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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.
Int J Nanomedicine ; 14: 6425-6437, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31496695

RESUMO

Introduction: Curcumin (CUR) is a general ingredient of traditional Chinese medicine, which has potential antitumor effects. However, its use clinically has been limited due to its low aqueous solubility and bioavailability. In order to improve the therapeutic effect of CUR on osteosarcoma (i.e., bone cancer), a multifunctional micelle was developed here by combining active bone accumulating ability with tumor CD44 targeting capacity. Methods: The CUR loaded micelles were self-assembled by using alendronate-hyaluronic acid-octadecanoic acid (ALN-HA-C18) as an amphiphilic material. The obtained micelles were characterized for size and drug loading. In addition, the in vitro release behavior of CUR was investigated under PBS (pH 5.7) medium containing 1% Tween 80 at 37℃. Furthermore, an hydroxyapatite (the major inorganic component of bone) affinity experiment was studied. In vitro antitumor activity was evaluated. Finally, the anti-tumor efficiency was studied. Results: The size and drug loading of the CUR loaded ALN-HA-C18 micelles were about 118 ± 3.6 nm and 6 ± 1.2%, respectively. CUR was released from the ALN-HA-C18 micelles in a sustained manner after 12 h. The hydroxyapatite affinity experiment indicated that CUR loaded ALN-HA-C18 micelles exhibited a high affinity to bone. CUR loaded ALN-HA-C18 micelles exhibited much higher cytotoxic activity against MG-63 cells compared to free CUR. Finally, CUR loaded ALN-HA-C18 micelles effectively delayed anti-tumor growth properties in osteosarcoma bearing mice as compared with free CUR. Conclusion: The present study suggested that ALN-HA-C18 is a novel promising micelle for osteosarcoma targeting and delivery of the hydrophobic anticancer drug CUR.


Assuntos
Alendronato/uso terapêutico , Curcumina/uso terapêutico , Sistemas de Liberação de Medicamentos , Ácido Hialurônico/química , Micelas , Osteossarcoma/tratamento farmacológico , Ácidos Esteáricos/química , Alendronato/química , Animais , Antineoplásicos/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Linhagem Celular Tumoral , Curcumina/química , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Humanos , Masculino , Camundongos Nus , Osteossarcoma/patologia , Tamanho da Partícula , Polímeros/química , Espectroscopia de Prótons por Ressonância Magnética
3.
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
4.
Medicine (Baltimore) ; 98(31): e16688, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31374054

RESUMO

The objectives of this study were to analyze the clinical features of patients with bone involved lymphoma and identify the prognostic factors and to explore the optimized treatment strategy for bone involved lymphoma.A total of 1948 patients with lymphoma in our cancer center from September 2006 to October 2017 were retrospectively evaluated. Among these, 109 patients with skeletal involvement in lymphoma were enrolled. According to the pathologic subtypes, the patients were divided into 3 subgroups: classic Hodgkin lymphoma (cHL), B-cell non-Hodgkin lymphoma (B-NHL), and T-cell non-Hodgkin lymphoma (T-NHL). The clinical characteristics and overall survival (OS) of 3 groups of patients were reviewed, and the prognostic factors were analyzed.There were 9 (3 unifocal, 6 multifocal) patients with primary bone lymphoma. The 5-year OS of cHL, B-NHL, and T-NHL patients was 88.24%, 54.09%, and 61.58%, respectively. Advanced stage, elevated lactate dehydrogenase (LDH), age above 60, high International Prognostic Index score, and treatment without radiotherapy for the bone involved were significant poor prognostic factors for OS of all patients in univariate analysis. There was a trend toward better OS not only in limited-stage but also in advanced-stage patients with radiotherapy for the bone involved compared with the patients without radiotherapy. Elevated LDH level and age above 60 were the independent unfavorable prognostic factor in multivariate analysis.Elevated LDH level and age above 60 predict the poor prognosis of patients with bone involvement. The potential for long-term survival suggests that additional consolidative radiotherapy for the site of skeleton involvement may have a better chance of long-term success.


