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)

Ecteinascidin-743 (ET-743) is a novel marine-derived anticancer drug with clinical activity in soft tissue sarcoma and ovarian cancer. Reversible transaminitis and subclinical cholangitis have frequently been described in patients who receive ET-743. To facilitate understanding of this adverse effect and help design suitable therapeutic rescue strategies, we characterized the hepatic effects of ET-743 in rats. Female rats received ET-743 (single dose, 40 microg/kg) i.v., and liver changes were assessed from 6 h up to 3 months after dosing by histopathology, immunohistochemistry, electron microscopy, hepatic and plasma biochemistry, and DNA microarray analysis. At 24 h posttreatment and beyond, livers displayed degeneration and patchy focal necrosis of bile duct epithelial cells associated with mild inflammation followed by fibrosis. Sporadic and focal zones of hepatic necrosis and hemorrhage were observed from day 2 onward, although the majority of hepatocytes appeared normal as judged by electron microscopy. Pathological alterations persisted up to 3 months after dosing. Plasma levels of total bilirubin were elevated up to 7-fold over those in untreated rats from day 2 onward and returned to control values by day 24. Activities of alkaline phosphatase and aspartate aminotransferase in plasma were elevated for 2 and 3 months, respectively. Activities of the hepatic microsomal drug-metabolizing enzymes cytochrome P-450 A1/2, CYP2E1, and CYP3A2 were decreased. DNA microarray analysis of livers from ET-743-treated animals showed a dramatic increase in the expression of ATP binding cassette transport genes Abcb1a and Abcb1b, which impart resistance to anticancer drugs, and of Cdc2a and Ccnd1, the rodent homologues of human cell cycle genes CDC2 and cyclin D1, respectively. The cell cycle gene expression changes mirrored ET-743-induced increases in liver weight and Ki-67 labeling of liver nuclei. The results suggest that the toxicity exerted by ET-743 in the rat liver is a consequence of biliary rather than hepatocellular damage and that it is accompanied by a wave of mitogenic activity, which may be driven by the transcriptional increase in Cdc2a expression.
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PMID:Hepatobiliary damage and changes in hepatic gene expression caused by the antitumor drug ecteinascidin-743 (ET-743) in the female rat. 1215 27

Yondelis (ET-743) is a novel anticancer agent isolated from the marine ascidian Ecteinascidia turbinata. ET-743 possesses potent antitumour activity and a novel mechanism of action at the level of gene transcription. We conducted two sequential phase I dose escalation and pharmacokinetic studies of ET-743 given as a 1- or a 3-h intravenous (i.v.) infusion. Seventy-two adults with metastatic or advanced solid tumours received ET-743 in escalating doses between 50 and 1100 microg/m(2), initially as a 1-h infusion, and later at doses between 1000 and 1800 microg/m(2) as a 3-h infusion every 3 weeks. The maximum tolerated dose (MTD) of ET-743 was 1100 microg/m(2) for the 1-h infusion schedule and 1800 microg/m(2) when given as a 3-h infusion. Dose-limiting toxicities (DLTs) were fatigue, neutropenia and thrombocytopenia. Transient non-cumulatives grade 3-4 increase in transaminases (not considered DLT) and grades 3-4 nausea and vomiting were frequently observed. Other toxicities (maximum grade 3) included anaemia, increased lactate dehydrogenase (LDH), bilirubin and alkaline phosphatase serum levels, and phlebitis; there were no toxic deaths. One pCR (melanoma), CR (uterine leiomyosarcoma), one PR (colon stromal sarcoma) and a MR (37% tumour shrinkage, gastric stromal sarcoma) were observed. A further 9 patients with colorectal, mesothelioma, bile duct carcinoma and bladder cancer had SD which lasted for six or more treatment cycles. ET-743 pharmacokinetics were linear with the 3-h infusion schedule. The haematological and hepatic toxicities of ET-743 were dose-dependent and not cumulative. Based on the current trial, the recommended dose of ET-743 for phase II studies is 1650 microg/m(2) given as a 3-h infusion.
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PMID:Phase I and pharmacokinetic study of Yondelis (Ecteinascidin-743; ET-743) administered as an infusion over 1 h or 3 h every 21 days in patients with solid tumours. 1293 61

