Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C1522084 (Osteosarcoma)
 2,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We previously reported that the recombinant adenovirus (Ad) vector containing the thymidine kinase (TK) gene driven by the osteocalcin (OC) promoter (Ad-OC-TK), when delivered concurrently with acyclovir (ACV), is highly selective in blocking the growth of osteosarcoma in experimental models (Cancer Res. 1996;56:4614-4619). To investigate the possible additive effects of the combined treatment of gene therapy and conventional chemotherapy (chemogene therapy), we compared the effect of low dose (IC10) methotrexate (MTX) and OC promoter-based toxic gene therapy with either of these single modalities alone. We choose low dose MTX with the intent of determining whether chemosensitization of the osteosarcoma may be possible in combination with gene therapy with an overall reduced toxicity profile and enhanced therapeutic efficacy when compared to a single agent alone. In vitro, the combined treatments of MTX (3 ng/mL) and Ad-OC-TK (20 multiplicity of infection (MOI)/target cell) plus ACV (10 mg/mL) had an additive therapeutic effect over that of either MTX (P < 0.05) or Ad-OC-TK plus ACV treatment alone (P < 0.05). In vivo, nude mice with subcutaneous tumors of either human osteosarcoma (MG-63) or rat osteosarcoma (ROS) received three intratumoral injections of Ad-OC-TK (5 x 10(8) PFU) plus daily intraperitoneal ACV (40 mg/kg body weight) for 2 weeks in combination with five weekly bolus intraperitoneal MTX (87.5 mg/kg). Osteosarcoma tumor growth was inhibited more efficiently than by either Ad-OC-TK plus ACV (P < 0.05) or MTX treatment (P < 0.005) alone. At day 45 in the ROS group, 100% of the animals survived when treated with chemogene therapy, whereas 80% survived with gene therapy and no animals survived in the MTX-treated or untreated controls. In summary, we developed a novel therapeutic strategy for the treatment of osteosarcoma employing both chemotherapy and gene therapy. Chemogene therapy could potentially achieve better antitumor effects with reduced toxicity than the conventional chemotherapy or gene therapy protocols alone.
Cancer Gene Ther
PMID:Chemogene therapy: osteocalcin promoter-based suicide gene therapy in combination with methotrexate in a murine osteosarcoma model. 940 6

Osteosarcoma is a common primary bone malignancy most often involving the long bones and occurring in the second decade of life. Orbital involvement in this disease process is rare and is usually due to extension of the tumor from an adjacent sinus cavity. Orbital osteosarcoma arising from preexisting Paget disease is exceedingly rare. We report the case of a 78-year-old female patient with Paget disease of the forehead who presented with rapidly increasing bilateral proptosis and visual loss for several months. Examination showed bilateral aphakia, decreased motility, proptosis with resistance to retropulsion, and tumorous infiltration of the eyelids and periorbital soft tissue. Fundus examination showed marked bilateral scleral indentation without overlying serous retinal detachment. A computed tomographic (CT) evaluation of the orbits demonstrated extensive soft tissue involvement of the paranasal sinuses, nasal cavity, periorbital soft tissue, and orbits, with compression of the optic nerve and globe bilaterally. Biopsy of the periorbital soft tissue demonstrated osteosarcoma. Radiation therapy failed to stem the progression of the disease process, and the patient died approximately 4 months later. Although osteosarcoma of the orbit associated with Paget disease is unusual, it should be considered in the differential diagnosis of older patients with a rapidly progressive orbital mass.
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PMID:Osteosarcoma of the orbit associated with Paget disease. 951 46

Oxidative stress has been frequently implicated in the initiation and promotion phases of carcinogenesis. Antioxidant enzymes, which can antagonize this process, are lowered in a number of malignancies even though different findings have been reported in the literature. It has been shown that tumors have less copper/zinc superoxide dismutase (Cu/Zn SOD) in comparison with the more metabolically active tissues, but there is a large overlap between normal and tumor tissue. In order to examine the relationship between osteosarcoma at different degrees of proliferation and differentiation and Cu/Zn SOD levels, four different human ostosarcoma cell lines: HOS, U-2 OS, MG63, Saos-2 were studied for their production and release of Cu/Zn SOD. A normal human stromal cell line was used as control. Osteosarcoma cells were stimulated with TNF alpha, a cytokine previously shown to have antiproliferative activity. The release of Cu/Zn SOD into the supernatant was higher for the HOS and U-2 OS lines when compared to the other cell lines evaluated both in basal condition and after incubation with TNF alpha. Elevated intracellular levels of Cu/Zn SOD were shown except for the HOS and U-2 OS which possess high concentrations of the enzyme at 24 hours declining during the other incubation periods. These concentrations were increased after TNF alpha treatment. The different behaviour of the four cell lines evaluated might be explained by their degree of differentiation.
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PMID:Copper/zinc superoxide dismutase expression by different human osteosarcoma cell lines. 961 84

