on autopsy at 180 days. In contrast, spontaneous mammary tumors were less susceptible to PTT.119; an ILS of only 15%-38% was observed in C3H/StRos mice, which eventually succumbed to tumor. Nevertheless, the total regression of initial tumors and the absence of further tumor incidence (greater than 180 days) was confirmed by autopsy in 5%-10% of the C3H/StRos mice receiving multiple i.p. injections of 5 or 7.5 mg/kg PTT.119. The drug was highly effective against spontaneous AKR leukemia; multiple s.c. or i.p. injections for a total of 15-40 mg/kg PTT.119 increased the average 25-day life span up to 723% and sustained remission in 9%-40% of the animals for greater than 6 months.
 ...
PMID:Evaluation of p-F-Phe-m-bis-(2-chloroethyl)amino-L-Phe-Met-ethoxy HCl against transplantable and spontaneous murine neoplasia. 235 70

Human parathyroid hormone (hPTH) is a peptide hormone consisting of 84 amino acids. Using the expression plasmid pKK223-3 with the strong tacpromoter, we have produced a variant of hPTH in E. coli. From the expression plasmid construct the expected product was hPTH with an N-terminal extension of Met-Gly. The peptide was extracted from E. coli cells and purified by high performance liquid chromatography. In two different gel electrophoresis systems including identification by immunoblotting the product behaved exactly as an hPTH standard. N-terminal amino acid sequence analysis of the purified product showed traces of Gly-hPTH. At least 90% of the expressed product was N-terminally blocked, suggesting the presence of N-formyl-methionine. This variant of hPTH did not stimulate adenylate cyclase activity in rat osteosarcoma cell membranes.
 ...
PMID:Expression of human parathyroid hormone in Escherichia coli. 240 51

The c-MET oncogene encodes the receptor for the Hepatocyte Growth Factor/Scatter Factor (HGF), a cytokine that stimulates the invasive growth of normal and neoplastic cells. The Met/HGF receptor is expressed by epithelial cells and its ligand by cells of mesenchymal origin. Receptor-ligand interaction occurs via a paracrine circuit. We studied the expression of the Met/HGF receptor and of its ligand in mesenchymal human tumours by examining 39 clinical samples of bone tumours. The Met/HGF receptor was not detectable in the majority of bone tumours, as expected from their mesenchymal origin. Notably, the receptor was overexpressed in 60% of the osteosarcomas examined. In 12 osteosarcoma cell lines the Met/HGF receptor was overexpressed, phosphorylated by HGF stimulation and fully functional. HGF was detected in two out of seven clinical specimens of osteosarcoma. The ligand and the receptor are co-expressed in two clonal osteosarcoma cell lines. In these lines the Met/HGF receptor was constitutively phosphorylated; phosphorylation was suppressed by suramin treatment, a known blocker of autocrine loops. These data suggest that activation of the Met/HGF receptor by a paracrine or an autocrine mechanism might play a role in the particularly aggressive behaviour of osteosarcomas.
 ...
PMID:The Met/HGF receptor is over-expressed in human osteosarcomas and is activated by either a paracrine or an autocrine circuit. 786 51

Overexpression of the hepatocyte growth factor receptor (Met/HGF receptor), a transmembrane tyrosine kinase encoded by the met proto-oncogene, has been associated with tumor progression in different human carcinomas. More recently, the Met/HGF receptor has also been described in tumor cell lines of mesenchymal origin, suggesting the existence of an autocrine loop that may contribute to the pathogenesis of sarcomas. In this study, we analyzed the expression of Met/HGF receptor by Western blotting and immunohistochemistry in frozen samples of 87 primary tumors of bone and soft tissues. Among benign tumors, overexpression was consistently found only in giant-cell tumor, a locally aggressive lesion that may also, although rarely, spread to the lung. Among malignant lesions, the presence of the Met/HGF receptor was detected in a relevant percentage of primaries and in almost all of the recurrences. The highest levels of Met/HGF receptor were found in osteosarcoma, a highly aggressive tumor that typically permeates the host bone and rapidly expands to the soft tissues. On the contrary, only low levels of Met/HGF receptor were found in chondrosarcoma, a slowly growing tumor that usually expands without massive destruction of the surrounding structures. These data indicate an association of Met/HGF expression with local aggressiveness in human mesenchymal tumors. The finding of Met/HGF receptor overexpression in all of the osteosarcomas suggests a role for the met proto-oncogene in the pathogenesis of this tumor.
 ...
PMID:Expression of Met/hepatocyte growth factor receptor gene and malignant behavior of musculoskeletal tumors. 886 70