ET-743, an experimental antitumor drug with promising activity in sarcoma, breast and ovarian carcinoma, is currently under phase 2 clinical evaluation. It is hepatotoxic in animals and patients. We tested the hypothesis that indole-3-carbinol (I3C), the hydrolysis product of glucosinolates occurring in cruciferous vegetables, may protect against ET-743-induced hepatotoxicity in the female Wistar rat, the animal species with the highest sensitivity toward the adverse hepatic effect of this drug. Hepatotoxicity was adjudged by measurement of plasma levels of bilirubin, alkaline phosphatase (ALP) and aspartate aminotransferase (AST) and by liver histopathology. The effect of I3C on the kinetics of ET-743 in rat plasma and liver was investigated by high-pressure liquid chromatography. The effect of I3C on the antitumor efficacy of ET-743 was explored in rats bearing the 13762 mammary carcinoma. ET-743 (40 microg/kg i.v.) alone caused an elevation of plasma bilirubin, ALP and AST levels and degeneration and patchy focal necrosis of bile duct epithelial cells. Addition of I3C to the diet (0.5%) for 6 days prior to ET-743 administration almost completely abolished manifestations of hepatotoxicity. In contrast, a dietary concentration of 0.1% I3C did not protect, nor did dietary diindolylmethane (0.2%), an acid-catalyzed condensation product of I3C. Ingestion by rats of I3C for 6 days prior to ET-743 (40 microg/kg i.v.) decreased plasma but not hepatic concentrations of ET-743 compared to animals that received ET-743 alone. I3C did not interfere with the antitumor efficacy of ET-743. The results suggest that ingestion of I3C may counteract the unwanted effect of ET-743 in the liver. I3C should be investigated as a hepatoprotectant in patients who receive ET-743 therapy.
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PMID:Dietary agent indole-3-carbinol protects female rats against the hepatotoxicity of the antitumor drug ET-743 (trabectidin) without compromising efficacy in a rat mammary carcinoma. 1530 Aug 10

Aspiration of lytic bone lesions is an excellent diagnostic test in the initial evaluation of primary bone neoplasia. However, cytologically, it can be difficult to differentiate osteosarcoma (OSA) from other bone neoplasms, including fibrosarcoma, chondrosarcoma, synovial cell sarcoma, and plasma cell myeloma. The purpose of this study is to determine the sensitivity and specificity of alkaline phosphatase (ALP) staining to differentiate OSA from other tumors that express vimentin by immunocytochemistry or immunohistochemistry. ALP is a hydrolytic enzyme present in multiple tissues including liver, kidney, intestine, placenta, and bone. Hypothetically, neoplasms actively producing bone should be specifically positive for ALP staining. Unstained, cytologic specimens were incubated for 8-10 minutes with nitroblue tetrazolium chloride/5-bromo-4-chloro-3-indolyl phosphate toluidine salt-phosphatase substrate. A positive reaction stains the membrane of the cells gray to black. Samples were counterstained with a Romanowsky's stain to determine whether the sample was of representative cellularity. A total of 61 vimentin-positive neoplasms have been evaluated and confirmed histopathologically. Tumors that expressed vimentin and were positive for ALP included 33 OSAs, one multi-lobular tumor of bone, one amelanotic melanoma, and one chondrosarcoma. Tumors that expressed vimentin and were negative for ALP included chondrosarcomas (three of four), multiple fibrosarcomas, and multiple synovial cell sarcomas. The sensitivity is 100%, and the specificity is 89%. In conclusion, ALP appears to be a highly sensitive and fairly specific marker in the diagnosis of OSA.
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PMID:Use of alkaline phosphatase staining to differentiate canine osteosarcoma from other vimentin-positive tumors. 1575 69

