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PubMed2026

Flavones in osteosarcoma: Molecular mechanisms, antitumor activity, and translational challenges.

Osteosarcoma remains the most common primary malignant bone tumor, and survival has improved little over recent decades because of metastasis and therapeutic resistance. Flavones exhibit diverse anti-osteosarcoma activities by suppressing proliferation, inducing apoptosis, ferroptosis and autophagy, inhibiting metastasis, and modulating oncogenic signaling pathways, including PI3K-Akt, Wnt-β-catenin, STAT3, MAPK, and NF-κB. This review summarizes the cell-line-specific molecular mechanisms of representative flavones, critically evaluates current experimental limitations, and discusses strategies to improve clinical translation through nanotechnology-based delivery and combination therapy. Although clinical evidence remains lacking, flavones represent promising adjunctive candidates for overcoming chemoresistance and improving osteosarcoma treatment.

apoptosis and metastasis↗
PubMed2005

Grade of chemotherapy-induced necrosis as a predictor of local and systemic control in 881 patients with non-metastatic osteosarcoma of the extremities treated with neoadjuvant chemotherapy in a single institution.

To determine whether necrosis induced by pre-operative chemotherapy correlates with the rate of systemic and local relapse, may change the pattern of relapse and/or may modify the chance of success of post-relapse treatments, we evaluated 881 patients with non-metastatic osteosarcoma of the extremities treated with five different protocols of neoadjuvant chemotherapy and surgery at the same institution between 1983 and 1999. The 5-year disease-free survival (DFS) and overall survival (OS) correlated significantly with the histological response to chemotherapy. Five-year DFS and OS in good and poor responders were 67.9% versus 51.3% (P < 0.0001) and 78.4% versus 63.7% (P < 0.0001), respectively. The prognostic value of the histological response was valid only for osteoblastic and telangiectatic osteosarcoma subtypes. Nonetheless, since they represent more than 70% of all osteosarcomas, we conclude that chemotherapy-induced necrosis has a significant prognostic value, regardless of the type of chemotherapy performed after surgery.

Adolescent↗
PubMed2005

4-Demethoxy-3'-deamino-3'-aziridinyl-4'-methylsulphonyl-daunorubicin (PNU-159548): a promising new candidate for chemotherapeutic treatment of osteosarcoma patients.

The effectiveness of the alkycycline 4-demethoxy-3'-deamino-3'-aziridinyl-4'-methylsulphonyl-daunorubicin (PNU-159548, ladirubicin), a new drug with high antitumour activity against a broad range of neoplasms, was evaluated by using a panel of 32 human osteosarcoma cell lines, including cell lines resistant to doxorubicin, methotrexate, or cisplatin. PNU-159548 resulted to be highly active in all cell lines. No cross-resistance was found with conventional drugs, being PNU-159548 active also in cells resistant to doxorubicin and with a multidrug resistance phenotype (associated with MDR1 gene/P-glycoprotein overexpression), as well as in cells resistant to methotrexate or to cisplatin. Analysis of drug-drug interactions showed that PNU-159548 could be successfully used in combination with all the most important drugs currently used in OS chemotherapy. In fact, the simultaneous administration of PNU-159548 and doxorubicin, methotrexate, or cisplatin produced mostly additive or synergistic effects. Sequential exposure to PNU-159548 followed immediately by doxorubicin, methotrexate, or cisplatin was the most effective sequence of administration, invariably resulting in additive or synergistic effects in both drug-sensitive and drug-resistant osteosarcoma cell lines. In conclusion, the high in vitro effectiveness, the absence of cross-resistance with doxorubicin, methotrexate, or cisplatin and the possibility to be successfully used in combination with these drugs indicate PNU-159548 as a promising candidate to be considered for planning new therapeutic regimens for osteosarcoma patients, who show a decreased response to conventional chemotherapy.

Antibiotics, Antineoplastic↗
PubMed2003

Osteosarcoma in a patient with McCune-Albright syndrome and Mazabraud's syndrome: a case report emphasizing the cytological and cytogenetic findings.

