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PubMed1995

Mutational activation of ras genes is absent in pediatric osteosarcoma.

Activation of ras oncogenes is found in human cancers; overall it is observed in 15% of all neoplasms. The purpose of this study was to assess the extent of involvement of ras oncogenes in osteosarcoma. Tumor samples from a series of 49 pediatric patients diagnosed with osteosarcoma and treated at our institution were evaluated. Paraffin-embedded tumor samples from diagnostic biopsies, from tumor en bloc resection tissue after neoadjuvant chemotherapy, and samples from metastases were examined in search of point mutations in H, K, and N-ras genes at codons 12 and 61 by means of polymerase chain reaction (PCR), slot-blotting, and radioactive labeled specific DNA probes. A total of 92 archival samples were studied. No point mutations activating these genes were found. These findings suggest that the activation by point mutations at codons 12 and 61 of the H, K, and N-ras genes does not play a role in the pathogenesis of human osteosarcoma. Since no point mutations in codons 12 and 61 were detected, it was not possible to establish any correlation between the ras genes and clinical or histologic findings.

Base Sequence↗
PubMed1986

Adriamycin-methotrexate high dose versus adriamycin-methotrexate moderate dose as adjuvant chemotherapy for osteosarcoma of the extremities: a randomized study.

Adjuvant chemotherapy comprising Adriamycin (ADM) and Methotrexate (MTX) with Citrovorum Factor (CF) was administered on a randomization basis to 2 groups of patients with osteosarcoma after surgical ablation of the primary tumor. One group received high dose MTX (regimen I) and the other moderate dose MTX (regimen II). In both groups a short period of heparin treatment was also administered to prevent neoplastic emboli during surgery. All patients were free of metastasis at the beginning of therapy. The efficacy of therapy was determined by recording the percentage of continuously disease-free patients. This was compared to the disease-free survival in 132 patients previously treated with other ADM or ADM-MTX regimens and to a group of 39 patients treated during this period with amputation only. The latter did not receive adjuvant chemotherapy for a variety of reasons and are equated to a concurrent control group. Over the ensuing 27-66 months, 31 of 56 patients (55%) treated with regimen I and 25 of 50 (50%) treated with regimen II were disease-free. The overall disease-free survival in both regimens was 53%. This is similar to the 132 patients treated with previous adjuvant chemotherapy protocols (45-50%). However, the percentage of continuously disease-free patients treated with adjuvant chemotherapy was significantly better than the 39 patients (12%) treated contemporaneously with surgery only (P less than 0.0005). Survival in the latter is similar to that of historical control patients. These results do not suggest any change in the natural history of osteosarcoma and reveal benefits which may accrue with adjuvant chemotherapy. These results also demonstrate that in adjuvant treatment of osteosarcoma performed with ADM and MTX the high and the moderate doses of MTX are equally efficacious.

Adult↗
PubMed1986

Osteosarcoma of the mandible: analysis of nine cases.

A total of 16 cases of mandibular osteosarcoma were diagnosed histologically in Finland and reported to the Finnish Cancer Registry between 1953 and 1983. Review of the histologic slides confirmed the diagnosis in only nine cases. The overall five-year survival rate was 44%. Three patients who were free of clinical disease at the end of the follow-up period (mean, 9.9 years) either had tumors of low-grade malignancy (two cases) or had undergone prompt radical surgery (one case). The importance of radiography in the diagnosis of mandibular osteosarcoma is stressed, because the widening of the periodontal membrane spaces, the sunray effect, and the widening of the mandibular canal are almost pathognomonic for osteosarcoma.

Adult↗
PubMed1990

Periosteal osteosarcoma of the maxilla: a case report and review of literature.

Juxtacortical osteosarcomas, including periosteal and parosteal subtypes, are uncommon neoplasms of the jaws. In long bones, the biologic behavior of the periosteal variant is reported to be more aggressive than the parosteal tumor. Juxtacortical osteosarcoma of the jaws appears to have a slightly more favorable prognosis than in long bones, although a larger series of cases needs to be evaluated before a definitive conclusion concerning the behavior of juxtacortical osteosarcoma of the jaws can be made.

Aged↗
PubMed1994

31P changes as a measure of therapy response in human osteosarcomas implanted into nude mice.