Myofibrosarcoma is a rare neoplasm that occurs mainly in the head and neck region and extremities of middle-aged patients. It often appears as a low-grade sarcoma and rarely metastasizes. We report the case of a 47-year-old male patient with a malignant mesenchymal pulmonary tumor affecting almost the entire lower left lobe. Clinically suggestive for a lung carcinoma, the tumor showed typical features of a myofibrosarcoma. A major spindle cell component was observed being positive for smooth-muscle actin, calponin, and vimentin, while stainings for desmin, h-caldesmon, alkaline phosphatase (ALK), and extensively studied cytokeratins were negative. Striking was a strong infiltrate with neutrophilic and eosinophilic granulocytes. DNA cytometry revealed aneuploidy with a peak in the near triploid range. Comparative genomic hybridization demonstrated multiple DNA gains and losses correlating with an aggressive clinical course. Shortly after resection of the primary tumor, the patient showed multiple distant metastases in the contralateral lung, the mediastinal lymph nodes, the left adrenal gland, and the pectoral and deltoid muscle, which responded well to chemotherapy. The case report will discuss the evidence for the final diagnosis of a primary pulmonary myofibrosarcoma and the differential diagnosis of sarcomatoid tumors of the lung.
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PMID:Unusual sarcomatoid neoplasm of the lung suggesting a myofibrosarcoma. 1615 84

Several studies have demonstrated the pleiotropic effects of statins. Since Wang and associates reported that in rabbits lovastatin reduced steroid-induced bone loss, numerous authors have confirmed these data, however, others have reported conflicting results. In this study, the effects of fluvastatin on bone formation were investigated in early and late phase of osteogenesis. In the first set of experiments (early phase of osteogenesis) CFW/Ll mice were randomly divided into three groups. Two groups were injected with Moloney-murine sarcoma virus (Mo-MSV) into right thighs to induce orthotopic bone formation. Mice in the experimental group received fluvastatin for 11 consecutive days. Thirty days after Mo-MSV inoculation, total serum cholesterol, triglycerides, high- and low-density lipoprotein cholesterol, alkaline phosphatase (AP) were measured and bone mineral increase was calculated. In the second set of experiments (late phase of osteogenesis), fluvastatin was administered from day 11 after Mo-MSV inoculation for 20 consecutive days. Fluvastatin administration in the early phase of osteogenesis made no significant difference in average bone increase compared with mice receiving placebo. Lipid profile and AP were not significantly affected. During late phase of osteogenesis, the average increase in femural dry mass was significantly lower in the group of mice receiving fluvastatin than in the control group. Also, Mo-MSV-initiated tumors disappeared earlier in mice treated with fluvastatin. This may be attributed to the antioncogenic potential of fluvastatin. These results also point out that orthotopic bone formation at the sites of Mo-MSV inoculation in mice seems to be a useful model to examine the pleiotropic effects of statins.
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PMID:Fluvastatin does not elevate periosteal osteogenesis induce by Moloney sarcoma virus (MSV) in mice. 1653 31

A 6-year-old, neutered male Rottweiler was presented to the University of Illinois Veterinary Teaching Hospital because of a lytic bone lesion involving the distal portion of the right radius and possible pulmonary metastases on thoracic radiographs. Results of serum biochemical analysis were unremarkable. Aspiration and cytologic examination of the bone lesion indicated likely sarcoma with reactive bone. Cutaneous masses were found on the left thigh, interscapular region, and dorsal lumbar region, 4 weeks after initial presentation. Neoplastic spindle cells were found in aspirates from 2 of the masses. The neoplastic cells stained positive for alkaline phosphatase activity using cytochemistry. Re-evaluation of serum biochemical values at this time revealed a marked increase in alkaline phosphatase activity (413 U/L, reference interval 12-110 U/L) compared with the initial value (26 U/L). Due to progressive disease, the dog was euthanized and a necropsy was performed. Histologic findings included primary osteosarcoma of the distal portion of the right radius, with metastases in the lungs, spleen, left fourth and fifth ribs, soft tissue of the right medial thigh, and T1-T3/interscapular region. Cutaneous metastasis of primary appendicular osteosarcoma has been reported rarely in animals and humans. Increased serum alkaline phosphatase activity may be a potential indicator of poor prognosis for this neoplasm.
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PMID:Cutaneous metastasis of primary appendicular osteosarcoma in a dog. 1696 27

