Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1261473 (sarcoma)
 25,952 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We identified antimycin A1 as an inhibitor of the hypoxia-response element (HRE) from screening using a reporter under the control of HRE under hypoxic conditions. Antimycin A1 was effective at 20 pg/ml in inhibiting the reporter activity. The expression of vascular endothelial growth factor (VEGF) mRNA during hypoxia was also inhibited by antimycin A1. Angiogenesis induced by implantation of mouse sarcoma-180 cells was significantly inhibited by non-toxic doses of antimycin A1. Hypoxia inducible factor (HIF)-1alpha protein levels were significantly decreased by antimycin A1, but its mRNA level was not affected. Antimycin A1 is known to be an inhibitor of mitochondrial electron transport system, and depletion of mitochondria abolished antimycin A1-effect, at least in part. Inhibitors of proteasome or protein synthesis did not affect the decrease in HIF-1alpha level induced by antimycin A1. These results indicate that antimycin A1 inhibited angiogenesis through decrease in VEGF production caused by inhibition of HIF-1alpha activation.
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PMID:Inhibition of angiogenesis and HIF-1alpha activity by antimycin A1. 1681 66

Pediatric undifferentiated soft tissue sarcomas represent a major challenge for pathologists and clinicians. The goal of this study was to identify cases that warranted this diagnosis by current standards of analysis and then determine if there are clinicopathological commonalities that may be useful for diagnosis, management, and prognosis. Eighteen potential patients were identified using the institutional pathology database. Three cases were reclassified as specific sarcomas, and 2 cases had insufficient material for molecular analysis, leaving 13 cases for pathological review and 12 patients for radiological and clinical review. There were 7 males and 6 females. The median age at diagnosis was 11 years (1 month to 16 years). Tumors commonly involved the trunk (7 of 13; 54%) and ranged in size from 1.7 to 14.5 cm (mean, 6.7 cm). Eleven patients received ifosfamide/etoposide chemotherapy and 4 received irradiation. Five-year event-free and overall survival (EFS and OS) rates were 54% and 74%, respectively. The predominant histological pattern was round to plump spindled cells forming sheets (9 of 13; 69%) and severe atypia was associated with decreased survival (P = 0.048). Immunohistochemistry showed positivity for vimentin (92%), CD117 (92%), and vascular endothelial growth factor (69%), and 8% to 23% showed focal positivity for epithelial, neural, or myogenic markers. Tumors were uniformly negative for translocations associated with pediatric sarcomas. The presence of certain common morphological and immunohistochemical features in the absence of specific molecular genetic abnormalities allows for a diagnosis of pediatric undifferentiated soft tissue sarcoma; however, whether this group of neoplasms forms a unique category of tumors or a common precursor pathway for a number of different sarcomas awaits further study.
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PMID:Pediatric undifferentiated sarcoma of the soft tissues: a clinicopathologic study. 1682 84

To better elucidate the role of vascular endothelial growth factor (VEGF)(165) in soft tissue sarcoma (STS) growth, metastasis, and chemoresistance, we generated stably transfected human STS cell lines with VEGF(165) to study the effect of VEGF(165) on STS cells in vitro and the effect of culture medium from these cells on human umbilical vascular endothelial cells. Severe combined immunodeficient mice bearing xenografts of transfected cell lines were used to assess the effect of VEGF overexpression and the effect of VEGF receptor (VEGFR) 2 inhibition on STS growth, metastasis, and response to doxorubicin. VEGF(165)-transfected xenografts formed highly vascular tumors with shorter latency, accelerated growth, enhanced chemoresistance, and increased incidence of pulmonary metastases. Blockade of VEGFR2 signaling using DC101 anti-VEGFR2 monoclonal antibody enhanced doxorubicin chemoresponse; this combined biochemotherapy inhibited tumor growth and decreased pulmonary metastases without overt toxicity. Combined therapy reduced microvessel counts while increasing vessel maturation index. VEGF overexpression did not affect on the sarcoma cells per se; however, conditioned medium from VEGF transfectants caused increased endothelial cell proliferation, migration, and chemoresistance. Addition of DC101 induced endothelial cell sensitivity to doxorubicin and suppressed the activity of matrix metalloproteinases secreted by endothelial cells. We therefore conclude that VEGF is a critical determinant of STS growth and metastasis and that STS chemoresistance, in our model, is a process induced by the interplay between STS cells and tumor-associated endothelial cells. STS growth and metastasis can be interrupted by combined low-dose doxorubicin and anti-VEGFR2, a strategy that attacks STS-associated endothelial cells. In the future, such therapeutic approaches may be useful in treating STS before the development of clinically apparent metastases.
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PMID:Vascular endothelial growth factor overexpression by soft tissue sarcoma cells: implications for tumor growth, metastasis, and chemoresistance. 1695 Nov 93