Our objective was to determine whether changes in PME and PCr/Pi can be used to predict lack of tumor response to chemotherapy in a murine model of human osteosarcoma. A chemotherapy-sensitive human osteosarcoma cell line was implanted into the flank of 22 nude mice. Cisplatin was administered to 11 of the mice 9 days postimplantation. 31P MR spectroscopy was performed pre- and post-chemotherapy in both sets of mice. Statistically significant changes in PCr/Pi occur from post-chemotherapy in the treated mice, but not in the untreated mice during the same time. Change in PME parallels changes in tumor volume. Changes in PCr/Pi predict lack of chemotherapy treatment in human osteosarcoma implanted into nude mice with a specificity of 80% and a sensitivity of 63%. The change in PCr/Pi occurs prior to any changes in volume of the tumor [corrected].

Animals↗
PubMed1995

Experimental induction of osteosarcoma by subperiosteal radioactive phosphorus injections in rats.

In search of a predictable experimental model for the study of therapeutic modalities for osteosarcoma, a group of rats had injections of phosphorus-32 (P-32) colloid subperiostally and were followed for the occurrence of malignant bone tumors until death or for 18 months. Of 50 rats, 26 died of unrelated causes and only 24 were included in the study. Two cases of osteosarcomas, one occurring in month 16 and the other at month 18 were induced; one case demonstrated multiple lung metastases. Clear evidence of the sarcoma inducing effect of P-32 has been obtained in this study. However, a high yield experimental osteosarcoma model was not produced.

Animals↗
PubMed1987

In vitro transformation of osteoblasts: putative formation of osteosarcoma in vitro.

The study of bone cancer has been difficult in part due to a lack of appropriate in vitro osteosarcoma model systems. The development of such systems is essential if a clearer understanding of the biology of and mechanisms behind the formation and progression of bone cancers is to be obtained. We report here the development of an in vitro model system which demonstrates important characteristics generally associated with osteosarcoma. The chick periosteal osteogenesis model was infected with the Fujinami Sarcoma Virus (FSV) containing the v-fps oncogene which encodes for a P140gag-fps protein-tyrosine kinase. Under the appropriate conditions FSV infected cultures developed bone and cartilaginous tissues which showed histopathological findings consistent with osteosarcoma. Biochemical data indicating massive increases in alkaline phosphatase activity, protein content, 3H-Thymidine incorporation as well as expression of active P140gag-fps confirm that transformation has occurred in FSV infected cultures. This novel in vitro model system should prove most useful in the study of bone cancer.

Animals↗
PubMed1990

Divergent in vitro effects of recombinant interferons on human osteosarcoma cells.

We investigated the in vitro effects of human recombinant interferon alpha (rIFN alpha) and interferon gamma (rIFN gamma) on the proliferation and MCH class II antigen expression of two human osteosarcoma cell lines SAOS-2 and U2-OS. Addition of low concentrations of either rIFN alpha (10 U/mL) or rIFN gamma (100 U/mL) to the cultures almost completely inhibited the 3H-thymidine incorporation in SAOS-2 cells while even high amounts (10,000 U/mL) of rIFN alpha or rIFN gamma did not affect the growth rate of U2-OS cells. This difference was not caused by lack of IFN receptors in U2-OS cells since both cell lines responded to rIFN gamma treatment with rapid accumulation of HLA class II mRNA and de novo surface expression of HLA-DR, -DP and -DQ antigens. The induced HLA class II antigens were functionally intact. Osteosarcoma cells treated with rIFN gamma stimulated a mixed lymphocyte culture (MLC) response in allogeneic T-lymphocytes while untreated osteosarcoma cells were unable to provoke T-lymphocyte proliferation. These findings indicate that IFNs display divergent effects on two phenotypically closely related tumor cell lines. This should be appreciated also when therapeutic effects of IFNs are evaluated.

Antibodies, Monoclonal↗
PubMed1991

Inducibility of neoplastic transformation by Fujinami sarcoma virus in an in vitro chick embryo model for osteosarcoma: (i) effect of differentiation and (ii) investigation for in vivo growth potential in athymic mice.