Osteosarcomatous transformation in fibrous dysplasia is unusual. The incidence is increased in patients with concomitant Mazabraud's syndrome and McCune-Albright syndrome. We report the cytological, histological, and cytogenetic findings of this rare entity arising from a mass in the right elbow of a 44-year-old African-American woman. The fine-needle aspiration (FNA) findings were diagnostic of malignancy, with markedly atypical spindle and polygonal cells admixed with osteoid. The diagnosis of osteosarcoma by FNA was subsequently further confirmed by histological evaluation of an above-elbow amputation specimen. Fluorescence in situ hybridization and comparative genomic hybridization demonstrated trisomies of chromosomes 5 and 7 in the fibrous dysplasia and osteosarcoma. In addition, multiple chromosomal abnormalities were also noted in the osteosarcoma. We are unaware of any previous reports of the cytogenetic findings in the tissue of this rare condition, and argue for the value of FNA in the evaluation of such patients under selected conditions.

Adult↗
PubMed2005

Radiotherapy for local control of osteosarcoma.

PURPOSE: Local control of osteosarcoma in patients for whom a resection with satisfactory margins is not achieved can be difficult. This study evaluated the efficacy of radiotherapy (RT) in this setting. METHODS AND MATERIALS: We identified 41 patients in our sarcoma database with osteosarcomas that either were not resected or were excised with close or positive margins and who underwent RT with external beam photons and/or protons at our institution between 1980 and 2002. Patient charts were reviewed to assess local control, progression-free survival, metastasis-free survival, and overall survival. RESULTS: The anatomic sites treated were head/face/skull in 17, extremity in 8, spine in 8, pelvis in 7, and trunk in 1. Of the 41 patients, 27 (65.85%) had undergone gross total tumor resection, 9 (21.95%) subtotal resection, and 5 (12.2%) biopsy only. The radiation dose ranged from 10 to 80 Gy (median 66). Twenty-three patients (56.1%) received a portion of their RT with protons. Chemotherapy was given to 35 patients (85.4%). Of the 41 patients, 27 (65.85%) were treated for localized disease at primary presentation, 10 (24.4%) for local recurrence, and 4 (9.8%) for metastatic disease. The overall local control rate at 5 years was 68% +/- 8.3%. The local control rate according to the extent of resection was 78.4% +/- 8.6% for gross total resection 77.8% +/- 13.9% for subtotal resection, and 40% +/- 21.9% for biopsy only (p < 0.01). The overall survival rate according to the extent of resection was 74.45% +/- 9.1% for gross total resection, 74.1% +/- 16.1% for subtotal resection, and 25% +/- 21.65% for biopsy only (p < 0.001). Patients with either gross or subtotal resection had a greater rate of local control, survival, and disease-free survival compared with those who underwent biopsy only at 5 years (77.7% +/- 7.5% vs. 40% +/- 21% [p <0.001], 73.9% +/- 8.1% vs. 25% +/- 21.6% [p <0.001], and 51.9% +/- 9.1% vs. 25% +/- 21.6% [p <0.01], respectively). Overall survival was better in patients treated at primary presentation (78.8% +/- 8.6% compared with 54% +/- 17.3% for recurrence) p <0.05). No definitive dose-response relationship for local control of tumor was seen, although the local control rate was 71% +/- 9% for 32 patients receiving doses > or =55 Gy vs. 53.6% +/- 20.1% for 9 patients receiving <55 Gy (p = 0.11). Of 15 patients with tumors >5.3 cm, 9 received doses > or =55 Gy and the local control rate was 80% +/- 17.9%, and 6 received doses <55 Gy with a local control rate of only 50% +/- 25% at 5 years (p = 0.16). Among patients who underwent gross total resection, the local control rate was 77.5% +/- 9.95% in 22 patients with negative margins vs 66.7% +/- 27.2% in 3 patients with positive margins (p = 0.54). Two patients had unknown margin status. CONCLUSION: RT can help provide local control of osteosarcoma for patients in whom surgical resection with widely, negative margins is not possible. It appears to be more effective in situations in which microscopic or minimal residual disease is being treated.