Novel therapy as part of sarcoma treatment schemas can enhance quality of life and is important in improving outcomes of high-risk sarcomas. Additional chemotherapy and biotherapy options to reduce tumor burden and prevent metastases include intra-arterial chemotherapy in osteosarcoma; intrapleural chemotherapy, aerosol 9-nitrocamptothecin, or protracted irinotecan and temozolomide in Ewing's sarcoma; continuous hyperthermic peritoneal perfusion for malignancy involving the peritoneum, such as desmoplastic small round cell tumor; and ifosfamide with muramyl tripeptide phosphatidyl ethanolamine liposomes in osteosarcoma. These treatments bring improved control of symptoms, including reduction in nausea, mucositis, cardiotoxicity, and central nervous system toxicity. Portable infusion devices have facilitated introduction of outpatient doxorubicin, ifosfamide, and methotrexate regimens and home-infusion irinotecan. Physical approaches to eliminate sarcoma tumors and metastases are critical for durable responses. Novel local control measures include embolization before surgery, radiosensitization, anti-vascular endothelial growth factor therapy during chemo-radiotherapy, proton therapy, samarium, thermal ablation (radiofrequency ablation), and cryoablation.
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PMID:Novel therapeutic approaches in pediatric and young adult sarcomas. 1725 32

For the subgroup of patients with inoperable gastrointestinal stromal tumors, progress has been made by the rapid development and approval of the targeted therapy imatinib mesylate. Small round cell sarcoma, such as Ewing/PNET, desmoplastic small round cell sarcoma and rhabdomyosarcoma, are chemotherapy-sensitive and potentially curable malignancies, which are treated with multimodality, dose-intensitive and neoadjuvant protocols regardless of size or overt metastatic disease. A limited number of effective agents available for the treatment of patients with metastatic adult soft-tissue sarcoma exists, which have failed anthracyline and ifosfamide-based chemotherapy. Most other high-grade (grading >I) so-called adult-type soft-tissue sarcomas such as fibro, lipo, pleomorphic and synovial sarcoma are treated with a anthracycline-based regimen with or without ifosfamide as front-line therapy. In this review, the therapeutic activities of drugs currently available as second-line treatment in patients with metastatic soft tissue sarcoma are summarized, providing an overview of contentious or emerging treatment issues. In relapsed 'adult-type' soft-tissue sarcomas trofosfamide, gemcitabine and ecteinascidin (ET-743) appear to be drugs associated with moderate activity and an acceptable toxicity profile. An interesting finding to be noted is that the different drugs have particular effects in distinct subtypes of soft-tissue sarcoma; however, it has to be taken into account that the number of patients included in those phase II trials are limited. The role of the newer agents (e.g. patupilone derivates, brostallicin) is currently not definable. The so-called selective therapy targeting vascular endothelial growth factor (receptor), epidermal growth factor receptor, c-kit, Raf kinase or platelet-derived growth factor receptor and bcl-2 antisensing, proteasome, protein kinase C/B, and mammalian target of rabamycin inhibition will continue to be tested in gastrointestinal stromal tumors patients refractory to imatinib mesylate as well as in selected sarcoma subtypes.
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PMID:Systemic treatment options for patients with refractory adult-type sarcoma beyond anthracyclines. 1726 55

The growth and dissemination of sarcomas depends on angiogenesis. A number of measurable markers related to tumor angiogenesis have been studied in patients with sarcoma. The available literature related to markers of angiogenesis and clinical features in patients with sarcoma was reviewed. Clinical features of interest included tumor size, tumor grade, tumor stage, presence of metastatic disease, and prognosis. In patients with soft-tissue sarcomas, tumor vascular endothelial growth factor (VEGF) expression correlates with stage, grade, and prognosis. Circulating VEGF levels also correlate with tumor grade. High circulating angiopoietin-2 levels are associated with increased tumor size in soft-tissue sarcoma. For patients with osteosarcoma, tumor VEGF expression correlates with outcome. Elevated tumor and circulating VEGF levels are associated with the development of lung metastases in osteosarcoma. Patients with Ewing sarcoma have increased circulating VEGF levels compared with controls. Angiogenesis markers correlate with important clinical features in patients with sarcomas ranging from soft-tissue sarcomas to bone sarcomas. Markers of angiogenesis may serve an important role in predicting a particular patient's clinical course and in identifying patients for possible antiangiogenic therapy. Cancer 2007 (c) 2006 American Cancer Society.
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PMID:Markers of angiogenesis and clinical features in patients with sarcoma. 1726 25

Electrochemotherapy was instituted for sarcoma, and the tumor inhibitory ratio, curing ratio, vascular endothelial growth factor, microvessel density and mechanism were measured and analyzed. The results indicate that the curing ratio of electrochemotherapy for sarcoma is 84.6%. The present research provides experimental evidence for the security, mechanism and feasibility of electrochemotherapy in clinical practice.
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PMID:[Electrochemotherapy for tumor and mechanism analysis]. 1843 55

