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1.
Anticancer Res ; 39(10): 5611-5615, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570457

RESUMO

BACKGROUND/AIM: Chemotherapy is the mainstay treatment of osteosarcoma. The purpose of this study was to elucidate the factors that affect the rate of chemotherapy treatment of osteosarcoma patients. MATERIALS AND METHODS: We queried the National Cancer Database for bone cancer patients. We included patients diagnosed with osteosarcoma of the upper extremities regardless of age and sex. With bivariate and multivariate models, we analyzed the demographic, facility, and tumor-specific characteristics, comparing the group that received chemotherapy with those that did not. RESULTS: Female patients (OR=0.567; 95%CI=0.337-0.955), non-White patients (OR=0.485; 95%CI=0.25-0.939), and patients with government insurance (OR=0.506; 95%CI=0.285-0.9) had lower odds of receiving chemotherapy treatment than male, white, and privately insured patients. Patients with stages II (OR=4.817; 95%CI=2.594-8.946) and IV disease (OR=0.457; 95%CI=1.931-10.286) had higher odds of receiving chemotherapy than those with stage I disease. CONCLUSION: Age, sex, race and insurance affected the rate of chemotherapy treatment in patients with upper limb osteosarcoma.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Osteossarcoma/tratamento farmacológico , Extremidade Superior/patologia , Adulto , Quimioterapia Adjuvante/métodos , Terapia Combinada/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
2.
Anticancer Res ; 39(9): 4653-4657, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519563

RESUMO

BACKGROUND/AIM: Osteosarcoma is a recalcitrant neoplasm which occurs predominantly in adolescents and young adults. Recently, using a patient-derived orthotopic xenograft (PDOX) model of malignant soft-tissue sarcoma (STS), we showed that oral recombinant methioninase (o-rMETase), in combination with caffeine, was more efficacious than o-rMETase alone in inhibiting STS tumor growth. In the present report, we determined the efficacy of o-rMETase combined with oral caffeine on a cisplatinum (CDDP)-resistant osteosarcoma PDOX model. MATERIALS AND METHODS: Osteosarcoma PDOX models were randomly divided into seven treatment groups (6 mice in each group): untreated control; CDDP alone; o-rMETase alone; o-rMETase with caffeine; CDDP plus o-rMETase; CDDP plus caffeine; and CDDP plus o-rMETase with caffeine. Tumor size and body weight were measured throughout the treatment. RESULTS: Tumors regressed after treatment with CDDP plus o-rMETase with caffeine. Tumors treated with CDDP plus o-rMETase with caffeine also had the most necrosis. CONCLUSION: The combination of o-rMETase and caffeine together with first-line chemotherapy was efficacious for drug-resistant osteosarcoma and has clinical potential in the treatment of this highly-resistant neoplasm.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Cafeína/administração & dosagem , Liases de Carbono-Enxofre/administração & dosagem , Cisplatino/administração & dosagem , Resistencia a Medicamentos Antineoplásicos , Administração Oral , Animais , Modelos Animais de Doenças , Humanos , Camundongos , Osteossarcoma/diagnóstico por imagem , Osteossarcoma/tratamento farmacológico , Osteossarcoma/patologia , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Anticancer Res ; 39(9): 4775-4779, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519578

RESUMO

BACKGROUND: Osteosarcoma is a recalcitrant disease treated with surgery and intensive chemotherapy as standard. The 5-year survival rate of patients with relapsed and lung metastatic osteosarcoma is as low as 20%. MATERIALS AND METHODS: A 16-year-old patient developed left distal femoral high-grade osteosarcoma and underwent cisplatinum-based neoadjuvant chemotherapy and surgery. From the resected tumor, a patient-derived orthotopic xenograft (PDOX) model was established in the femur of nude mice. PDOX models were randomized into the following groups: untreated control, or treatment with doxorubicin (3 mg/kg, i.p., weekly for 14 days), sunitinib (40 mg/kg, oral gavage, daily for 14 days), pazopanib (100 mg/kg, oral gavage, daily for 14 days), temozolomide(25 mg/kg, oral gavage, daily for 14 days), and eribulin (1.5 mg/kg, i.p., daily for 14 days). Tumor volume and body weight were monitored twice a week. RESULTS: The osteosarcoma PDOX was resistant to doxorubicin, sunitinib, and pazopanib. In contrast, eribulin and temozolomide arrested tumor growth. CONCLUSION: This study demonstrated the utility of the PDOX model in allowing effective from non-effective drugs to be distinguished in a model in which the tumor was growing on the organ corresponding to that of the patient.