Adolescent↗
PubMed2006

Computed tomographic scan of the chest underestimates the number of metastatic lesions in osteosarcoma.

PURPOSE: Survival in osteosarcoma correlates with complete resection of primary and metastatic disease. The feasibility of complete pulmonary metastasectomy using thoracoscopy has been raised. Because palpation is not possible, minimally invasive techniques require preoperative radiological enumeration and localization of metastases not presenting at the lung surface. We hypothesized that computed tomographic (CT) scanning underestimated the number of pulmonary metastases in these patients. METHODS: Institutional review board approval was obtained. We determined the association between the number of lesions identified by CT scanning and the number of metastases found at thoracotomies for metastatic osteosarcoma from May 1996 to October 2004. Correlations between CT findings and pathology results were computed using the Kendall tau-b correlation coefficient. Depth, in millimeters, from the pleural surface was measured for those lesions seen on CT scan. RESULTS: We analyzed 54 consecutive thoracotomies performed in 28 patients for whom complete imaging was available. Computed tomographic scanning was performed a median of 20 days before thoracotomy (range, 1-85 days). Correlation between the number of lesions identified by CT and the number of metastases resected at surgery was poor, with a Kendall tau-b correlation coefficient of 0.45 (P < .001). In 19 (35%) of 54 thoracotomies, CT scanning underestimated the number of pathologically proven, viable and nonviable metastases found by the surgeon. Accounting for viable metastases only, correlation between the number of lesions identified by CT and the number of metastases resected at surgery was 0.50 (P < .001), and CT scanning underestimated the number of viable metastases present in 14 (26%) of 54 thoracotomies. Many lesions (32%) were pleural-based, but nearly half (47%) were 5 mm or deeper from the pleural surface of the lung. CONCLUSIONS: Even in the era of modern CT scanning, only a very rough correlation exists between CT findings and the number of lesions identified at thoracotomy. In more than one third of thoracotomies in our series, metastases would have been missed by any tactic besides manual palpation of the lung during open thoracotomy. Minimal access procedures should not be the approach of choice if the goal is resection of all pulmonary metastases in osteosarcoma.

Adolescent↗
PubMed2005

Pigment epithelium-derived factor (PEDF)-induced apoptosis and inhibition of vascular endothelial growth factor (VEGF) expression in MG63 human osteosarcoma cells.

Pigment epithelium-derived factor (PEDF) has been shown to be the most potent inhibitor of angiogenesis in the mammalian eye, thus suggesting that loss of PEDF is involved in angiogenic eye diseases such as proliferative diabetic retinopathy. Angiogenesis is required for tumor growth and progression as well. We, along with others, have recently found that PEDF could inhibit growth of melanoma and hepatocellular carcinoma in nude mice through its anti-angiogenic effects on tumor endothelial cells. However, the possibility of the direct effect of PEDF on tumor cells has remained. In this study, we investigated the effects of PEDF on growth and vascular endothelial growth factor (VEGF) expression in MG63 human cultured osteosarcoma cells. PEDF decreased viable cell number as well as DNA synthesis in MG63 cells in a dose-dependent manner. Furthermore, PEDF was found to increase caspase-3/7 activity and to subsequently induce apoptotic cell death in MG63 cells. PEDF also inhibited VEGF expression in MG63 cells at both mRNA and protein levels. Our present study provides novel beneficial aspects of PEDF on osteosarcoma cells; one is induction of apoptotic cell death of tumor cells, and the other is the suppression of VEGF expression, which would lead to inhibition of tumor angiogenesis. PEDF therefore might be a promising therapeutic agent for treatment of patients with osteosarcoma.

