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)

Interferon (IFN) is an important immune system molecule capable of inducing an antiviral state within cells. Herpes simplex virus type 1 (HSV-1) replication is somewhat reduced in tissue culture in the presence of IFN, presumably due to decreased viral transcription. Here, we show mutations that inactivate immediate-early (IE) gene product ICP0 render HSV-1 exquisitely sensitive to IFN inhibition, resulting in greatly decreased levels of viral mRNA transcripts and the resulting polypeptides and a severe reduction in plaque formation ability. Mutations in other HSV-1 genes, including the genes coding for virion transactivator VP16 and the virion host shutoff protein vhs, IE gene ICP22, and the protein kinase UL13 gene, do not increase the IFN sensitivity of HSV-1. Interestingly, ICP0 mutants demonstrate the same level of sensitivity to IFN as wild-type virus on U2OS cells, an osteosarcoma cell line that is known to complement mutations in ICP0 and VP16. Thus, in some cell types, functional ICP0 is required for HSV-1 to efficiently bypass the inhibitory effects of IFN in order to ensure its replication. The significance of this link between ICP0 and IFN resistance is discussed.
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PMID:Herpes simplex virus ICP0 mutants are hypersensitive to interferon. 1064 80

We constructed a series of adenoviral (Ad) vectors that express the Candida albicans cytosine deaminase (CD) suicide gene under the transcriptional control of either the human alpha-lactalbumin (ALA) or ovine beta-lactoglobulin (BLG) promoter (Ad.ALA.CD and Ad.BLG.CD, respectively). The Ad.ALA.CD and the Ad.BLG.CD vectors converted the prodrug 5-fluorocytosine (5-FC) to the toxic nucleotide analog 5-fluorouracil in a breast cancer cell-specific manner, with a conversion rate of 40% and 52% in T47D cells and 50% and 41% in MCF7 cells, respectively. No significant conversion (< or =3%) was observed in an immortalized nontumorigenic breast epithelial cell line (MCF10A) and a human osteosarcoma cell line (U2OS). Adenovirus vector-based prodrug conversion of the 5-FC in T47D and MCF7 in the presence of 1 mg/mL of 5-FC led to cytotoxicity that resulted in a nearly complete cell death (> or =90%) after 5 days, whereas MCF10A and U2OS cells remained resistant (< or =10%). Nude mice harboring T47D-derived breast tumors that were injected intratumorally (i.t.) with therapeutic adenovirus vectors at a dose of 2 x 10(8) plaque-forming units and treated systemically with 5-FC at a concentration of 500 mg/kg/day showed a marked reduction in tumor mass within 30 days when compared with animals that received vector alone. Animal survival was significantly prolonged after 72 days in mice treated with therapeutic vectors in conjunction with prodrug when compared with control animals. These preclinical data are sufficiently promising to warrant further studies of this transcriptional targeting approach to breast cancer treatment.
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PMID:Breast cancer-specific expression of the Candida albicans cytosine deaminase gene using a transcriptional targeting approach. 1088 14

The calponin (basic or h1) gene, normally expressed in maturated smooth muscle cells, is aberrantly expressed in a variety of human soft tissue and bone tumors. In this study, we show that expression of the calponin gene in human soft tissue and bone tumor cells is regulated at the transcriptional level by the sequence between positions -260 and -219 upstream of the translation initiation site. A novel conditionally replicating herpes simplex virus-1 vector (d12.CALP) in which the calponin promoter drives expression of ICP4, a major trans-activating factor for viral genes was constructed and tested as an experimental treatment for malignant human soft tissue and bone tumors. In cell culture, d12.CALP at low multiplicity of infection (0.001 plaque-forming unit/cell) selectively killed calponin-positive human synovial sarcoma, leiomyosarcoma, and osteosarcoma cells. For in vivo studies, 10 animals harboring SK-LMS-1 human leiomyosarcoma cells were randomly divided and treated twice on days 0 and 9 intraneoplastically with either 1 x 10(7) plaque-forming units of d12.CALP/100 mm(3) of tumor volume or with medium alone. The viral treatment group showed stable and significant inhibition of tumorigenicity with apparent cure in four of five mice by day 35. Replication of viral DNA demonstrated by PCR amplification and expression of the inserted LacZ gene visualized by 5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside histochemistry was associated with oncolysis of d12.CALP-treated tumors, while sparing normal vascular smooth muscle cells. In mice harboring two SK-LMS-1 tumors, replication of d12.CALP was detected in a nontreated tumor distant from the site of virus inoculation. These results indicate that replication-competent virus vectors controlled by the calponin transcriptional regulatory sequence may be a new therapeutic strategy for treatment of malignant human soft tissue and bone tumors.
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PMID:Identification of the transcriptional regulatory sequences of human calponin promoter and their use in targeting a conditionally replicating herpes vector to malignant human soft tissue and bone tumors. 1135 14