Assuntos
Cisplatino/farmacologia , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Furanos/farmacologia , Cetonas/farmacologia , Neoplasias Pulmonares/secundário , Osteossarcoma/patologia , Adolescente , Animais , Modelos Animais de Doenças , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Camundongos , Osteossarcoma/tratamento farmacológico , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Anticancer Res ; 39(9): 4781-4786, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519579

RESUMO

BACKGROUND/AIM: Osteosarcoma is a rare but recalcitrant type of bone cancer. To discover an effective therapy for osteosarcoma, we used a patient-derived orthotopic xenograft (PDOX) mouse model. A PDOX mouse model has been established for all major cancer types. Strong synergistic efficacy of sorafenib (SFN) and everolimus (EVL) has been demonstrated in several cancers. In the present study, we examined the efficacy of a SFN and EVL combination on a doxorubicin (DOX)-resistant osteosarcoma PDOX. MATERIALS AND METHODS: The osteosarcoma PDOX models were randomly divided into five treatment groups, each containing six mice: Control; DOX; SFN; EVL; and a combination of SFN and EVL. Mice were treated for 14 days. To observe the efficacy of these treatments, tumor size and body weight were measured, and histological sections were analyzed. RESULTS: Tumor growth regression was observed only in the mice treated with the combination of SFN-EVL. Histological analysis revealed necrosis with degenerative changes in tumors treated with a combination of SFN-EVL. CONCLUSION: A SFN-EVL combination could be a novel effective treatment option for osteosarcoma.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Osteossarcoma/patologia , Animais , Modelos Animais de Doenças , Progressão da Doença , Doxorrubicina/farmacologia , Everolimo/administração & dosagem , Humanos , Camundongos , Osteossarcoma/tratamento farmacológico , Sorafenibe/administração & dosagem , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Yonsei Med J ; 60(9): 832-841, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31433581

RESUMO

PURPOSE: Epirubicin is one of the most effective drugs against osteosarcoma. miR-1301 is involved in the occurrence and development of osteosarcoma. Whether miR-1301 is responsible for the chemosensitivity of osteosarcoma cells to epirubicin remains largely unknown. MATERIALS AND METHODS: U2OS and SAOS-2 cells were treated with various concentrations of epirubicin. Flow cytometry was employed to evaluate cell apoptotic rate. Cell proliferation was measured by Cell Counting Kit-8 assay. Western blot and quantitative real-time polymerase chain reaction were utilized to detect the expressions of B-cell lymphoma-2 (Bcl-2), Bcl-2 assaciated X protein (Bax), cleaved-caspase-3, cleaved-poly (ADP-ribose) polymerases (PARP1), TP53-regulated inhibitor of apoptosis 1 (TRIAP1), and microRNA-1301 (miR-1301). The relationship between miR-1301 and TRIAP1 was determined by luciferase reporter assay. RESULTS: Epirubicin inhibited proliferation in a dose-dependent manner, induced apoptosis, decreased the expression of Bcl-2, and increased the expressions of Bax, cleaved-caspase-3, and cleaved-PARP1 in osteosarcoma cells. miR-1301 was downregulated in U2OS and SAOS-2 cells. Importantly, epirubicin significantly increased the levels of miR-1301. Overexpression of miR-1301 suppressed proliferation and promoted apoptosis. Interestingly, those effects were enhanced by epirubicin. In contrast, miR-1301 depletion attenuated the epirubicin-mediated anti-osteosarcoma effect. miR-1301 negatively regulated the expression of TRIAP1 in U2OS and SAOS-2 cells. Furthermore, epirubicin inhibited the mRNA and protein levels of TRIAP1 by upregulating miR-1301 levels. Epirubicin suppressed cell proliferation by downregulating TRIAP1. CONCLUSION: miR-1301 was implicated in the chemosensitivity of osteosarcoma to epirubicin by modulating TRIAP1.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias Ósseas/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Epirubicina/uso terapêutico , Peptídeos e Proteínas de Sinalização Intracelular/genética , MicroRNAs/genética , Osteossarcoma/tratamento farmacológico , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Caspase 3/biossíntese , Linhagem Celular Tumoral , Regulação para Baixo , Epirubicina/farmacologia , Citometria de Fluxo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , MicroRNAs/metabolismo , Osteossarcoma/genética , Osteossarcoma/patologia , Reação em Cadeia da Polimerase em Tempo Real , Regulação para Cima
6.
Anticancer Res ; 39(8): 4079-4084, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366491