We have described previously a novel in vitro model for the study of osteosarcoma. In this system, chick periosteal explants (CEP) transformed by the P140gag-fps oncoprotein of Fujinami avian sarcoma virus (FSV) exhibit biochemical and histological manifestations characteristic of osteosarcoma. In the present study, a hypothesis suggesting that more differentiated bone cells may resist FSV-induced oncogene changes was tested. In one set of experiments, CEP cultures were pretreated with a high dose of dexamethasone (10(-7) M), a bone cell differentiating agent, prior to FSV infection. In another experiment, CEP explants were allowed to grow and thus differentiate for various lengths of time in culture prior to infection with FSV. Another goal of this study was to show that FSV-transformed cultures were tumorigenic in nude mice. In experiments focusing on differentiation and FSV-transformation, it was found that groups that had been infected at stages where osteogenic differentiation had been induced or allowed to occur, exhibited significantly decreased values for biochemical parameters associated with osteosarcomatous transformation. Specifically, these parameters were alkaline and acid phosphatase activity, protein content, [3H]thymidine incorporation, mineral profile, and acidification of culture media. Furthermore, osteosarcomatous histopathological features were more prominent in cultures subjected to FSV infection prior to differentiation. These findings indicate that differentiated osteogenic cells are less susceptible to oncogene-mediated transformation than their progenitors. The tumorigenic potential of some CEP cultures transformed in vitro with FSV was examined by transplantation into athymic mice. FSV-transformed CEP cultures xenografted subcutaneously exhibited tumor formation, whereas xenografts of uninfected cultures did not grow or were completely resorbed. This demonstrates that FSV-transformed cultures are tumorigenic, and confirms that this model system is useful for the investigation of the mechanisms governing the development of osteosarcoma in vitro.

Animals↗
PubMedDate not supplied

Are MG-63 and HOS TE85 human osteosarcoma cell lines representative models of the osteoblastic phenotype?

The aim of this study was to perform a systematic comparison of two widely used osteosarcoma cell lines and ascertain their relevance as experimental models for investigating osteoblast function. We have therefore compared growth, differentiated cell function, integrin expression and adhesive profiles of MG-63, HOS TE85, and human bone derived cells. Both osteosarcoma cell lines proliferated more rapidly than osteoblast-like cells with HOS cells exhibiting the shortest doubling time. HOS cells expressed higher levels of alkaline phosphatase than MG-63 cells under basal conditions but only MG-63 cells showed the increased enzyme activity following 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) administration, which is characteristic of bone derived cells. Osteocalcin was not detected in supernatants from any cells under basal conditions but levels produced by MG-63 cells on addition of 1,25(OH)2D3 were comparable with those of osteoblast-like cells. alpha 1, alpha 2, alpha 3, alpha 5, alpha V, and beta 1 integrin subunits were detected on all cells and there was no staining for alpha L, alpha M, beta 2, and beta 3. alpha 3 and beta 1 were the major subunits detected on MG-63, HOS, and bone derived cells but relative concentrations of other alpha subunits were dependent on cell type; alpha 4 and alpha 6 subunits could only be detected on osteosarcoma cell lines. Short term, serum-free cell adhesion assays showed that the three cell types adhered in a saturable manner to collagen I, fibronectin, and laminin.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMedDate not supplied

Surface osteosarcoma: 2 case reports.

Surface osteosarcoma of the jaw bone is extremely rare, and it differs from the central type in its clinicopathologic features. This type of osteosarcoma generally shows low-grade malignancy, grows slowly, metastasizes less often, and the prognosis is better than that of the central type. We report 2 cases of surface osteosarcoma of the jaw bone, and discuss some clinical important issues.

Adolescent↗
PubMed2004

Functional analysis of altered reduced folate carrier sequence changes identified in osteosarcomas.

Osteosarcomas are common primary malignant bone tumors that do not respond to conventional low-dose treatments of methotrexate (Mtx), suggesting an intrinsic resistance to this drug. Previous work has shown that cDNAs generated from osteosarcoma mRNA from a fraction of patients contain sequence changes in the reduced folate carrier (RFC), the membrane protein transporter for Mtx. In this study, the functionality of the altered RFC proteins was assessed by fusing the green fluorescent protein (GFP) to the C-terminal, and examining the ability of the transfected constructs to complement a hamster cell line null for the carrier. Confocal microscopy and cell surface biotinylation indicated that all altered proteins were properly localized at the cell membrane. Only one of those examined, Leu291Pro, was unable to complement the null carrier line, but did bind Mtx at the cell surface. Thus, this alteration confers drug resistance since the carrier is unable to translocate the substrate across the cell membrane. Three alterations, Ser46Asn, Ser4Pro and Gly259Trp, while able to complement the carrier null line, conferred some degree of resistance to Mtx via a decreased rate of transport (Vmax). Another set of alterations, Glu21Lys, Ala7Val, and the combined changes Thr222Ile, Met254Thr, complemented the carrier null line and did not confer resistance to Mtx. Thus, some, but not all of these identified alterations in the RFC may contribute to the lack of responsiveness of osteosarcomas to Mtx treatment.