The mechanism of metastasis of osteosarcoma cells to other bones has not yet fully been clarified. The purpose of the present study was to examine whether various factors involve the formation of osteosarcoma metastatic foci in other bones. Immunohistochemically, CD31 expression in osteosarcoma with no bone metastasis and osteosarcoma with bone metastasis was noted in 10 and 75% of cases, respectively. Met/hepatocyte growth factor (HGF) receptor expression in osteosarcoma with no bone metastasis and osteosarcoma with bone metastasis was noted in 90 and 25% of cases, respectively. Bone morphogenetic protein (BMP) expression in osteosarcoma with no bone metastasis and osteosarcoma with bone metastasis was noted in 20 and 75% of cases, respectively. Metastasis of osteosarcoma cells to other bones was significantly correlated with expression of BMP and CD31 and with no expression of Met/HGF receptor protein in osteosarcoma cells. In contrast, expression of insulin-like growth factor receptor in osteosarcoma cells did not correlate significantly with bone metastasis. These results suggest that formation of metastatic foci of osteosarcoma cells in other bones is regulated by CD31, which is associated with migration between endothelial cells, by BMP, which can induce and activate various mesenchymal cells affecting bone formation, and by escape of effect by HGF, which promotes differentiation of osteosarcoma cells.
 ...
PMID:Expression of CD31, Met/hepatocyte growth factor receptor and bone morphogenetic protein in bone metastasis of osteosarcoma. 1116 48

Osteosarcoma is the most common malignant bone neoplasia occurring in young patients in the first two decades of life, and represents 20% of all primitive malignant bone tumours. At present, treatment of metastatic osteosarcoma is unsatisfactory. High-dose chemotherapy followed by CD34+ leukapheresis rescue may improve these poor results. Neoplastic cells contaminating the apheresis may, however, contribute to relapse. To identify markers suitable for detecting osteosarcoma cells in aphereses we analysed the expression of bone-specific genes (Bone Sialoprotein (BSP) and Osteocalcin) and oncogenes (Met and ErbB2) in 22 patients with metastatic osteosarcoma and six healthy stem cell donors. The expression of these genes in aphereses of patients affected by metastatic osteosarcoma was assessed by RT-PCR and Southern blot analysis. Met and Osteocalcin proved to be not useful markers since they are positive in aphereses of both patients with metastatic osteosarcoma and healthy stem cell donors. On the contrary, BSP was expressed at significant levels in 85% of patients. Moreover, 18% of patients showed a strong and significantly positive (seven to 16 times higher than healthy stem cell donors) ErbB2 expression. In all positive cases, neoplastic tissue also expressed ErbB2. Our data show that ErbB2 can be a useful marker for tumour contamination in aphereses of patients affected by ErbB2-expressing osteosarcomas and that analysis of Bone Sialoprotein expression can be an alternative useful marker.
 ...
PMID:ErbB2 and bone sialoprotein as markers for metastatic osteosarcoma cells. 1256 82

Estrogen receptors alpha (ERalpha) and beta (ERbeta) have distinct functions and differential expression in certain tissues. These differences have stimulated the search for subtype-selective ligands. Therapeutically, such ligands offer the potential to target specific tissues or pathways regulated by one receptor subtype without affecting the other. As reagents, they can be utilized to probe the physiological functions of the ER subtypes to provide information complementary to that obtained from knock-out animals. A fluorescence resonance energy transfer-based assay was used to screen a 10,000-compound chemical library for ER agonists. From the screen, we identified a family of ERbeta-selective agonists whose members contain bulky oxabicyclic scaffolds in place of the planar scaffolds common to most ER ligands. These agonists are 10-50-fold selective for ERbeta in competitive binding assays and up to 60-fold selective in transactivation assays. The weak uterotrophic activity of these ligands in immature rats and their ability to stimulate expression of an ERbeta regulated gene in human U2OS osteosarcoma cells provides more physiological evidence of their ERbeta-selective nature. To provide insight into the molecular mechanisms of their activity and selectivity, we determined the crystal structures of the ERalpha ligand-binding domain (LBD) and a peptide from the glucocorticoid receptor-interacting protein 1 (GRIP1) coactivator complexed with the ligands OBCP-3M, OBCP-2M, and OBCP-1M. These structures illustrate how the bicyclic scaffolds of these ligands are accommodated in the flexible ligand-binding pocket of ER. A comparison of these structures with existing ER structures suggests that the ERbeta selectivity of OBCP ligands can be attributed to a combination of their interactions with Met-336 in ERbeta and Met-421 in ERalpha. These bicyclic ligands show promise as lead compounds that can target ERbeta. In addition, our understanding of the molecular determinants of their subtype selectivity provides a useful starting point for developing other ER modulators belonging to this relatively new structural class.
 ...
PMID:Identification of ligands with bicyclic scaffolds provides insights into mechanisms of estrogen receptor subtype selectivity. 1664 39