RESUMO

BACKGROUND/AIM: Recurrent osteosarcoma is a recalcitrant disease; therefore, an improved strategy is urgently needed to provide therapy. In order to develop a novel strategy for this disease, our lab has developed a patient-derived orthotopic xenograft (PDOX) mouse model for osteosarcoma. The combination of sorafenib (SFN) and palbociclib (PAL) was shown to be effective of hepatocellular carcinoma. However, whether this combination is efficacious on osteosarcoma has not been reported. The aim of this study was to determine the efficacy of the SFN and PAL combination on a cisplatinum (CDDP)-resistant osteosarcoma PDOX model. MATERIALS AND METHODS: Osteosarcoma PDOX models were randomly divided into five treatment groups: untreated-control, CDDP, SFN, PAL and the combination of SFN and PAL. RESULTS: Of these agents, the SFN-PAL combination significantly regressed tumor growth, and enhanced tumor necrosis with degenerative changes in the osteosarcoma PDOX. CONCLUSION: The SFN-PAL combination is an effective treatment strategy for osteosarcoma and therefore holds promise for clinical efficacy.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Osteossarcoma/tratamento farmacológico , Piperazinas/administração & dosagem , Piridinas/administração & dosagem , Sorafenibe/administração & dosagem , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Linhagem Celular Tumoral , Cisplatino/administração & dosagem , Modelos Animais de Doenças , Doxorrubicina/administração & dosagem , Humanos , Camundongos , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Osteossarcoma/genética , Osteossarcoma/patologia , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
7.
J Assoc Physicians India ; 67(4): 76-78, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31299847

RESUMO

A 21-year old female, recently diagnosed with osteosarcoma of right humerus, presented to the emergency with history of fever, productive cough, chest pain and progressive respiratory distress for six days. Initial investigations suggested pneumonia but she did not respond to parenteral antibiotics. CT pulmonary angiogram revealed bilateral pulmonary artery embolism. Thrombolysis was performed using alteplase, which failed to improve the clinical condition. In view of underlying malignancy, a possibility of tumour-embolism was considered and she was started on chemotherapy for osteosarcoma. There was dramatic improvement in her respiratory symptoms after the first chemotherapy cycle, along with radiological resolution of the embolism. This case highlights the importance of suspecting tumour embolism in a known case of malignancy with respiratory distress.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Ósseas/diagnóstico , Osteossarcoma/diagnóstico , Embolia Pulmonar/diagnóstico , Adulto , Angiografia , Neoplasias Ósseas/complicações , Neoplasias Ósseas/tratamento farmacológico , Feminino , Humanos , Osteossarcoma/complicações , Osteossarcoma/tratamento farmacológico , Pneumonia , Embolia Pulmonar/complicações , Embolia Pulmonar/tratamento farmacológico , Adulto Jovem
8.
Neoplasma ; 66(5): 766-775, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31288526

RESUMO

Zoledronate is clinically used for preventing skeletal complications of osteoporosis and specific types of cancer associated with bone metastasis. Zoledronate inhibits osteoclast development and induces osteoclast apoptosis, thereby reducing bone lysis. Zoledronic acid (ZOL) plays a key role in treating osteosarcoma (OS) and improving the prognosis of patients with OS; however, its mechanism remains unclear. The effect of zoledronic acid on osteosarcoma cells was examined, and MTT was performed to determine the effect of ZOL on osteosarcoma cell proliferation. Cells were treated with 0, 25, 50, 100 or 200 µM ZOL for 24 h, 48 h and 72 h. p-AKT/AKT and p-GSK-3ß/GSK-3ß expression levels were checked by western blotting. Further study compared 100 µM ZOL alone for 48 h, Li2CO3 (1mM) alone and ZOL (100 µM) plus Li2CO3 (1 mM) with no treatment (control). The effects of GSK-3ß on ZOL-induced apoptosis among these groups were characterized by flow cytometry, MTT assay, transmission electron microscopy (TEM) and western blot. In this study, we found that the proliferation of MG-63 cells was significantly decreased after treatment with 25, 50, 100 or 200 µM ZOL for 48 and 72 h compared to untreated control cells. The expression levels of p-AKT/AKT and p-GSK-3ß/GSK-3ß in MG-63 cells and U-2 OS cells were inhibited by ZOL in both a dose- and time-dependent manner. Significant decreases in the expression of Cyclin D1, ß-Catenin, and c-Myc were observed in the groups that underwent ZOL treatment. Additionally, compared to ZOL (100 µM) treatment alone, co-treatment with ZOL (100 µM) and Li2CO3 (1 mM) rescued cell proliferation and restored a significant percentage of apoptotic cells. Our study suggests that the specific mechanism by which ZOL affects apoptosis of osteosarcoma cells is through the AKT/GSK-3ß/ß-Catenin signaling pathway.