Assuntos
Neoplasias Ósseas/radioterapia , Doença de Hodgkin/radioterapia , Linfoma de Células B/radioterapia , Linfoma de Células T/radioterapia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/mortalidade , Estudos de Casos e Controles , Terapia Combinada , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Feminino , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/mortalidade , Humanos , Estimativa de Kaplan-Meier , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/mortalidade , Linfoma de Células T/tratamento farmacológico , Linfoma de Células T/mortalidade , Masculino , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Estudos Retrospectivos , Vincristina/uso terapêutico
5.
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
6.
Pan Afr Med J ; 32: 133, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31303906

RESUMO

Gastrointestinal stromal tumours (GIST) are rare mesenchymal tumours which represent 1% to 3% of gastrointestinal neoplasm. Rectal location of GIST is extremely rare reaching 5% of GIST and only 0.1% of rectal tumours. They usually metastases to the liver (65%) and exceptionally to the bone (3%). We reported a case of rectal stromal tumour with an exceptional metastasis located in the rib. A 40-year-old man who presented with pelvic pain, associated with rectal syndrome, rectal bleeding and subocclusive episodes. Physical examination objectified a tough, budding rectal mass, with a smooth wall, localized 3cm above of anal margin. A Thoraco-abdominal computed tomography showed a large heterogeneous tissue mass, taking the whole pelvis, coming from the right-side wall of the rectum of 17.3 x 14cm. It was associated with liver and bone secondary locations. Biopsies confirmed the secondary locations of an intermediate risk GIST. Immunohistochemical study showed an overexpression of c-kit protein (CD117) and Dog1. Imatinib was prescribed to reduce the tumour size. Stromal metastatic rectal tumours in bone level are extremely rare conditions. The diagnosis is confirmed by histological examination with immune histochemical analysis. The prognosis remains poor in metastatic forms but it has been improved since the introduction of Imatinib.


Assuntos
Neoplasias Ósseas/diagnóstico , Tumores do Estroma Gastrointestinal/diagnóstico , Neoplasias Hepáticas/diagnóstico , Neoplasias Retais/diagnóstico , Adulto , Antineoplásicos/administração & dosagem , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/secundário , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/patologia , Humanos , Mesilato de Imatinib/administração & dosagem , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Masculino , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/patologia , Tomografia Computadorizada por Raios X
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.
N Engl J Med ; 381(2): 121-131, 2019 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-31157964

RESUMO

BACKGROUND: Enzalutamide, an androgen-receptor inhibitor, has been associated with improved overall survival in men with castration-resistant prostate cancer. It is not known whether adding enzalutamide to testosterone suppression, with or without early docetaxel, will improve survival in men with metastatic, hormone-sensitive prostate cancer. METHODS: In this open-label, randomized, phase 3 trial, we assigned patients to receive testosterone suppression plus either open-label enzalutamide or a standard nonsteroidal antiandrogen therapy (standard-care group). The primary end point was overall survival. Secondary end points included progression-free survival as determined by the prostate-specific antigen (PSA) level, clinical progression-free survival, and adverse events. RESULTS: A total of 1125 men underwent randomization; the median follow-up was 34 months. There were 102 deaths in the enzalutamide group and 143 deaths in the standard-care group (hazard ratio, 0.67; 95% confidence interval [CI], 0.52 to 0.86; P = 0.002). Kaplan-Meier estimates of overall survival at 3 years were 80% (based on 94 events) in the enzalutamide group and 72% (based on 130 events) in the standard-care group. Better results with enzalutamide were also seen in PSA progression-free survival (174 and 333 events, respectively; hazard ratio, 0.39; P<0.001) and in clinical progression-free survival (167 and 320 events, respectively; hazard ratio, 0.40; P<0.001). Treatment discontinuation due to adverse events was more frequent in the enzalutamide group than in the standard-care group (33 events and 14 events, respectively). Fatigue was more common in the enzalutamide group; seizures occurred in 7 patients in the enzalutamide group (1%) and in no patients in the standard-care group. CONCLUSIONS: Enzalutamide was associated with significantly longer progression-free and overall survival than standard care in men with metastatic, hormone-sensitive prostate cancer receiving testosterone suppression. The enzalutamide group had a higher incidence of seizures and other toxic effects, especially among those treated with early docetaxel. (Funded by Astellas Scientific and Medical Affairs and others; ENZAMET (ANZUP 1304) ANZCTR number, ACTRN12614000110684; ClinicalTrials.gov number, NCT02446405; and EU Clinical Trials Register number, 2014-003190-42.).


Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/secundário , Antagonistas de Receptores de Andrógenos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feniltioidantoína/análogos & derivados , Neoplasias da Próstata/tratamento farmacológico , Adenocarcinoma/mortalidade , Idoso , Antagonistas de Receptores de Andrógenos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/secundário , Neoplasias do Sistema Digestório/tratamento farmacológico , Neoplasias do Sistema Digestório/secundário , Fadiga/induzido quimicamente , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Feniltioidantoína/efeitos adversos , Feniltioidantoína/uso terapêutico , Intervalo Livre de Progressão , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia , Convulsões/induzido quimicamente
9.
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
10.
Cancer Immunol Immunother ; 68(7): 1187-1194, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31187176

RESUMO

BACKGROUND: PD-1 inhibition (PD-1i) is the standard of care in melanoma and other malignancies. In patients with bone metastases of solid tumors, the monoclonal antibody denosumab directed against RANKL is approved for the prevention of skeletal-related events. However, RANKL is not only relevant in osteoclastogenesis, but also has immunological effects. Hence, we aimed at investigating, whether the combination of PD-1i and denosumab produces synergistic effects in metastatic melanoma treatment. METHODS: We retrospectively collected and analyzed clinical data of metastatic melanoma patients with bone metastases, who received PD-1i and denosumab therapy. RESULTS: 29 patients were identified with a median age of 60.7 years: 20 were male and 9 were female. 20 patients (69%) were in stage IV M1c and 9 (31%) in stage IV M1d; 52% had an increased serum LDH. 24 patients (83%) received PD-1i as first-line therapy and five patients (17%) as second- or third-line therapy. 13 patients received the triple combination nivolumab, ipilimumab and denosumab (N + I+D), 16 patients received PD-1i and denosumab (PD-1i + D). Within a median follow-up time of 19.8 months, 17 patients progressed with a median time to progression of 6 months. The objective response rate was 54% in the N + I + D group and 50% in the PD-1i + D group. Recalcification of bone metastases was radiologically observed in 18 (62%) patients. No unexpected treatment-related adverse events emerged. CONCLUSIONS: The combination therapy of metastatic melanoma with PD-1i and denosumab was feasible without unexpected safety issues and showed a promising efficacy signal. Further investigation in prospective studies is needed.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Denosumab/uso terapêutico , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Ósseas/imunologia , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/secundário , Denosumab/farmacologia , Feminino , Humanos , Ipilimumab/farmacologia , Ipilimumab/uso terapêutico , Estimativa de Kaplan-Meier , Masculino , Melanoma/imunologia , Melanoma/mortalidade , Melanoma/secundário , Pessoa de Meia-Idade , Nivolumabe/farmacologia , Nivolumabe/uso terapêutico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Intervalo Livre de Progressão , Ligante RANK/antagonistas & inibidores , Ligante RANK/imunologia , Estudos Retrospectivos , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia
11.
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
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.
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
14.
Medicine (Baltimore) ; 98(19): e15546, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31083212