Apoptosis↗
PubMed2005

The p33ING1b tumor suppressor cooperates with p53 to induce apoptosis in response to etoposide in human osteosarcoma cells.

p33ING1b induces cell cycle arrest and stimulates DNA repair, apoptosis and chemosensitivity. The magnitude of some p33ING1b effects may be due to activation of the tumor suppressor p53. To investigate if the p33ING1b protein affected chemosensitivity of osteosarcoma cells, we overexpressed p33ING1b in p53+/+ U2OS cells or in p53-mutant MG63 cells, and then assessed for growth arrest and apoptosis after treatment with etoposide. p33ING1b increased etoposide-induced growth inhibition and apoptosis to a much greater degree in p53+/+ U2OS cells than in p53-mutant MG63 cells. Moreover, ectopic expression of p33ING1b markedly upregulated p53, p21WAF1 and bax protein levels and activated caspase-3 protein kinase in etoposide-treated U2OS cells. Together, our data indicate that p33ING1b prominently enhances etoposide-induced apoptosis through p53-dependent pathways in human osteosarcoma cells. p33ING1b may be an important marker and/or therapeutic target in the prevention and treatment of metastatic osteosarcoma.

Apoptosis↗
PubMed2006

Green tea polyphenols-induced apoptosis in human osteosarcoma SAOS-2 cells involves a caspase-dependent mechanism with downregulation of nuclear factor-kappaB.

Development of chemotherapy resistance and evasion from apoptosis in osteosarcoma, a primary malignant bone tumor, is often correlated with constitutive nuclear factor-kappaB (NF-kappaB) activation. Here, we investigated the ability of a polyphenolic fraction of green tea (GTP) that has been shown to have antitumor effects on various malignant cell lines to inhibit growth and induce apoptosis in human osteosarcoma SAOS-2 cells. Treatment of SAOS-2 cells with GTP (20-60 microg/ml) resulted in reduced cell proliferation and induction of apoptosis, which correlated with decreased nuclear DNA binding of NF-kappaB/p65 and lowering of NF-kappaB/p65 and p50 levels in the cytoplasm and nucleus. GTP treatment of cells reduced IkappaB-alpha phosphorylation but had no effect on its protein expression. Furthermore, GTP treatment resulted in the inhibition of IKK-alpha and IKK-beta, the upstream kinases that phosphorylate IkappaB-alpha. The increase in apoptosis in SAOS-2 cells was accompanied with decrease in the protein expression of Bcl-2 and concomitant increase in the levels of Bax. GTP treatment of SAOS-2 cells also resulted in significant activation of caspases as was evident by increased levels of cleaved caspase-3 and caspase-8 in these cells. Treatment of SAOS-2 cells with a specific caspase-3 inhibitor Ac-Asp-Glu-Val-Asp-CHO (Ac-DEVD-CHO) and general caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp (OMe)-fluoromethyl ketone (Z-VAD-FMK) rescued SAOS-2 cells from GTP-induced apoptosis. Taken together, these results indicate that GTP is a candidate therapeutic for osteosarcoma that mediates its antiproliferative and apoptotic effects via activation of caspases and inhibition of NF-kappaB.

Amino Acid Chloromethyl Ketones↗
PubMed2005

Endostatin cDNA/cationic liposome complexes as a promising therapy to prevent lung metastases in osteosarcoma: study in a human-like rat orthotopic tumor.

Antiangiogenesis or destruction of tumor neovessels is an effective strategy to prevent tumor growth. Endostatin, one of the many inhibitors of angiogenesis that have been discovered, has shown conflicting results in preclinical assays. We studied the therapeutic potential of lipid/DNA complexes consisting of cationic liposomes and an endostatin-coding plasmid (Endo cDNA/CLP) in an orthotopic osteosarcoma model in rats. Empty plasmid without the endostatin gene complexed with cationic liposomes served as control. Animals were treated intravenously three times a week starting on the day tumors were detectable by (18)FDG tomoscintigraphy. During treatment, tumor progression was followed by PET scan and angioscintigraphy, and the effects of antivascular therapy on primary tumor, metastases, and tumor vascular density were confirmed by histologic analysis. Our results demonstrate that therapy using Endo cDNA/CLP is associated with pronounced delay in tumor growth. Moreover, it effectively prevented the occurrence of lung metastases, the major reason for bad prognosis and death in osteosarcoma patients. This approach could be used as an adjuvant therapy for osteosarcoma.