Assuntos
Neoplasias Ósseas/patologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Osteossarcoma/patologia , Ácido Zoledrônico/farmacologia , Apoptose , Neoplasias Ósseas/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Osteossarcoma/tratamento farmacológico , Transdução de Sinais
9.
Anticancer Res ; 39(7): 3669-3675, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262893

RESUMO

BACKGROUND/AIM: Amentoflavone has been implicated in reducing the metastatic potential of osteosarcoma (OS) cells in vitro. The aim of the present study was to verify the antitumoral efficacy and the potential mechanism of amentoflavone osteosarcoma progression inhibition in vivo. MATERIALS AND METHODS: A U-2 OS osteosarcoma xenograft mouse model was used in this study. Mice were treated with a vehicle control or amentoflavone (100 mg/kg/day) for 15 days. Tumor growth, signal transduction, and expression of tumor progression-associated proteins were evaluated using a digital caliper, bioluminescence imaging (BLI), animal computed tomography (CT), and ex vivo western blotting assay. RESULTS: Amentoflavone significantly inhibits tumor growth and reduces protein levels of phospho-extracellular signal-regulated kinase (P-ERK), nuclear factor-kappaB (NF-κB) p65 (Ser536), vascular endothelial growth factor (VEGF), matrix metallopeptidase 9 (MMP-9), X-linked inhibitor of apoptosis protein (XIAP), and cyclin-D1 in osteosarcoma in vivo. CONCLUSION: The inhibition of ERK/NF-κB activation is associated with amentoflavone-inhibited osteosarcoma progression in vivo.


Assuntos
Antineoplásicos/farmacologia , Biflavonoides/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , NF-kappa B/metabolismo , Osteossarcoma/metabolismo , Animais , Antineoplásicos/uso terapêutico , Biflavonoides/uso terapêutico , Linhagem Celular Tumoral , Humanos , Masculino , Camundongos Nus , Osteossarcoma/tratamento farmacológico , Osteossarcoma/patologia , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Int J Oncol ; 55(1): 167-178, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31180533

RESUMO

Vascular endothelial growth inhibitor (VEGI; also referred to as TNFSF15 or TL1A) is involved in the modulation of vascular homeostasis. VEGI is known to operate via two receptors: Death receptor­3 (DR3) and decoy receptor­3 (DcR3). DR3, which is thus far the only known functional receptor for VEGI, contains a death domain and induces cell apoptosis. DcR3 is secreted as a soluble protein and antagonizes VEGI/DR3 interaction. Overexpression of DcR3 and downregulation of VEGI have been detected in a number of cancers. The aim of the present study was to investigate the effects of sodium valproate (VPA), a histone deacetylase inhibitor, in combination with hydralazine hydrochloride (Hy), a DNA methylation inhibitor, on the expression of VEGI and its related receptors in human osteosarcoma (OS) cell lines and human microvascular endothelial (HMVE) cells. Combination treatment with Hy and VPA synergistically induced the expression of VEGI and DR3 in both OS and HMVE cells, without inducing DcR3 secretion. In addition, it was observed that the combination of VPA and Hy significantly enhanced the inhibitory effect on vascular tube formation by VEGI/DR3 autocrine and paracrine pathways. Furthermore, the VEGI/VEGF­A immune complex was pulled down by immunoprecipitation. Taken together, these findings suggest that DNA methyltransferase and histone deacetylase inhibitors not only have the potential to induce the re­expression of tumor suppressor genes in cancer cells, but also exert anti­angiogenic effects, via enhancement of the VEGI/DR3 pathway and VEGI/VEGF­A interference.


Assuntos
Neoplasias Ósseas/tratamento farmacológico , Hidralazina/farmacologia , Osteossarcoma/tratamento farmacológico , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/biossíntese , Ácido Valproico/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Neoplasias Ósseas/irrigação sanguínea , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Sinergismo Farmacológico , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Inibidores Enzimáticos/farmacologia , Epigênese Genética , Humanos , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Osteossarcoma/irrigação sanguínea , Osteossarcoma/genética , Osteossarcoma/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Membro 25 de Receptores de Fatores de Necrose Tumoral/biossíntese , Membro 25 de Receptores de Fatores de Necrose Tumoral/genética , Transcrição Genética/efeitos dos fármacos , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética
11.
Asia Pac J Clin Oncol ; 15(4): 218-224, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31111666

RESUMO

Osteosarcoma (OS) is one of the most common malignant bone tumors in children and adolescents, and the eighth leading form of childhood cancer. Matrix metalloproteinases (MMPs) are proteolytic enzymes implicated in certain cancers including OS. In this review, we discuss the mechanism of actions of MMPs in progression of OS, and the therapeutic use of MMPs inhibitors in the treatment of OS with subsequent clinical studies and future management. The expression of MMPs is upregulated in cancer cells by a variety of cytokines and growth factors, and upregulation of MMPs induces degradation of the extracellular matrix that contributes to cell proliferation by releasing growth factors. MMPs promote the detachment and migration of endothelial cells, cross the basement membrane as well as invade the surrounding lymphatic vessels and causes cancer metastasis. The use of selective MMP inhibitors with limited side effects might be promising therapeutic strategy in the treatment of OS. More clinical trials are necessary to evaluate the role of selective MMPs inhibitors in the prevention and treatment of OS along with their assessment of toxicity.