Osteosarcoma is the most frequent second primary cancer occurring during the first 20 years following treatment for a solid cancer in childhood. Using a cohort study of children treated for a solid cancer, we investigated the incidence and etiology of osteosarcoma as a second malignant neoplasm after childhood cancer in a cohort and a case-control study. We analysed the relationship between the local dose of radiation and the risk of osteosarcoma, taking into account chemotherapy received. A cohort study of 4,400 3-year survivors of a first solid cancer during childhood diagnosed in France or the United Kingdom, between 1942 and 1986, revealed 32 subsequent osteosarcomas. In a nested case-control study, we matched 32 cases and 160 controls for sex, type of first cancer, age at first cancer and the duration of follow-up. Parameters studied were the incidence of osteosarcoma, the cumulative local dose of irradiation and the cumulative dose of chemotherapy received by cases and controls. The risk of a osteosarcoma was found to be a linear function of the local dose of radiation (excess relative risk per gray=1.8), and was found to increase with the number of moles of electrophilic agents per square meter but not with other drugs. No interaction was noted between radiotherapy and chemotherapy. Bilateral retinoblastoma, Ewing's sarcoma and soft tissue sarcoma were found to render patients susceptible to a higher risk of developing an osteosarcoma as a second malignant neoplasm. We recommend long-term surveillance of patients who were treated during childhood for bilateral retinoblastoma, Ewing's sarcoma, soft tissue sarcoma, as well as other first cancer treated with radiotherapy plus high doses of chemotherapy, without focusing exclusively on the radiation field.
Int J Cancer 1998 Jul 29
PMID:Radiation dose, chemotherapy and risk of osteosarcoma after solid tumours during childhood. 966 98

CD40, a membrane glycoprotein of the tumor necrosis factor receptor family, is expressed by several tumor types, including B-cell lymphomas, carcinomas, and melanoma, but little is known concerning its expression by sarcoma. We used flow cytometry to analyze the expression of CD40 in human cell lines derived from 12 osteosarcomas, 6 Ewing's sarcomas, and 5 rhabdomyosarcomas. Detectable CD40 levels ranging from low to very high were found in one-third of osteosarcomas, whereas five of six Ewing's sarcomas expressed intermediate levels of CD40; all rhabdomyosarcomas were CD40-negative. At the tissue level, two of eight primary high-grade osteosarcomas showed CD40-positive immunostaining. Osteosarcoma cells and Ewing's sarcoma cells expressing CD40 were treated with recombinant soluble CD40 ligand to analyze CD40 function. Treatment with soluble CD40 ligand increased the level of apoptotic cells and stimulated the transcription of matrix metalloproteinase 9 gene, enhancing matrix metalloproteinase 9 enzyme secretion. The results indicate that in human osteosarcoma and Ewing's sarcoma, CD40 is a functional receptor whose engagement can have opposite effects on tumor cell survival and malignancy.
Clin Cancer Res 1998 Aug
PMID:Expression of functional CD40 on human osteosarcoma and Ewing's sarcoma cells. 971 10

The definition of osteosarcoma requires that a malignant tumor of bone produce osteoid or bony matrix. With this as a basic definition, osteosarcoma of bone can be divided into several clinicopathologic entities based on clinical, roentgenographic, and pathologic features. The tumors can be broadly divided into those arising within the bone and those arising on the surface of bone. Most intraosseous osteosarcomas are high-grade malignant tumors that occur in children and adolescents. A small number occur in older patients, and they may be related to a preexisting condition, such as Paget's disease or radiation. The site of the lesion has prognostic importance. Osteosarcoma of the jaws is associated with an especially good prognosis, whereas the same kind of tumor involving the skull has a very poor prognosis. Most osteosarcomas of the surface of bone are well or moderately differentiated and are associated with an excellent prognosis.
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PMID:Osteosarcoma of bone. 973 64

Although in recent years the outcome of patients with osteosarcoma has considerably been improved by combining neoadjuvant chemotherapy with radical surgery, there still remains the problem of nonresponse to chemotherapy. T-lymphocytes play a critical role in tumor immunology, and MHC molecules are of central importance in the regulation of the immune response. It is the aim of this study to investigate whether T-lymphocyte infiltration of osteosarcomas and HLA-DR expression on tumor cells and infiltrating immune cells are of predictive or diagnostic value. Expression of CD3, CD8 and HLA-II was evaluated immunohistochemically on paraffin-embedded sections of 35 patients with high-grade osteosarcoma at the time of biopsy before chemotherapy and correlated with histologic response to chemotherapy, tumor size, age, alkaline-phosphatase serum levels and duration of symptoms. Thirty-four patients with osteoblastoma (n = 7), osteoid osteoma (n = 7) or fibrous dysplasia (n = 20) served as controls. Osteosarcomas were infiltrated by CD3+ (33/35, 95%) and CD8+ T-lymphocytes (24/35, 68%), non malignant bone tumors by CD3+ in 91% (31/34) and CD8+ T-lymphocytes in 74% (25/34), respectively. T-lymphocytes were positive for HLA-DR expression in 29% (10/35) in osteosarcomas and in 11% (4/34) in non-malignant controls. Osteosarcoma cells were positive for HLA-DR in 11/35 (31%) and non-malignant tumor cells in only 9% (3/34). Therefore, HLA-DR is overexpressed in osteosarcoma (p < 0.05). HLA-DR expression on osteosarcoma cells showed a positive correlation with HLA-DR expression on lymphocytes (p < 0.001) as well as with duration of symptoms and age (p < 0.05). Response to preoperative chemotherapy, gender, tumor size and serum alkaline-phosphatase levels did not correlate with the expression of the molecules tested. Our results show that HLA-DR is overexpressed in osteosarcoma cells compared to non-malignant bone-tumors. This overexpression, however, fails to serve as a predictive marker for response to neoadjuvant chemotherapy. The same is also true for tumor-infiltrating lymphocytes expressing CD3, CD8 and HLA-DR. Increased HLA-DR expression in osteosarcoma is most likely due to the immune response against the tumor.
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PMID:Evaluation of HLA-DR expression and T-lymphocyte infiltration in osteosarcoma. 982 Aug 63