Animals↗
PubMed1998

Parosteal osteosarcoma from a rib.

Comprising 1.6% of primary bone malignancies, parosteal osteosarcomas are rare. Rib parosteal osteosarcomas are even rarer, with only 2 cases in the literature. We report a third such case, with a 32-month disease-free survival. Issues relevant to the management of rib parosteal osteosarcomas are discussed.

Adult↗
PubMed1991

Osteosarcoma. Clinical features and evolving surgical and chemotherapeutic strategies.

Osteosarcoma is the most common neoplasm of bone in children and adolescents. The first effective therapy became available in the early 1970s, and although controversy existed for several years regarding the relative value of aggressive multiagent chemotherapy, presently about 60% of patients with resectable primary tumors and no metastases at diagnosis will be cured. New imaging methods, including computerized tomography, magnetic resonance imaging, and radionuclide techniques, that are sensitive to changes in local tumor perfusion have improved the ability to define the extent of tumor and the response to chemotherapy, and to plan surgery. Although amputation historically has been the primary method for local tumor control, newer surgical techniques and endoprosthetic devices, coupled with effective preoperative chemotherapy, have offered less radical surgery for 50% to 80% of patients with osteosarcoma. New therapeutic agents, including ifosfamide and the immunosuppressive drug, muramyl tripeptide phosphatidylethanolamine, hold promise for improvement in the cure rate of osteosarcoma.

Adolescent↗
PubMed2006

[Inaugural cutaneous metastases of an osteosarcoma: a case report].

Inaugural cutaneous metastasis is exceptional in osteosarcoma. We report a case of a woman with osteosarcoma of the right knee who presented two tumefactions of the scalp at the time of diagnosis. Magnetic resonance imaging identified a high intensity T2 signal in the femur and also a high-intensity signal in the soft tissues. The head scan confirmed the presence of two subcutaneous tumors. Biopsy of the two sites demonstrated the metastatic nature of the cutaneous lesions. The patient was given preoperative and postoperative chemotherapy. Wide resection followed by prosthesis reconstruction was performed. Pulmonary metastases developed and led to two thoracotomy procedures. The patient has remained in remission 22 months. Six cases of cutaneous metastases of osteosarcoma have been reported in the literature. The cutaneous metastases were secondary in five of six cases, occurring after other metastatic localizations had been discovered. The present case is the first published observation of synchronous cutaneous metastases. The duration of remission suggests that cutaneous localizations should be treated like other inaugural metastatic localizations with intensive chemotherapy and wide resection of the primary tumor.

Adult↗
PubMed2002

Alterations in the INK4a/ARF locus and their effects on the growth of human osteosarcoma cell lines.

Two different proteins, p16(INK4a) and p14(ARF), encoded by the INK4a/ARF locus play important roles in the RB and p53 pathways, respectively. This study was performed to determine genetic and epigenetic alterations in the INK4a/ARF locus and their effects on the growth of osteosarcoma. Among six cell lines examined, both p16(INK4a) and p14(ARF) exons were homozygously deleted in two cell lines, MG63 and HOS, and both p16(INK4a) and p14(ARF) promoters were methylated in one cell line, U2OS. Wild-type mRNA and proteins for p16(INK4a) and p14(ARF) were expressed in three other cell lines, SaOS2, HuO9, and G292. Transfection studies were performed using two cell lines, U2OS and MG63. Both the RB and p53 genes were wild types in U2OS, whereas p53 but not RB was mutated in MG63. Both p16(INK4a) and p14(ARF) suppressed the growth of U2OS, whereas p16(INK4a) but not p14(ARF) suppressed the growth of MG63. p53 only did not suppress the growth of MG63 either; however, coexpression of p14(ARF) with p53 increased the fraction of the G0/G1 phase in MG63 cells. The data presented here demonstrate the importance of genetic and epigenetic alterations in the INK4a/ARF locus for the growth of osteosarcoma and thus will be useful to further understand the biologic behavior of osteosarcoma in association with the defects in the p53 and RB pathways.