Assuntos
Neoplasias Ósseas/tratamento farmacológico , Metaloproteinases da Matriz/uso terapêutico , Osteossarcoma/tratamento farmacológico , Neoplasias Ósseas/patologia , Progressão da Doença , Humanos , Metaloproteinases da Matriz/farmacologia , Osteossarcoma/patologia
12.
Int J Oncol ; 54(6): 1969-1980, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31081055

RESUMO

Previous research has reported that salidroside exerts antitumor properties on numerous types of tumor cells; however, its effect on osteosarcoma cells remains unknown. The present study aimed to investigate the effects of salidroside on the viability, apoptosis and invasion of osteosarcoma cells in vitro, and determine the underlying mechanism of action. The results of an MTT revealed that salidroside suppressed the viability of osteosarcoma cells (MG63 and U2OS cells) in a time­ and concentration­dependent manner. The results of cell morphological analysis (profile observations and Hoechst 33258 staining) and the detection of apoptosis by flow cytometry further indicated that the decrease in osteosarcoma cell viability induced by salidroside was associated with cell apoptosis. Western blot analysis not only confirmed these results but also suggested that salidroside induced the apoptosis of osteosarcoma cells by activating the caspase­9­dependent apoptotic pathway. In addition, we reported that salidroside induced G0/G1 phase arrest and suppressed the invasion of osteosarcoma cells, as measured by flow cytometric cell cycle analysis and a Transwell invasion assay, respectively. Western blot analysis confirmed the aforementioned results. Furthermore, our findings demonstrated that salidroside induced the apoptosis, G0/G1 phase arrest and suppressed the invasion of osteosarcoma cells by inhibiting the janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway, as determined by western blot analysis. In summary, the findings of the present study suggested that salidroside may inhibit the progression of osteosarcoma by suppressing the growth and invasion of osteosarcoma cells. Furthermore, the investigations into the underlying mechanism demonstrated that salidroside exerted notable antitumor activity in osteosarcoma cells by inhibiting the JAK2/STAT3 signaling pathway.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Ósseas/metabolismo , Glucosídeos/farmacologia , Osteossarcoma/metabolismo , Fenóis/farmacologia , Transdução de Sinais/efeitos dos fármacos , Neoplasias Ósseas/tratamento farmacológico , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Janus Quinase 2/metabolismo , Osteossarcoma/tratamento farmacológico , Fator de Transcrição STAT3/metabolismo
13.
Medicine (Baltimore) ; 98(19): e15582, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31083238

RESUMO

BACKGROUND: We designed the study to investigate whether methotrexate, doxorubicin, and cisplatinum (MAP) chemotherapy strategy was still the preferred option for the survival of osteosarcoma patients. METHOD: We collected some trials of osteosarcoma to make a meta-analysis first. Then, we retrospectively collected data from 115 patients with osteosarcoma and performed further analysis to verify the impact of MAP regimen on the survival of patients. RESULTS: Seven studies including 3433 participants met the preliminary inclusion criteria. Meta-analysis of the 3-year disease-free survival (odds ratio [OR] = 1.06, 95% confidence interval [CI]: 0.88-1.28; P = .52) and overall survival (OR = 1.21, 95% CI: 0.70-2.11; P = .54), 5-year disease-free survival (OR = 1.07, 95% CI: 0.87-1.30; P = .54) and overall survival (OR = 0.86, 95% CI: 0.65-1.12; P = .26), and mortality rate (OR = 0.90, 95% CI: 0.70-1.17; P = .44), showed no statistically significant differences. The most common grade 3/4 adverse events were neutropenia (498 [85.9%] patients in MAP vs 533 [93.3%] in MAP plus ifosfamide and etoposide, or other adjuvant therapy drugs [MAP]). MAP was associated with less frequent toxicities than MAP group with statistical significance in thrombocytopenia, febrile neutropenia, anemia, and hypophosphatemia. The same phenomenon could also be seen in the analysis of clinical data. CONCLUSION: MAP regimen remains the preferred option for osteosarcoma chemotherapy.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Cisplatino/uso terapêutico , Doxorrubicina/uso terapêutico , Metotrexato/uso terapêutico , Osteossarcoma/tratamento farmacológico , Antineoplásicos/efeitos adversos , Neoplasias Ósseas/mortalidade , Cisplatino/efeitos adversos , Doxorrubicina/efeitos adversos , Quimioterapia Combinada , Feminino , Humanos , Masculino , Metotrexato/efeitos adversos , Osteossarcoma/mortalidade , Estudos Retrospectivos , Análise de Sobrevida
14.
Phytother Res ; 33(7): 1837-1850, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31050072