Bone tumours are comparatively uncommon, constituting only 0.5% of the total world cancer incidence. As Bone tumors consist of several distinct clinico-pathological entities, descriptive epidemiology of tumors at this site can be based only on studies where they can be distinguished. Ewing's sarcoma Chondrosarcoma and Osteosarcoma are the principal tumors involving bones. The basic data utilized for this study was collected from the Bombay Cancer Registry which was established in 1963, and is the first population based registry to be established in India. For studying the descriptive epidemiological variables the most recent 5 year incidence rates have been used. As a group, bone cancers represent 0.9% of the total number of incident cancer are seen in Greater Bombay. Males in general are seen to have a higher incidence of bone cancers than females. Ewing's sarcoma was found to be the commonest bone cancer in Bombay. The age specific incidence curves present striking differences according to cell types of bone cancer. Time trends in the incidence of these cancers, over the past 30 years have been presented. Our data indicate that there is a decreasing trend in incidence of bone cancers in females, whilst the rates are stable in males. Ionising radiation is the only environmental agent to cause this cancer. The discovery of other risk factors is the key prevention and will depend upon the experimental work undertaken to develop sub-clinical measures of risk that can be applied in interdisciplinary studies to identify more completely the causes of bone cancers.
Indian J Cancer 1998 Sep
PMID:Descriptive epidemiology of bone cancer in greater Bombay. 1022 99

Osteosarcoma is the commonest malignant tumour of the bones. The presence of micrometastases at the time of primary diagnosis is associated with poor prognosis. Despite developments in surgery and aggressive chemotherapy, about 50% of the patients still succumb to the disease. Thus, there is a need to develop alternative treatment modalities. One such strategy is to use antibodies with improved effector functions. The two monoclonal antibodies, TP-1 and TP-3, recognize a tumour-associated antigen on human osteosarcoma cells. In the present study, we describe the cloning of the TP-1 variable genes, and the production of complete chimeric mouse/human monoclonal antibodies. Constructs containing the constant genes from human IgG1, IgG3 or a mutant IgG3 with a shortened hinge region, called m15, were expressed in the mouse myeloma cell line, NS0. The m15 mutant has been shown to be very potent in triggering complement-mediated lysis. Our goal was to investigate whether this mutant could overcome the complement protection on human osteosarcoma cells, which is generally present on all human cells. We found that the target cells expressed several membrane-bound complement inhibitors, and that masking of these inhibitors rendered the cells sensitive to lysis. The m15 mutant exhibited greater lytic activity than both IgG3 and IgG1, although it could not cause extensive killing of the target cells alone.
Cancer Immunol Immunother 1999 Oct
PMID:Complement-mediated lysis of cultured osteosarcoma cell lines using chimeric mouse/human TP-1 IgG1 and IgG3 antibodies. 1050 55

Vascular endothelial growth factor (VEGF) is a major angiogenic factor. Osteosarcoma is characterised by hypervascularity and metastatic potential. We examined VEGF mRNA expression, VEGF isoform pattern and VEGF receptor (flt-1 and KDR) by RT-PCR analysis in 30 osteosarcomas. All 30 osteosarcomas expressed VEGF mRNA. 17 osteosarcomas (57%) expressed flt-1 mRNA, whilst 20 (67%) expressed KDR mRNA. 6/30 (20%) osteosarcomas were positive for VEGF121 only, 8 (27%) for VEGF121 + VEGF165, and 16 (53%) for VEGF121 + VEGF165 + VEGF189. Patients with osteosarcomas with VEGF165 (n = 24) had significantly poorer prognosis in comparison with those without VEGF165 (P = 0.022, Wilcoxon's test). The osteosarcomas with VEGF165 had significantly increased vascularity assessed on sections immunostained for CD34 (P < 0.001, Mann-Whitney U test). Although VEGF165 is a soluble isoform, it is also retained on the cellular surface. These results suggest that cell-retained VEGF isoforms (VEGF165, VEGF189) might be essential for neovascularisation in osteosarcoma, whilst the soluble VEGF121 isoform is not sufficient to stimulate neovascularisation in this type of neoplasm.
Eur J Cancer 1999 Jul
PMID:Cell-retained isoforms of vascular endothelial growth factor (VEGF) are correlated with poor prognosis in osteosarcoma. 1053 53


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