The conformationally locked nucleoside, (north)-methanocarbathymine (1a), is a potent and selective anti-herpes agent effective against herpes simplex type 1 (HSV1) and type 2 (HSV2) viruses. Hereby, we report on the synthesis and biological evaluation of a small set of 5-substituted pyrimidine nucleosides belonging to the same class of bicyclo[3.1.0]hexane nucleosides. Both the 5-bromovinyl (4) and the 5-bromo analogue (3) appeared to be exclusive substrates of HSV1 thymidine kinase (TK), contrasting with the 5-iodo analogue (2), which was significantly phosphorylated by the human cytosolic TK. The binding affinity constant and catalytic turnover for HSV1 TK were measured to assess the influence of the substitution on these parameters. In the plaque reduction and cytotoxicity assays, the 5-bromo analogue (3) showed good activity against HSV1 and HSV2 with less general toxicity than 1a. Against varicella-zoster virus (VZV), the north-locked 5-bromovinyl analogue (4) proved to be as potent as its conformationally unlocked 2'-deoxyriboside equivalent BVDU. The three compounds were also tested in vitro as prodrugs used in a gene therapy context on three osteosarcoma cell lines, either deficient in TK (TK(-)), nontransduced, or stably transduced with HSV1 TK. The 5-iodo compound (2, CC(50) 25 +/- 7 microM) was more efficient than ganciclovir (GCV, CC(50) 75 +/- 35 microM) in inhibiting growth of HSV1-TK transfected cells and less inhibitory than GCV toward TK(-) cells, whereas compound 3 inhibited transfected and nontransfected cell lines in a relatively similar dose-dependent manner.
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PMID:Synthesis and biological evaluation of 5-substituted derivatives of the potent antiherpes agent (north)-methanocarbathymine. 1458 54

Different strains of simian virus 40 (SV40) exist and are associated with some human malignancies, but it is not known if SV40 strains differ in biological potential in vivo. In two long-term experiments, Syrian golden hamsters 21 days of age were inoculated by the intraperitoneal route with two different strains of SV40 (10(7) plaque-forming units/animal) and were followed for 8 or 12 months. In vivo responses to strain VA45-54, isolated originally from monkey kidney cells, and to strain SVCPC, recovered from human cancers, were compared. Control animals of the same age were inoculated intraperitoneally with cell culture media. Malignancies developed only in animals infected with SV40 and not in controls. The rate of tumor development was more frequent among animals infected with strain SVCPC than with VA45-54, both in experiments held for 8 months (11/22, 50% vs. 4/20, 20%) and for 12 months (7/15, 47% vs. 3/13, 23%). Histologically, the tumors resembled mesotheliomas, osteosarcoma, and poorly differentiated sarcomas. Metastases to lung and lymph nodes occurred with both viral strains. T-antigen expression was detected in most tumor cells by immunohistochemistry. Anti-T-antigen antibodies were produced by almost all tumor-bearing animals and by about two-thirds of those that did not develop tumors after virus inoculation. SV40 viral neutralizing antibodies were detected in all tumor-bearing animals and in 92% and 38% of those inoculated with SVCPC and VA45-54, respectively, that failed to develop tumors. Antibody titers were usually higher in animals with tumors than in those without. Control animals did not develop viral antibodies. Infectious virus was recovered from 2 of 15 tumors tested. This study showed that there are biological differences between these two SV40 strains that influence the outcome of infections in normal hosts, including the development of malignancies and neutralizing antibody, and proved the principle that SV40 strains from different clades can vary in biological properties in vivo.
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PMID:Differential ability of two simian virus 40 strains to induce malignancies in weanling hamsters. 1552 43