RESUMO

A major problem in osteosarcoma treatment is cisplatin resistance. We have reported the anti-osteosarcoma effect of oleandrin; however, whether oleandrin sensitizes osteosarcoma to cisplatin is unknown. We investigated the chemosensitization of oleandrin and potential mechanisms in osteosarcoma cells U-2OS, SaOS-2, and MG-63. The median-effect analysis demonstrated that cisplatin + oleandrin exerted synergistic (U-2OS and MG-63) or additive effects (SaOS-2), which were consistent with the changes of the intracellular accumulation of platinum (Pt) and Pt-DNA adducts. Immunohistochemistry staining showed that the expression level of the mature form CTR1, the major influx transporter of cisplatin, was low in osteosarcoma tissue. However, oleandrin with or without cisplatin significantly increased the expression and membrane localization of the mature CTR1. Furthermore, CTR1 knockdown reversed the synergistic effect and decreased cisplatin uptake. The mRNA microarray analysis suggested that oleandrin downregulated the expression of proteasome-related genes, which was verified by the proteasome activity assay. Besides, the proteasome inhibitor MG132 upregulated the expression of the mature CTR1 in U-2OS and MG-63 cells. Overall, we conclude that oleandrin sensitizes osteosarcoma cells to cisplatin in synergistic or additive manners. The synergy results from the enhanced cisplatin uptake via oleandrin-mediated inhibition of proteasome activity and subsequent blockage of the mature CTR1 degradation.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Cardenolídeos/farmacologia , Proteínas de Transporte de Cátions/metabolismo , Cisplatino/farmacologia , Osteossarcoma/tratamento farmacológico , Neoplasias Ósseas/metabolismo , Linhagem Celular Tumoral , Humanos , Osteossarcoma/metabolismo
15.
Biomed Pharmacother ; 114: 108839, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30978523

RESUMO

Osteosarcoma is an aggressive malignant neoplasm and cancerous bone tumor. Quercetin is a well-known flavonoid abundant in vegetables, fruits, grains, leaves, and red onions. In the present study, we evaluated the effects of quercetin-induced inhibition of parathyroid hormone receptor 1 (PTHR1) on proliferation, migration, and invasion in U2OS and Saos-2 cells. Following incubation with quercetin (20, 40, 60, 80, or 100 µM) for 48 h, the cell viability of U2OS and Saos-2 cells were significantly reduced in a dose-dependent manner. Additionally, there were significant decreases in cell adhesion, invasion, and migration as well as reduced cell viability at higher concentrations of quercetin. Furthermore, the mRNA expression levels of matrix metalloproteinases (MMP)-2 and -9 were attenuated, whereas the mRNA expression levels of tissue inhibitors of metalloproteinases (TIMP)-1 and -2 were elevated. Quercetin treatment also significantly reduced the mRNA expression levels of PTHR1 by 0.27-, and 0.55-fold at 80, and 100 µM, respectively, whereas 0.19 and 0.41 folds in Saos-2 cells. PTHR1 protein expression in U2OS cells was reduced by 0.19-, and 0.43-fold at 80, and 100 µM of quercetin, respectively (P < 0.05), whereas 0.17 and 0.35 folds in Saos-2 cells. Immunofluorescence analyses revealed reduced expression of PTHR1 following treatment with quercetin. PTHR1 expression in U2OS cells was reduced by 0.18-, and 0.41-fold at 80, and 100 µM, respectively, whereas 0.15 and 0.38 folds in Saos-2 cells. The knockdown of PTHR1enhanced quercetin-inhibited proliferation and invasion. Taken together, the present findings indicate that quercetin reduced human metastatic osteosarcoma cell invasion, adhesion, proliferation, and migration by inhibiting PTHR1.