RESUMO

INTRODUCTION: Epithelioid hemangioendothelioma (EHE) of the bone is a very rare malignant vascular neoplasm, with biologic behavior between that of locally aggressive epithelioid hemangioma and malignant epithelioid angiosarcoma. We report a case of a patient with EHE who underwent bone scintigraphy, try to identify the characteristics of it, to highlight the clinical importance of whole-body bone scintigraphy and single-photon emission computed tomography/computed tomography (SPECT/ CT) in the diagnosis and treatment of EHE. PATIENT CONCERNS: A 67-year-old man with no history of trauma who reported pain in both lower limbs for 6 months, which had been worsening over the last 20 days. Anteroposterior and lateral radiographs of both lower limbs revealed numerous osteolytic lesions in the tibia and fibula bilaterally. Tc-methylene diphosphonate (MDP) bone scintigraphy demonstrated increased tracer uptake in the pelvic and bilateral lower limb bones. SPECT/CT bone imaging showed numerous osteolytic lesions cluster in the same anatomic region, with high tracer uptake in lesion margins. DIAGNOSIS: EHE of the bone. INTERVENTIONS: Two months after the diagnosis was confirmed, the patient was rehospitalized. Nonopioid analgesic use had not provided pain relief. Magnetic resonance imaging (MRI) of both thighs showed the bone cortex was destroyed with numerous irregular lesions, and soft-tissue was involved. A second bone scintigraphy did not show any new lesions. He was administrated with recombination human endostatin injection 15 mg ivgtt qd for 14 days, combined with apatinib mesylate tablets 500 mg po qd for 18 days. OUTCOMES: He was discharged voluntarily and died 2 months later. CONCLUSION: EHE of the bone is a very rare malignant vascular neoplasm with no specific radiographic imaging features. Whole-body bone scintigraphy, especially SPECT/CT bone imaging, significantly reduces ambiguous diagnoses and is recommended before treatment.


Assuntos
Neoplasias Ósseas/diagnóstico por imagem , Hemangioendotelioma Epitelioide/diagnóstico por imagem , Idoso , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/patologia , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/patologia , Diagnóstico Diferencial , Evolução Fatal , Hemangioendotelioma Epitelioide/tratamento farmacológico , Hemangioendotelioma Epitelioide/patologia , Humanos , Imagem por Ressonância Magnética , Masculino , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único , Imagem Corporal Total
15.
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
16.
Cancer Treat Rev ; 76: 57-67, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31136850

RESUMO

Patients with solid tumours are at risk of impaired bone health from metastases and cancer therapy-induced bone loss (CTIBL). We review medical management of bone health in patients with solid tumours over the past 30 years, from first-generation bisphosphonates to the receptor activator of nuclear factor κB ligand (RANKL)-targeted monoclonal antibody, denosumab. In the 1980s, first-generation bisphosphonates were shown to reduce the incidence of skeletal-related events (SREs) in patients with breast cancer. Subsequently, more potent second- and third-generation bisphosphonates were developed, particularly zoledronic acid (ZA). Head-to-head studies showed that ZA was significantly more effective than pamidronate for reducing SREs in patients with breast and castrate-resistant prostate cancer (CRPC), becoming the standard of care for more than a decade. The RANKL inhibitor denosumab was licensed in 2010, and head-to-head studies and integrated analyses confirmed its superiority to ZA for preventing SREs, particularly in breast cancer and CRPC. Bisphosphonates and denosumab have also been investigated for prevention of CTIBL in patients receiving hormonal therapy for breast and prostate cancer, and denosumab is licensed in this indication. Despite advances in management of bone health, several issues remain, notably the optimal time to initiate therapy, duration of therapy, and dosing frequency, and how to avoid toxicity, particularly with long-term treatment. In summary, introduction of ZA and denosumab has protected patients with bone metastasis from serious bone complications and improved their quality of life. Ongoing research will hopefully guide the optimal use of these agents to help maintain bone health in patients with solid tumours.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/secundário , Difosfonatos/uso terapêutico , Animais , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/etiologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Denosumab/uso terapêutico , Feminino , Humanos , Masculino , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Ácido Zoledrônico/uso terapêutico
17.
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
18.
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
19.
Indian J Pathol Microbiol ; 62(2): 199-205, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30971540