Purpose. The antimicrobial effect of a silver-coated tumor endoprosthesis has been proven in clinical and experimental trials. However, in the literature there are no reports concerning the effect of elementary silver on osteoblast behaviour. Therefore, the prosthetic stem was not silver-coated because of concerns regarding a possible inhibition of the osseointegration. The aim of the present study was to investigate the effect of 5-25 mg of elementary silver in comparison to Ti-6Al-4V on human osteosarcoma cell lines (HOS-58, SAOS). Methods. Cell viability was determined by measuring the MTT proliferation rate. Cell function was studied by measuring alkaline phosphatase (AP) activity and osteocalcine production. Results. In the HOS-58 cells, the AP activity was statistically significant (P < 0.05) higher at a supplement of 5-10 mg of silver than of Ti-6 Al-4V at the same doses. For both cell lines, a supplement above 10 mg of silver resulted in a reduced AP activity in comparision to the Ti-6 Al-4V group, but a statistically significant difference (P < 0.05) was observed at a dose of 25 mg for the SAOS cells only. At doses of 20-25 mg in the HOS-58 cells and 10-25 mg in the SAOS cells, the reduction of the proliferation rate by silver was statistically significant (P < 0.05) compared to the Ti-6 Al-4V supplement. Discussion. In conclusion, elementary silver exhibits no cytotoxicity at low concentrations. In contrast, it seems to be superior to Ti-6 Al-4V concerning the stimulation of osteogenic maturation at these concentrations, whereas at higher doses it causes the known cytotoxic properties.
Sarcoma 2007
PMID:The influence of elementary silver versus titanium on osteoblasts behaviour in vitro using human osteosarcoma cell lines. 1768 31

We analysed a series of 119 patients presenting with Paget's bone disease treated at the Istituto Ortopedico Rizzoli (Bologna Italy) over 35 years (from 1970 to 2006). Among these, we found 18 cases that had degenerated into sarcoma. The first goal of this study was to underline the potential factors of Paget's disease transformation into sarcoma. In detail we considered: age, gender, duration of disease, clinical expression, levels of total alkaline phosphatase and type of therapy. The results highlighted an interesting correlation between therapy and degeneration into sarcoma; more specifically, malignant transformation occurred both in patients who had not received any therapy and those who had received regular calcitonin treatment; otherwise, no sarcoma degeneration occurred in the patients treated with bisphosphonates. These data seem to indicate a preventing effect of bisphosphonates towards the degeneration of Paget's disease into sarcoma.
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PMID:Degeneration of Paget's disease into sarcoma: clinical and therapeutic influencing factors. 1840 34

Granulocytic sarcoma mimicking a synchronous second primary neoplasm (SPN) constitutes a diagnostic and therapeutic challenge particularly in elderly patients. We report on a 75-year-old female presenting with a Core-binding Factor (CBF) AML of M4eo subtype. The patient also had jaundice, highly elevated bilirubin, lipase, alkaline phosphatase (AP), CA 19-9, and a pancreatic mass highly suspicious of infiltrating pancreatic carcinoma. However, a biopsy demonstrated granulocytic sarcoma. Since the patient had no comorbidities and had been in excellent performance status until the diagnosis of AML, induction chemotherapy was initiated, with subsequent normalization of bilirubin, CA 19-9, lipase and AP. Complete hematologic remission of AML was attained and the pancreatic mass could not be detected anymore. Retrospective analysis of the c-kit protooncogene did not disclose activating mutations of exons 8 or 17. Following one consolidation treatment, the patient remained in excellent health until relapse occurred 7 months later and she succumbed to AML. In conclusion, AML can rarely mimic the clinical picture of pancreatic cancer. The initially good response of this CBF leukemia highlights the principal usefulness of aggressive induction chemotherapy also in older AML patients, if they are carefully selected not only according to biological risk factors such as cytogenetics, but also to "host factors" (good performance status, lack of comorbidities, etc.).
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PMID:Granulocytic sarcoma of Core-binding Factor (CBF) acute myeloid leukemia mimicking pancreatic cancer. 1845 26


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