Assuntos
Neoplasias Ósseas/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Osteossarcoma/tratamento farmacológico , Quercetina/farmacologia , Receptor Tipo 1 de Hormônio Paratireóideo/metabolismo , Neoplasias Ósseas/metabolismo , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Invasividade Neoplásica/patologia , Osteossarcoma/metabolismo , Inibidor Tecidual de Metaloproteinase-1/metabolismo
16.
Biomed Pharmacother ; 114: 108854, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30978524

RESUMO

Huangqi Fuzheng decoction (HFD) is a traditional Chinese medicine and has been used as adjuvant clinical therapy for breast, ovarian and thyroid cancer. However, the potential roles and molecular mechanisms of HFD in osteosarcoma remain unclear. Here, we investigated the antitumor activity of HFD in osteosarcoma and analyzed its active compounds and therapeutic targets using an integrated systems pharmacology approach. We found that HFD treatment obviously suppressed cell proliferation and induced cell death of U2OS and Saos-2 cells. In addition, HFD treatment significantly inhibited tumor growth and in combination with Cisplatin treatment without obvious serious side effects in the osteosarcoma xenograft mice. Based on systems pharmacology analysis, we identified 105 active compounds and 23 potential targets for HFD in osteosarcoma. Finally, multi-targets were validated as therapeutic targets of HFD for osteosarcoma using Western blot. Our study provides a liable strategy to explore the molecular mechanisms of traditional Chinese medicine. These findings also suggest HFD as a promising candidate medicine for osteosarcoma treatment.


Assuntos
Antineoplásicos/farmacologia , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Inibidores do Crescimento/farmacologia , Osteossarcoma/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Neoplasias Ósseas/tratamento farmacológico , Linhagem Celular Tumoral , Cisplatino/farmacologia , Humanos , Masculino , Medicina Tradicional Chinesa/métodos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus
17.
Zhonghua Zhong Liu Za Zhi ; 41(4): 309-314, 2019 Apr 23.
Artigo em Chinês | MEDLINE | ID: mdl-31014058

RESUMO

Objective: To compare the clinical efficacy and drug safety between oral apatinib combined with conventional chemotherapy and conventional chemotherapy alone for the treatment of osteosarcoma and soft tissue sarcoma patients with pulmonary metastasis. Methods: Thirty-three osteosarcoma and soft tissue sarcoma patients with pulmonary metastasis who were treated in the Department of Bone and Soft Tissue Tumor Surgery, Cancer Hospital of China Medical University from January 2015 to December 2017 were enrolled in this study. Patients with osteosarcoma received methotrexate, adriamycin (ADM), cisplatin (CDDP), ifosfamide (IFO) sequential regimen; patients with soft tissue sarcoma were treated with IFO and ADM regimen. Eighteen of these patients received an additional oral dose of apatinib. The patients were followed up regularly for changes in primary tumors and metastases, adverse reactions and prognosis. Results: Before treatment, the maximum diameter of pulmonary metastases in patients of apatinib group and routine treatment group were (4.46±1.70) cm and (4.53±2.00) cm, respectively, without significant difference (P=0.909). After treatment, the maximum diameter of pulmonary metastases in patients of apatinib group was (1.46±1.39) cm, significantly smaller than (3.02±1.20) cm of routine treatment group (P=0.002). After treatment, the maximum diameter of the primary lesions in the apatinib group and the conventional treatment group median decreased 0.31 cm and 0.12 cm, respectively, without significant difference (P=0.542). After treatment, the maximum diameter of the lung metastases in the apatinib group median decreased 0.59 cm, significantly more than 0.18 cm of the conventional treatment group (P=0.027). The median progression-free survival (PFS) was 9.4 months in the 33 patients. The median PFS was 9.6 months and 8.3 months in the apatinib group and the conventional treatment group, respectively, without significant difference (P=0.593). Specific adverse reactions both occurred in apatinib group and routine treatment group, mainly including oral mucosal reactions and digestive tract reactions (including nausea, vomiting and diarrhea). Conclusions: Apatinib can effectively reduce the volume of primary and metastatic lesions in patients with bone and soft tissue sarcoma accompanied by lung metastasis without reducing the survival rate or causing uncontrollable adverse reactions. The safety and clinical efficacy of apatinib are significant.


Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Pulmonares/secundário , Osteossarcoma/tratamento farmacológico , Osteossarcoma/secundário , Piridinas/uso terapêutico , Neoplasias de Tecidos Moles/tratamento farmacológico , Adulto , Neoplasias Ósseas/patologia , Criança , China , Humanos , Sarcoma/tratamento farmacológico , Sarcoma/secundário , Neoplasias de Tecidos Moles/patologia , Resultado do Tratamento
18.
Anticancer Res ; 39(4): 1711-1718, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30952710

