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

CD4 and one of the G-protein-coupled receptors (GPCRs) on the cell surface function as a receptor and a coreceptor, respectively, in infection of cells with human and simian immunodeficiency viruses (HIV/SIV). To determine which GPCRs can be coreceptors for HIV (HIV-1 and HIV-2) or SIV infection, several cell lines, including human osteosarcoma HOS-T4 cells and human glioma U87/CD4 cells, have been used. However, these cells often show susceptibilities to some HIV or SIV strains before transduction of GPCRs. The results of this study showed that a CD4-transduced human glioma cell line, NP-2/CD4, a human erythroleukemia cell line, K562/CD4, and a human ovarian cancer cell line, TYK/CD4, were completely resistant to the HIV-1 and HIV-2 strains tested. After transduction of several GPCRs into NP-2/CD4, K562/CD4, or TYK/CD4 cells, NP-2/CD4 cells but not K562/CD4 or TYK/CD4 cells mostly showed expected susceptibilities to several HIV strains. Therefore, an NP-2 cell system would be useful to determine the coreceptor usage of HIV isolates, to find a new coreceptor for HIV/SIV, and to analyze the early stages of HIV/SIV infection.
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PMID:Establishment of a new system for determination of coreceptor usages of HIV based on the human glioma NP-2 cell line. 1032 84

4-Carbethoxy-1-methyl-2-phenacyl-3-phenylpyrrole (9), 4-carbethoxy-2-(4-methoxybenzoyl)-3-(4-methoxyphenyl)pyrrole (10) and 2-(4-methoxybenzoyl)-3,4-bis-(4-methoxyphenyl)pyrrole (11) proved to be potent cytotoxic agents against the growth of murine and human leukemias and lymphomas. Selective toxicity was demonstrated against the growth of solid tumors, e.g., human adenocarcinoma of the colon SW480 and ileum HCT-8, glioma U-87-MG, and rat UMR-106 osteosarcoma. A mode of action study in Tmolt4 leukemia cells demonstrated that the agents inhibited de novo purine synthesis at the regulatory sites PRPP-amido transferase, IMP dehydrogenase as well as dihydrofolate reductase resulting in significant inhibition of DNA synthesis in 60 min. Other biochemical sites which were affected significantly were thymidylate synthetase, DNA polymerase alpha, RNA polymerases, nucleoside kinase and ribonucleoside reductase.
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PMID:The cytotoxicity and mode of action of 2,3,4-trisubstituted pyrroles and related derivatives in human Tmolt4 leukemia cells. 1052 73

A number of thiosemicarbazones have been tested previously and herein are included three bis(thiosemicarbazones) for comparison to the previous derivatives. In general the uncomplexed thiosemicarbazones were more potent in the cytotoxic screens than the bis(thiosemicarbazone) except in the murine L1210 and the human colon SW480 screens. Mode of action studies have only demonstrated slight differences in the effects of the two types of compounds on nucleic acid metabolism. The symmetrical and unsymmetrical bis(thiosemicarbazones) complexes of copper, nickel, zinc, and cadmium have been examined to compare them to the heterocyclic N(4)-substituted thiosemicarbazones metal complexes. These new derivatives demonstrated excellent activity against the growth of suspended lymphomas and leukemias although it should be pointed out that generally they were not as active as the copper complexes of N(4)-substituted thiosemicarbazones. Nevertheless, selected bis(thiosemicarbazones) complexes were active against the growth of human lung MB9812, KB nasopharynx, epidermoid A431, glioma UM-86, colon SW480, ovary 1-A9, breast MCK-7, and osteosarcoma Saos-2. In human HL-60 promyelocytic leukemia cells the complexes preferentially inhibited DNA and purine syntheses over 60 min. The regulatory enzyme of the de novo purine pathway, IMP dehydrogenase, appeared to be a major target of the complexes. However, minor inhibition of the activities of DNA polymerase alpha, PRPP-amido transferase, ribonucleotide reductase, and nucleoside kinases occurred over the same time period. No doubt these effects of the complexes on nucleic acid metabolism were additive since the d[NTP] pool levels were reduced after 60 min as was DNA synthesis. The symmetrical and unsymmetrical bis(thiosemicarbazones) and their metal complexes did not cause as severe DNA fragmentation as the heterocyclic N(4)-substituted thiosemicarbazone metal complexes; furthermore, their metabolic effects in the tumor cell were more focused on a single synthetic pathway.
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PMID:The cytotoxicity of symmetrical and unsymmetrical bis(thiosemicarbazones) and their metal complexes in murine and human tumor cells. 1096 96