The common beta chain subunit (beta(c)), also known as CDw131, shared by the interleukin-3 (IL-3), granulocytic macrophage colony-stimulating factor (GM-CSF) and IL-5 receptors, is required for high-affinity ligand binding and signal transduction. The present study explored the expression of CDw131 in 105 de novo cases of acute myeloid leukaemia (AML). The levels of CDw131 expression were used to identify two AML subgroups characterized by low (75/105) and high (30/105) expression of this receptor chain. It was observed that (i) the level of CDw131 expression strictly correlated with the level of CD116 (GM-CSFalpha receptor chain) and CD123 (IL-3Ralpha chain); (ii) AMLs with high CDw131 expression were characterized by low CD34 expression and usually high CD11b, CD14 expression; (iii) AMLs with high CDw131 expression frequently co-expressed receptors for angiogenic growth factors (vascular endothelial growth factor R2, Tie-2); (iv) AMLs with high CDw131 expression were more cycling than those with low CDw131 expression; (v) AMLs with high CDw131 frequently displayed Feline Murine Sarcoma (FMS-related) tyrosine kinase 3 (FLT3) internal tandem duplication and constitutively activated Signal Transducer and Activator of Transcription-5 (STAT5). In conclusion, the analysis of the level of CDw131 expression enabled the identification of a subset of AMLs characterized by a high cycling status, the expression of myelo-monocytic markers, mutated FLT3 and the co-expression of receptors for angiogenic growth factors. These findings are of value for the development of new therapeutic strategies for the treatment of these AMLs.
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PMID:Interleukin (IL)-3/granulocyte macrophage-colony stimulating factor/IL-5 receptor alpha and beta chains are preferentially expressed in acute myeloid leukaemias with mutated FMS-related tyrosine kinase 3 receptor. 1903 83

We report the detailed molecular study of angiogenesis-ralated genes and target therapy of the case of a male 46-year-old patient with extrarenal rhabdoid tumor of pelvic retroperitoneum. The patient was found to have a huge pelvic soft tissue sarcoma and underwent pelvic tumorectomy and appendectomy. The microscopically morphological features and molecular profile by immunohistochemical analysis supported the surgical histological diagnosis of extrarenal rhabdoid tumor. The tumor recurred two weeks after surgery and metastasized to the lung, left abdominal wall and mesenteric lymph nodes. Systemic chemotherapy including ifosfamide, liposomal doxorubicin, Taxol and cisplatin, concurrently with pelvic radiotherapy (58 Gy of total dose). However, the patient did not respond to the combination of chemotherapy and radiotherapy. Immunohistochemical staining and fluorescence in situ hybridization of tumor cells indicated negative expression of human epidermal growth factor receptor-2 (HER-2) and epidermal growth factor receptor (EGFR) and positive expression of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR). So anti-VEGF targeted therapy (Bevacizumab) was administered following the fourth course chemotherapy. However, the condition worsened after the administration of the second cycle of Bevacizumab. Multiple organ failure led to the death of the patient. The patient only survived five months and 20 days after the surgery of the primary tumor.
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PMID:Case report of extrarenal rhabdoid tumor of pelvic retroperitoneum molecular profile of angiogenesis and its implication in new treatment strategy. 1927 48

Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma of adolescence and childhood. Because RMS tumors are highly vascularized, we sought to determine which factors secreted by RMS cells are crucial in stimulating angiogenesis in response to hypoxia. To address this issue, we evaluated expression of several proangiogenic factors [interleukin (IL)-8, vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF)-2, stromal-derived factor (SDF)-1, hepatocyte growth factor (HGF) and leukemia inhibitory factor (LIF)] in 8 human RMS cell lines in both normal steady-state and hypoxic conditions. We found by real-time quantitative polymerase chain reaction (RQ-PCR) and confirmed by enzyme-linked immunosorbent assay (ELISA) that from all the factors evaluated, IL-8, whose expression is very low in normoxia, had been very highly expressed and secreted by RMS cells lines during hypoxic conditions ( approximately 40-170 times). Interestingly, this upregulation was not affected by knocking down hypoxia-inducible factor (HIF)-1alpha, but was inhibited by mitogen-activated protein kinase (MAPK)p42/44 and phosphatidylinositaol 3-kinase (PI3K)/AKT pathway inhibitors. This suggests that IL-8 expression is regulated in an activating protein (AP)-1- and nuclear factor (NF)-kappaB-dependent manner. Furthermore, we found that conditioned media (CM) harvested from RMS cells exposed to hypoxia activated and stimulated chemotactic responses in human umbilical vein endothelial cells (HUVECs) and that IL-8 was responsible for hypoxia-related effects. Finally, by employing shRNA, the expression of IL-8 in human RH-30 cells was downregulated. We noticed that such RMS cells, if injected into skeletal muscles of immunodeficient mice, have a reduced ability for tumor formation. We conclude that IL-8 is a pivotal proangiogenic factor released by human RMS cells in hypoxic conditions and that the targeting of IL-8 may prove to be a novel and efficient strategy for inhibiting RMS growth.
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PMID:Selective upregulation of interleukin-8 by human rhabdomyosarcomas in response to hypoxia: therapeutic implications. 1958 9


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