RESUMO

BACKGROUND/AIM: Osteosarcoma (OS) is a diagnosed primary cancer of the bone. Despite the great advances that have been made during the past decades in OS therapy, drug resistance and tumor recurrence are still major problems. It is urgent to find novel strategies to overcome drug resistance in order to prolong the survival time of OS patients. MATERIALS AND METHODS: Cell viability was investigated by the cell count kit-8 (CCK-8) and colony formation assays. P-Glycoprotein (P-gp) expression was analyzed by RT-qPCR and western blot. A xenograft mouse model was used to identify the synergistic efficacy of a P-gp inhibitor with cisplatin. Student's t-test was used to determine statistically significant differences. RESULTS: P-gp expression levels were associated with cisplatin efficacy in OS patients. OS cells with higher P-gp expression were more resistant to cisplatin. Knockdown or inhibition of P-gp sensitized OS cells to cisplatin. CONCLUSION: Down-regulating the expression of P-gp in OS maybe a promising strategy to overcome cisplatin resistance.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Osteossarcoma/tratamento farmacológico , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Animais , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos Nus , Osteossarcoma/genética , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Fatores de Tempo , Carga Tumoral/efeitos dos fármacos , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Eur Radiol ; 29(7): 3945-3954, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30859285

RESUMO

PURPOSE: To investigate whether tumor texture features derived from pretreatment with 18F-fluorodeoxyglucose positron emission tomography (FDG PET) can predict histological response or event-free survival (EFS) in patients with localized osteosarcoma of the extremities treated by neoadjuvant chemotherapy (NAC). METHODS: We retrospectively reviewed 35 patients with American Joint Committee on Cancer stage II extremity osteosarcoma treated with NAC and surgery. Primary tumor traditional parameters and texture features were measured for all 18F-FDG PET images prior to treatment. After surgery, histological responses to NAC were evaluated on the postsurgical specimens. A receiver operating characteristic curve (ROC) was constructed to evaluate the optimal predictive performance among the various indices. EFS was calculated using the Kaplan-Meier method and prognostic significance was assessed by Cox proportional hazards analysis. RESULTS: Pathologic examination revealed 16 (45.71%) good responders and 19 (54.29%) poor responders. Although both the texture features (least axis, dependence nonuniformity, run length nonuniformity, and size zone nonuniformity) and metabolic tumor volume (MTV) can predict tumor response of osteosarcoma to NAC, the traditional indicator MTV has the best performance according to ROC curve analysis (area under the curve = 0.918, p < 0.0001). In multivariate analysis, MTV (p < 0.0001), histological response (p = 0.0003), and texture feature of coarsenessNGTDM (neighboring gray tone difference matrix) (p = 0.005) were independently associated with EFS. CONCLUSIONS: Intratumoral heterogeneity of baseline 18F-FDG uptake measured by PET texture analysis can predict tumor response and EFS of patients with extremity osteosarcoma treated by NAC, but the conventional parameter MTV provides better predictive power and is a strong independent prognostic factor. KEY POINTS: • The baseline 18 F-FDG PET tumor texture features can predict tumor NAC response for patients with osteosarcoma. • Coarseness NGTDM is a new and independent prognostic factor for osteosarcoma. • MTV provides the best predictive power and is a strong independent prognostic factor for patients with osteosarcoma.


Assuntos
Neoplasias Ósseas/tratamento farmacológico , Quimioterapia Adjuvante/métodos , Osteossarcoma/tratamento farmacológico , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Adolescente , Adulto , Idoso , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/patologia , Criança , China , Feminino , Fluordesoxiglucose F18/administração & dosagem , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Osteossarcoma/diagnóstico por imagem , Osteossarcoma/patologia , Valor Preditivo dos Testes , Prognóstico , Curva ROC , Compostos Radiofarmacêuticos/administração & dosagem , Estudos Retrospectivos , Imagem Corporal Total , Adulto Jovem
20.
Mater Sci Eng C Mater Biol Appl ; 98: 1097-1113, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30812994

RESUMO

The formation of structurally stable composites of cubic zirconia (c-ZrO2) with selective transition metal oxides (α-Fe2O3, Mn3O4, NiO, Co3O4) is investigated. The results affirm the prospect to retain unique c-ZrO2 and transition metal oxide (TMO) structures in the composite form until 1400 °C. It is also shown that 30 mol% Y2O3 possess the ability to retain stable c-ZrO2 despite the existence of assorted TMO content in the composites. The elemental states of Fe3+, Mn2+/4+, Ni2+ and Co2+/3+ are confirmed from the corresponding α-Fe2O3, Mn3O4, NiO, and Co3O4. The magnetic properties are highly influenced by the quantity of TMO component while the c-ZrO2 plays a decisive role in the resultant mechanical properties. The wide range of properties delivered by the composites extends the possibility to probe for osteosarcoma treatment that demands optimal mechanical and magnetic features.


Assuntos
Osteossarcoma/tratamento farmacológico , Óxidos/química , Elementos de Transição/química , Zircônio/química , Zircônio/farmacologia , Magnetismo/métodos , Teste de Materiais
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