Blotting, Western↗
PubMed2002

Amplification of 17p11.2 approximately p12, including PMP22, TOP3A, and MAPK7, in high-grade osteosarcoma.

Amplification of region 17p11.2 approximately p12 has been found in 13%-29% of high-grade osteosarcomas, suggesting the presence of an oncogene or oncogenes that may contribute to their development. To determine the location of these putative oncogenes, we established 17p11.2 approximately p12 amplification profiles by semiquantitative PCR, using 15 microsatellite markers and seven candidate genes in 19 high-grade osteosarcomas. Most of the tumors displayed complex amplification profiles, with frequent involvement of marker D17S2041 in 17p12 and TOP3A in 17p11.2 and, in some cases, very high-level amplification of PMP22 and MAPK7 in 17p11.2. Our findings suggest that multiple amplification targets, including PMP22, TOP3A, and MAPK7 or genes close to these candidate oncogenes, may be present in 17p11.2 approximately p12 and thus contribute to osteosarcoma tumorigenesis.

Bone Neoplasms↗
PubMed2003

Update on the biology and management of canine osteosarcoma.

Osteosarcoma (OSA) is the most common primary bone tumor diagnosed in dogs. Our understanding of the risk factors and genetic changes in canine OSA patients is growing, but specific, innovative therapeutic strategies are slow in coming. Appendicular skeletal osteosarcoma, the most frequent form of this disease, is typically seen in large to giant breeds, with males being overrepresented in most reports. Axial skeletal OSA is less common than appendicular OSA, but the biologic behavior of the disease is equally aggressive in all skeletal sites except for the mandible. Though the current standard of care for dogs with osteosarcoma remains surgical resection of the affected site, followed by chemotherapy with either a platinum- (cisplatin or carboplatin) or doxorubicin-based protocol, novel therapies are being actively investigated.

Animals↗
PubMed1990

Management of canine appendicular osteosarcoma.

Canine appendicular osteosarcoma is a highly malignant primary bone cancer that closely resembles the same disease in humans. Although amputation alone usually controls local disease, metastatic cancer is common and is the cause of death or euthanasia in 90% of dogs by 1 year. Cisplatin (+/- doxorubicin) chemotherapy appears to improve survival time in dogs; however, metastatic cancer remains a problem. Pulmonary metastasectomy may prolong survival in carefully selected dogs. Limb-sparing, although involved and potentially fraught with complications, can result in local disease control and a functional, pain-free limb in selected dogs without adversely affecting their survival. Studies are ongoing to improve local disease control with limb-sparing and improve disease-free survival in dogs with appendicular osteosarcoma. In conclusion, dogs with osteosarcoma were previously thought to have a hopeless prognosis, but the outlook is beginning to appear more optimistic. Limb-sparing in dogs is still evolving; however, it is possible in selected cases to optimize survival and preserve limb function.

Animals↗
PubMed2001

[Bone scintigraphy in two cases of primary vertebral osteosarcoma in adults].

The primary vertebral osteosarcoma in adults is a rare tumor which represents less than 2% of all osteosarcomas. We present the cases of two men (40 and 33 years old) who began with pain and neurological compression symptoms. The imaging methods used to study the tumors were X-rays, CT, MRI and bone scintigraphy with 99mTc-HMDP. After the pathological diagnosis, the tumors were removed surgically and the treatment was completed with chemotherapy and radiotherapy. In this report the authors review the published cases of vertebral osteosarcoma, its epidemiology, clinical presentation and characteristics in the different imaging techniques.

Adult↗