A Phase I trial of irinotecan was performed to determine the maximum tolerated dose (MTD), the dose-limiting toxicities (DLTs), and the incidence and severity of other toxicities in children with refractory solid tumors. Thirty-five children received 146 courses of irinotecan administered as a 60-min i.v. infusion, daily for 5 days, every 21 days, after premedication with dexamethasone and ondansetron. Doses ranged from 30 mg/m2 to 65 mg/m2. An MTD was defined in heavily pretreated and less-heavily pretreated (i.e., two prior chemotherapy regimens, no prior bone marrow transplantation, and no radiation to the spine, skull, ribs, or pelvic bones) patients. Myelosuppression was the primary DLT in heavily pretreated patients, and diarrhea was the DLT in less-heavily pretreated patients. The MTD in the heavily pretreated patient group was 39 mg/m2, and the MTD in the less-heavily pretreated patients was 50 mg/m2. Non-dose-limiting diarrhea that was well controlled and of brief duration was observed in approximately 75% of patients. A partial response was observed in one patient with neuroblastoma, and in one patient with hepatocellular carcinoma. Stable disease (4-20 cycles) was observed in seven patients with a variety of malignancies including neuroblastoma, pineoblastoma, glioblastoma, brainstem glioma, osteosarcoma, hepatoblastoma, and a central nervous system rhabdoid tumor. In conclusion, the recommended Phase II dose of irinotecan administered as a 60-min i.v. infusion daily for 5 days, every 21 days, is 39 mg/m2 in heavily treated and 50 mg/m2 in less-heavily treated children with solid tumors.
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PMID:A phase I study of irinotecan in pediatric patients: a pediatric oncology group study. 1120 14

The in vivo uptake of dodecahydro-closo-dodecaborate derivatives substituted with phosphate- and bisphosphonate groups was evaluated in two different experimental tumor model systems and compared to other boronated and non-boronated compounds. These phosphorous-containing boron clusters may have potential for use in boron neutron capture therapy, a chemoradiotherapeutic form of cancer treatment. Using the F98 rat glioma as a brain tumor model in syngeneic Fischer rats, there was selective tumor uptake of the phosphate derivative with 21.5 micrograms boron/g tumor versus 5.2 micrograms/g normal brain and a tumor:blood ratio of 2.7. However, this compound was toxic to test animals and lethal at relatively low doses. The uptake of the bisphosphonate by the murine K8 osteosarcoma was approximately 18 micrograms boron/g tumor with a T:Bl ratio of 7.6 and a tumor:bone ratio of 1.5. This compound was non toxic to the test animals. The results indicate that phosphate- and bisphosphonate derivatives of dodecahydro-closo-dodecaborate may have potential for BNCT of gliomas and osteosarcomas, respectively.
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PMID:In vivo evaluation of phosphorous-containing derivatives of dodecahydro-closo-dodecaborate for boron neutron capture therapy of gliomas and sarcomas. 1139 73

A noninvasive method for molecular imaging of the activity of different signal transduction pathways and the expression of different genes in vivo would be of considerable value. It would aid in understanding the role specific genes and signal transduction pathways have in various diseases, and could elucidate temporal dynamics and regulation at different stages of disease and during various therapeutic interventions. We developed and assessed a method for monitoring the transcriptional activation of endogenous genes by positron-emission tomography (PET) imaging. The HSV1-tk/GFP (TKGFP) dual reporter gene was used to monitor transcriptional activation of p53-dependent genes. A retrovirus bearing the Cis-p53/TKGFP reporter system was constructed in which the TKGFP reporter gene was placed under control of an artificial cis-acting p53-specific enhancer. U87 glioma and SaOS-2 osteosarcoma cells were transduced with this retrovirus and used to establish xenografts in rats. We demonstrated that DNA damage-induced up-regulation of p53 transcriptional activity correlated with the expression of p53-dependent downstream genes, such as p21, in U87 (wild-type p53), but not in SaOS-2 osteosarcoma (p53 -/-) cells. We showed that PET, with [(124)I]FIAU (2'-fluoro-2'-deoxy-1-beta-d-arabinofuranosyl-5-[(124)I]iodouracil) and the Cis-p53TKGFP reporter system, is sufficiently sensitive to image the transcriptional regulation of genes in the p53 signal transduction pathway. These imaging results were confirmed by independent measurements of p53 activity and the expression levels of downstream genes (e.g., p21) by using conventional molecular-biological assays. PET imaging of p53 transcriptional activity in tumor xenografts by using the Cis-p53TKGFP reporter system may be useful in assessing novel therapeutic approaches.
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PMID:Imaging transcriptional regulation of p53-dependent genes with positron emission tomography in vivo. 1148 88

The neurofibromatosis 2 tumour suppressor merlin/schwannomin is structurally related to the ezrin-radixin-moesin family of proteins, which anchor actin cytoskeleton to specific membrane proteins and participate in cell signalling. Merlin inhibits cell growth with a yet unknown mechanism. As most tumour suppressors are linked to cell cycle control, we investigated merlin's behaviour during cell cycle. In glioma and osteosarcoma cells, endogenous merlin was targeted to the nucleus in a cell cycle-specific manner. Merlin accumulated perinuclearly at the G2/M phase, and shifted to the nucleus at early G1. During mitosis, merlin localized to mitotic spindles and at the contractile ring. Nuclear merlin was strongly reduced in confluent cells. Blocking of the CRM1/exportin nuclear export pathway led to accumulation of merlin in the nucleus. Activation of the p21-activated kinase or protein kinase A, which result in phosphorylation of merlin, did not affect its nuclear localization. Merlin regulates the activity of extracellular signal-regulated kinase 2 (ERK2) and nuclear localization of both proteins was induced by cell adhesion. Unlike ERK2, nuclear localization of merlin was not, however, dependent on intact actin cytoskeleton. These results link merlin to events related to cell cycle control and may help to resolve its tumour suppressor function.
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PMID:Cell cycle-dependent nucleocytoplasmic shuttling of the neurofibromatosis 2 tumour suppressor merlin. 1558 Feb 88