Amino Acid Sequence↗
PubMed2005

Vitamin D fails to prevent serum starvation- or staurosporine-induced apoptosis in human and rat osteosarcoma-derived cell lines.

Previous studies have suggested that 1,25(OH)2D3, the active form of vitamin D3, may increase the survival of bone-forming osteoblasts through an inhibition of apoptosis. On the other hand, vitamin D3 has also been shown to trigger apoptosis in human cancer cells, including osteosarcoma-derived cell lines. In the present study, we show that 1,25(OH)2D3 induces a time- and dose-dependent loss of cell viability in the rat osteosarcoma cell line, UMR-106, and the human osteosarcoma cell line, TE-85. We were unable, however, to detect nuclear condensation, phosphatidylserine externalization, or other typical signs of apoptosis in this model. Moreover, 1,25(OH)2D3 failed to protect against apoptosis induced by serum starvation or incubation with the protein kinase inhibitor, staurosporine. These in vitro findings are thus at variance with several previous reports in the literature and suggest that induction of or protection against apoptosis of bone-derived cells may not be a primary function of vitamin D3.

Animals↗
PubMed2005

Enhanced tumor regression and tissue repair when zoledronic acid is combined with ifosfamide in rat osteosarcoma.

The efficacy of zoledronic acid (ZOL), with or without the anticancer drug ifosfamide (IFO), was tested on primary bone tumor growth using a rat-transplantable model of osteosarcoma. The effects on bone remodeling and tumor growth were analyzed by radiography, micro-computed tomography (micro-CT), and histological staining. The in vitro effects of ZOL were studied by proliferation, apoptosis, and cell cycle analyses on the osteosarcoma cells OSRGA compared to rat primary osteoblasts. Treatment with ZOL was effective in preventing the formation of osteolytic lesions that developed in bone sites and in reducing the local tumor growth, as compared to the untreated rats. The combination of ZOL and IFO was more effective than each agent alone in preventing tumor recurrence, improving tissue repair, and increasing bone formation as revealed by the analysis of trabecular architecture. In vitro studies demonstrated that ZOL was more potent against the OSRGA cell line than osteoblasts (with a half-maximal inhibitory effect on proliferation seen at 0.2 and 20 microM, respectively), the ZOL-induced inhibition of OSRGA proliferation being due to cell cycle arrest in S-phase. No effect on OSRGA apoptosis could be observed in vitro, as assessed by Hoechst staining and caspase-1 and -3 activation. In situ cell death was determined by TUNEL staining on tumor tissue sections. No significant difference in TUNEL-positive cells could be observed between ZOL-treated and -untreated rats. This is the first report of the anti-bone resorption and antitumoral activities of zoledronic acid in a rat model of osteosarcoma, and its beneficial association with an antitumoral chemotherapeutic drug in preventing tumor recurrence.

Animals↗
PubMed2006

Evolving gene therapy approaches for osteosarcoma using viral vectors: review.

This review begins with an introduction to the malignant bone tumor, osteosarcoma [OS] and then moves to a discussion of the commonly used vectors for gene transfer. We first briefly highlight non-viral vectors including polymeric and liposomal delivery systems but concentrate predominantly on the 5 leading viral vectors used in cancer gene therapy, specifically retroviruses, adeno-associated viruses, herpes viruses and lentiviruses with the most detailed analysis reserved for adenoviruses. The 3 main strategies for gene therapy in osteosarcoma are next summarized. As part of this review, the several prodrug-converting enzymes utilized in OS suicide gene therapy are examined. The text then turns to a discussion of adenovirus-mediated gene transfer and the need for tumor targeting via transductional or transcriptional approaches. Because of practical problems with use of replication-incompetent viruses in achieving complete tumor kill in vivo, virotherapy utilizing replication competent viruses has come to the fore. This topic is, thus, next reviewed which allows for a natural transition to a discussion of armed therapeutic viruses many of which are conditionally replicating adenoviruses carrying transgenes with established anti-tumor efficacy. We recognize that several other issues have arisen which hamper progress in the field of cancer gene therapy. We, therefore, review viral-induced toxicity in the host and vector delivery issues which have been found to potentially influence safety. We end with a brief perspective including commenting on animal models used in examining delivery strategies for osteosarcoma gene therapy. The challenges remaining are touched upon most especially the need to deal with pulmonary metastatic disease from OS.