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

Previous studies have indicated that one of the causes of alveolar bone destruction with periodontitis is lipopolysaccharide (LPS) from the cell wall of gram-negative bacteria in plaque, and that prostaglandin E(2) (PGE(2)) is one of the bone resorption factors that stimulate osteoclast formation through an intercellular interaction between osteoblasts and osteoclast precursors. The present study was undertaken to determine the effect of LPS on cell growth, alkaline phosphatase (ALPase) activity, the production of PGE(2), and the expression of receptors by PGE(2), cyclooxygenase (COX)-1, and COX-2, using human osteosarcoma cell line Saos-2 as osteoblasts. The cells were cultured with 0, 1, or 10 microg mL(-1) of LPS for up to 14 days. The production of PGE(2) and the gene expression of COX-1, COX-2, and PGE(2) receptors, including Ep1, Ep2, Ep3, and Ep4, were determined using enzyme-linked immunosorbent assay (ELISA) and real-time reverse transcription-polymerase chain reaction (real-time RT-PCR), respectively. With the addition of LPS, cell growth and ALPase activity decreased by day 5 of the culture, while PGE(2) production increased in a dose-dependent manner throughout the entire 14-day culture period. LPS-reduced ALP activity and LPS-induced PGE(2) production returned to the control level by the addition simultaneously with indomethacin. The expression of COX-1, Ep1, Ep2, and Ep3 receptors decreased on day 14 of the culture, whereas the expression of COX-2 and Ep4 receptors increased significantly with the addition of LPS. These results suggest that LPS promotes PGE(2) production by increasing the expression of COX-2, and that LPS promotes the production of Ep4 receptors in osteoblasts. These results also indicate that LPS-induced PGE(2) may combine with osteoblast Ep4 receptors in autocrine or paracrine modes, and may promote the formation of osteoclasts.
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PMID:Lipopolysaccharide stimulates the production of prostaglandin E2 and the receptor Ep4 in osteoblasts. 1628 20

About 70% of all Ewing sarcoma (EWS) patients are diagnosed under the age of 20 years. Over the last decades little progress has been made towards finding effective treatment approaches for primarily metastasized or refractory Ewing sarcoma in young patients. Here, in the context of the search for novel therapeutic options, the potential of oncolytic protoparvovirus H-1 (H-1PV) to treat Ewing sarcoma was evaluated, its safety having been proven previously tested in adult cancer patients and its oncolytic efficacy demonstrated on osteosarcoma cell cultures. The effects of viral infection were tested in vitro on four human Ewing sarcoma cell lines. Notably evaluated were effects of the virus on the cell cycle and its replication efficiency. Within 24 h after infection, the synthesis of viral proteins was induced. Efficient H-1PV replication was confirmed in all four Ewing sarcoma cell lines. The cytotoxicity of the virus was determined on the basis of cytopathic effects, cell viability, and cell lysis. These in vitro experiments revealed efficient killing of Ewing sarcoma cells by H-1PV at a multiplicity of infection between 0.1 and 5 plaque forming units (PFU)/cell. In two of the four tested cell lines, significant induction of apoptosis by H-1PV was observed. H-1PV thus meets all the in vitro criteria for a virus to be oncolytic towards Ewing sarcoma. In the first xenograft experiments, however, although an antiproliferative effect of intratumoral H-1PV injection was observed, no significant improvement of animal survival was noted. Future projects aiming to validate parvovirotherapy for the treatment of pediatric Ewing sarcoma should focus on combinatorial treatments and will require the use of patient-derived xenografts and immunocompetent syngeneic animal models.
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PMID:Preclinical Testing of an Oncolytic Parvovirus in Ewing Sarcoma: Protoparvovirus H-1 Induces Apoptosis and Lytic Infection In Vitro but Fails to Improve Survival In Vivo. 2986 80

We evaluated the long-term effects of sirolimus on three different cell in vitro models, cultured in physiological conditions mimicking sirolimus-eluted stent, in order to clarify the effectiveness of sirolimus in blocking cell proliferation and survival. Three cells lines (WPMY-1 myofibroblasts, HT-29 colorectal adenocarcinoma, and U2OS osteosarcoma) were selected and growth in 10 ml of Minimum Essential Medium for 5 weeks with serial dilutions of sirolimus. The number of colonies and the number of cells per colony were counted. As main result, the number of WPMY-1 surviving colonies increased in a dose-dependent manner when treated with sirolimus (p = 0.0011), while the number of U2OS colonies progressively decreased (p = 0.0011). The clonal capacity of HT-29 was not modified by the exposure to sirolimus (p = 0.6679). In conclusion sirolimus showed the well-known cytostatic effect, but with an effect on clonogenic potential different among the different cell types. In the practice, the plaque typology and composition may influence the response to sirolimus and thus the effectiveness of eluted stent.
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PMID:Sirolimus-eluting stents: opposite in vitro effects on the clonogenic cell potential on a long-term exposure. 3282 43


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