We previously reported the Wnt receptor low-density lipoprotein receptor-related protein 5 (LRP5) was frequently expressed in osteosarcoma (OS) tissue and correlated with metastasis and a lower disease-free survival. Subsequent in vitro analysis revealed that dominant-negative, soluble LRP5 (sLRP5) can reduce in vitro cellular invasion. In the current study, we examined the molecular mechanisms of blocking canonical Wnt signaling by sLRP5 in Saos-2 osteosarcoma cells. Transfection of sLRP5 caused a marked up-regulation of E-cadherin in this cell line. This increase in E-cadherin, seen primarily at the cell-cell contact borders, was associated with down-regulation of Slug and Twist, transcriptional repressors which mediate cancer invasion and metastasis. In contrast, N-cadherin, a mesenchymal marker, was reduced by sLRP5. In addition, blocking Wnt signaling by sLRP5 modulated other epithelial and mesenchymal markers (keratin 8 and 18, fibronectin), suggesting a reversal of epithelial-mesenchymal transition (EMT) seen during cancer progression. SLRP5 also reduced the expression of matrix metalloproteinase (MMP) 2 and 14, consistent with a decrease in invasive capacity. SLRP5 transfection decreased both Met expression and hepatocyte growth factor (HGF)-induced cell motility. Taken together, these results support a role for Wnt/LRP5 signaling in invasiveness of a subset of OS cells.
 ...
PMID:Blocking Wnt/LRP5 signaling by a soluble receptor modulates the epithelial to mesenchymal transition and suppresses met and metalloproteinases in osteosarcoma Saos-2 cells. 1731

Chemokines and their receptors are key factors in the onset and progression of AIDS. Among them, accumulating evidence strongly indicates the involvement of IL-8 and its receptors, CXCR1 and CXCR2, in AIDS-related conditions. Through extensive investigation of genetic variations of the human CXCR1-CXCR2 locus, we identified a haplotype of the CXCR1 gene (CXCR1-Ha) carrying two nonsynonymous single nucleotide polymorphisms, CXCR1_300 (Met to Arg) in the N terminus extracellular domain and CXCR1_142 (Arg to Cys) in the C terminus intracellular domain. Transfection experiments with CXCR1 cDNAs corresponding to the CXCR1-Ha and the alternative CXCR1-HA haplotype showed reduced expression of CD4 and CXCR4 in CXCR1-Ha cells in human osteosarcoma cells as well as in Jurkat and CEM human T lymphocytes. Furthermore, the efficiency of X4-tropic HIV-1(NL4-3) infection was significantly lower in CXCR1-Ha cells than in CXCR1-HA cells. The results were further confirmed by a series of experiments using six HIV-1 clinical isolates from AIDS patients. A genetic association study was performed by using an HIV-1(+) patient cohort consisting of two subpopulations of AIDS with extreme phenotypes of rapid and slow progression of the disease. The frequency of the CXCR1-Ha allele is markedly less frequent in patients with rapid disease onset than those with slow progression (P = 0.0003). These results provide strong evidence of a protective role of the CXCR1-Ha allele on disease progression in AIDS, probably acting through modulation of CD4 and CXCR4 expression.
 ...
PMID:A haplotype of the human CXCR1 gene protective against rapid disease progression in HIV-1+ patients. 1736 Jun 50

Caveolin-1 (Cav-1) is highly expressed in normal osteoblasts. This article reports that Cav-1 down-regulation is part of osteoblast transformation and osteosarcoma progression and validates its role as oncosuppressor in human osteosarcoma. A survey of 6-year follow-up indicates a better overall survival for osteosarcoma expressing a level of Cav-1 similar to osteoblasts. However, the majority of primary osteosarcoma shows significantly lower levels of Cav-1 than normal osteoblasts. Accordingly, Met-induced osteoblast transformation is associated with Cav-1 down-regulation. In vitro, osteosarcoma cell lines forced to overexpress Cav-1 show reduced malignancy with inhibited anchorage-independent growth, migration, and invasion. In vivo, Cav-1 overexpression abrogates the metastatic ability of osteosarcoma cells. c-Src and c-Met tyrosine kinases, which are activated in osteosarcoma, colocalize with Cav-1 and are inhibited on Cav-1 overexpression. Thus, Cav-1 behaves as an oncosuppressor in osteosarcoma. Altogether, data suggest that Cav-1 down-modulation might function as a permissive mechanism, which, by unleashing c-Src and Met signaling, enables osteosarcoma cells to invade neighboring tissues. These data strengthen the rationale to target c-Src family kinases and/or Met receptor to improve the extremely poor prognosis of metastatic osteosarcoma.
 ...
PMID:Caveolin-1 reduces osteosarcoma metastases by inhibiting c-Src activity and met signaling. 1769 71


1 2 3 Next >>