Bone Neoplasms↗
PubMed2004

Amplification and overexpression of genes in 17p11.2 ~ p12 in osteosarcoma.

We summarize and briefly discuss recent findings with respect to the amplification and overexpression of candidate oncogenes in 17p11.2 ~p12 in high-grade osteosarcomas. Amplification of this region occurs in about 25% of cases. The amplification profiles are often complex and suggest the involvement of more than one oncogene. The 17p11.2 ~ p12 region harbors many low-copy repeats (LCRs). We propose LCR-mediated repeated duplication by mitotic nonallelic homologous recombination as mechanism for the generation of the amplifications in this region. Genes PMP22 and COPS3 and three expressed sequence tags from within 17p11.2 ~ p12 have been found to be frequently overexpressed and consistently overexpressed after amplification, which identifies them as candidate oncogenes in this region. Overexpression of COPS3 has been linked to TP53 protein degradation and, being equivalent to TP53 mutation, the induction of genomic instability, which frequently occurs in high-grade osteosarcoma. These findings may serve as a framework for future work aimed to identify the causative oncogenes in 17p11.2 ~p12, to clarify the mechanism of their amplification, and to determine their importance in osteosarcoma tumorigenesis.

Bone Neoplasms↗
PubMed2005

Allelic loss at 10q26 in osteosarcoma in the region of the BUB3 and FGFR2 genes.

Loss of heterozygosity at 10q26 was mapped using microsatellite markers in 20 osteosarcomas. A four-megabase region centered on marker D10S587 was affected by allelic loss in 60 percent of osteosarcomas. The most frequently lost marker was D10S1723. Around 15 known genes are found in this region. The gene immediately adjacent to D10S1723 encodes BUB3, an element of the spindle assembly mitotic checkpoint. Loss of BUB3 function could contribute to chromosomal instability. The fibroblast growth factor receptor 2 (FGFR2) gene is located 2 Mb from the BUB3 gene and has the potential for a role in cancer. Inherited mutations of the FGFR2 gene result in skeletal dysplasias. FGFR2 alterations have also been implicated in gastric cancer. Human genome project data were used to design primers for amplifying FGFR2 in 18 genomic segments and BUB3 in 7 genomic segments. In each case, the segments encompassed coding exons and flanking intron sequences. The primers were used to search for mutations by polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP). Several shifted bands were detected in the BUB3 exon 3 fragment. Sequencing resolved the BUB3 exon 3 fragment shifts into polymorphisms in intron 2. No mutations of BUB3 or FGFR2 were detected. It remains possible that BUB3 or FGFR2 hemizygosity alone contributes to osteosarcoma, or that one of the genes is cryptically inactivated by a higher-order modification or mutation outside the coding region. There may also be a yet undiscovered tumor suppressor gene in this region.

Alleles↗
PubMed2006

Growth inhibition and sensitization to cisplatin by zoledronic acid in osteosarcoma cells.

Since osteosarcoma is a drug-resistant disease, the aim of the present study was to explore the possible interest of therapeutic approaches including nitrogen-containing biphosphonate zoledronic acid using osteosarcoma cell lines with different genetic backgrounds. Parental p53+/pRb+ U2-OS, p53-mutant U2-OS (U2-OS/175) and p53-/pRb- SAOS were sensitive to zoledronic acid with no significant differences in IC50 values. Analysis of cell cycle distribution revealed a time-dependent shifting of U2-OS cells towards G2 phase with cell cycle arrest in G2 phase at 96 h of exposure to the compound. Conversely, U2-OS/175 and SAOS cells responded to treatment with transient cell accumulation in S phase up to 48-72 h, respectively. Cell lines were exposed to increasing concentrations of cisplatin alone or combined with sub-toxic doses of zoledronic acid. A growth inhibitory effect was seen after combined treatment in U2-OS, otherwise resistant to cisplatin up to 100 ng/ml. Zoledronic acid did not efficiently sensitized U2-OS/175 and SAOS to cisplatin, thereby suggesting that different behavior may depend on p53 mutation. This data was confirmed in U2-OS cells where p53 expression was downregulated by RNA interference. Present findings indicate occurrence of sensitization to cisplatin by zoledronic acid in wild-type p53 osteosarcoma cells but not in p53-null cells nor in cells expressing a dominant-negative form of p53, supporting that wild-type p53 is required for synergistic interaction of cisplatin and zoledronic acid.

Antineoplastic Agents↗