RESUMO

Small round cell lesions of the bone encompass a heterogeneous group of tumors and tumor-like lesions, including Ewing sarcoma, small cell osteosarcoma, mesenchymal chondrosarcoma, neuroblastoma, non-Hodgkin's lymphoma (NHL), "Ewing-like" undifferentiated round cell sarcomas, metastasizing small cell carcinoma, along with plasma cell dyscrasia and Langerhan's cell histiocytosis. At the same time, there are tumor mimics, for example, chronic osteomyelitis, which has overlapping radiologic features with Ewing sarcoma and a primary intraosseous NHL. An exact diagnosis necessitates integration of clinical, radiologic, pathologic, and ancillary test results, including immunohistochemical and molecular results. Currently, there are several immunohistochemical markers and specific molecular signatures, driving most of these tumors, available, for an exact diagnosis. This review focuses on a pragmatic approach towards uncovering specific small round cell lesions of the bone, emphasizing upon integration of traditional morphology with ancillary techniques, including immunohistochemical markers and molecular techniques, the latter, especially in cases of Ewing sarcoma, Ewing-like undifferentiated round cell sarcoma, mesenchymal chondrosarcoma, and neuroblastoma. Subsequent to the diagnostic approach, including an impact on treatment, individual intraosseous round cell lesions have been described in detail. The references include updated articles from PUBMED.


Assuntos
Doenças Ósseas/diagnóstico , Doenças Ósseas/tratamento farmacológico , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/tratamento farmacológico , Osso e Ossos/patologia , Biomarcadores Tumorais , Doenças Ósseas/genética , Carcinoma de Células Pequenas/diagnóstico , Carcinoma de Células Pequenas/tratamento farmacológico , Citogenética , Diagnóstico Diferencial , Humanos , Sarcoma de Ewing/diagnóstico , Sarcoma de Ewing/patologia
20.
Dev Period Med ; 23(1): 39-44, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30954980

RESUMO

OBJECTIVE: Background: Patients with Ewing sarcoma have a dismal outcome. Maintenance treatment with trofosfamide has been proposed as an effective regimen for some paediatric malignancies. Aim: We sought to evaluate the schedule of trofosfamide for patients with high-risk primary bone Ewing sarcoma. PATIENTS AND METHODS: Materials and methods: Fifteen patients with primary bone Ewing sarcoma received treatment with trofosfamide (150 mg/m2 p.o. days 1-10) every 28 days. All patients had standard tumour imaging and laboratory evaluation. All toxicities were documented. RESULTS: Results: A total of 90 cycles (median 5 cycles/patient) were administered. A complete response was maintained in nine patients, while six patients had disease progression during treatment. Median time to progression was 1.9 months (range 1.8 to 4.6). Eleven patients (73.3%) are alive including nine with no evidence of disease with a median follow-up of 3.9 years (range 1.4 to 7.6). All patients with active disease at the start of the trofosfamide treatment died. There were no significant toxicities. CONCLUSION: Conclusions: Treatment with trofosfamide is well-tolerated and could have a role to maintain response in patients with primary bone Ewing sarcoma. Further studies are needed to better define the use of this regimen in the upfront management of those patients.


Assuntos
Neoplasias Ósseas/tratamento farmacológico , Ciclofosfamida/análogos & derivados , Sarcoma de Ewing/tratamento farmacológico , Adolescente , Antineoplásicos Alquilantes/efeitos adversos , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/diagnóstico por imagem , Criança , Pré-Escolar , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Feminino , Humanos , Masculino , Sarcoma de Ewing/diagnóstico , Sarcoma de Ewing/diagnóstico por imagem , Resultado do Tratamento , Adulto Jovem
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