Research on HIV vaccines, as well as studies on HIV pathogenesis in human and SIV in the macaque model, require the availability of simple and standardized assays for quantification of neutralizing antibodies to primary virus isolates. We have recently developed and standardized assays using human cell lines engineered to express CD4 and co-receptors for HIV and SIV entry. One cell line originated from a glioma (U87) and the other from an osteosarcoma (HOS). Both cell lines and their derivatives form monolayer cultures, a prerequisite for counting plaques. HIV-infected U87.CD4-CCR5 or -CXCR4 cells form syncytia, that is, plaques that can be stained with hematoxylin and enumerated by light microscopy. In addition to CD4 and co-receptors (most often used CCR5 and CXCR6 by SIV), GHOST(3) cells have been engineered to express the green fluorescent protein following virus infection. Infected cells show green fluorescence and can be enumerated by fluorescence microscopy. Neutralization is determined by the ability of a serum to reduce the number of plaque-forming units (PFU) relative to controls exposed to medium or negative serum. Both assays are run in microtiter format and neutralization is evaluated after 3 d. Intra-assay variation has been used for estimation of the cutoff for neutralization. Testing 15 serum-virus combinations in the U87.CD4 assay and four serum-virus combinations in the GHOST(3) assay revealed that standard deviation of differences ranged from 9.1% to 9.9% in the two assays. This allowed the use of a cutoff >3 SD; that is, 30% neutralization. Virus titration experiments showed that neutralization results were dependent on virus dose and therefore the neutralization assays should be performed with a virus dose of 10-100 PFU/well. The assays have high specificity and reproducibility, and are simple and sensitive high-throughput assays.
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PMID:Plaque-reduction assays for human and simian immunodeficiency virus neutralization. 1606 83

DES carcinogenicity has been investigated in 2 mouse knockout models, the Xpa homozygous knockout, and the combined Xpa homozygous and p53 heterozygous knockout. Wild-type (WT) mice were also included. Xpa mice received diets containing DES at concentrations of 0, 100, 300, and 1500 ppb for 39 weeks; Xpa/p53 and WT mice received diets containing 0 or 1500 ppb. There were 15 of each sex per group. Both Xpa and WT mice had a similar incidence of tumors at the high dosage of 1500 ppb, including pituitary adenomas in 4 WT mice and 7 Xpa mice, and single incidences of osteosarcoma (Xpa), T-cell lymphoma (WT and Xpa), and testicular interstitial cell adenoma (WT and Xpa). The incidence of tumors was higher in the Xpa/p53 mice at 1500 ppb, mainly attributable to 5 osteosarcomas in males and 2 in females, but also 4 pituitary adenomas, testicular interstitial cell adenomas in 4 males, and single incidences of cerebral glioma, phaeochromocytoma, and cervical fibrosarcoma. The incidence of osteosarcomas was related to the severity of fibro-osseous lesions in the bone marrow. It was concluded that for carcinogenicity screening, Xpa mice were no more sensitive than wild-type mice for compounds like DES, but the Xpa/p53 model showed an increased sensitivity.
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PMID:Diethylstilbestrol (DES): carcinogenic potential in Xpa-/-, Xpa-/- / p53+/-, and wild-type mice during 9 months' dietary exposure. 1617 26

Facial swelling is a common clinical problem in pediatric patients. The causes of swelling are diverse, and knowledge of the typical clinical and imaging manifestations and the most common sites of occurrence of these conditions is needed to formulate a differential diagnosis. The general clinical manifestations may be classified into the following four groups: (a) acute swelling with inflammation, (b) nonprogressive swelling, (c) slowly progressive swelling, and (d) rapidly progressive swelling. Conditions that may account for acute swelling accompanied by inflammation include lymphadenitis, sinusitis, odontogenic infection, and abscess. Contrast-enhanced computed tomography is the modality of choice for detection of abscesses requiring surgical drainage. Nonprogressive midfacial swelling is suggestive of a congenital anomaly (eg, a cephalocele, nasal glioma, or nasal dermoid or epidermoid cyst). Slowly progressive swelling may indicate the presence of a neurofibroma, hemangioma, lymphangioma, vascular malformation, or pseudocyst, or of fibrous dysplasia. The differential diagnosis for rapidly progressive facial swelling in association with cranial nerve deficits should include rhabdomyosarcoma, Langerhans cell histiocytosis, Ewing sarcoma, osteogenic sarcoma, and metastatic neuroblastoma.
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PMID:Causes of facial swelling in pediatric patients: correlation of clinical and radiologic findings. 1641 50


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