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1.
Zhonghua Zhong Liu Za Zhi ; 42(8): 692-696, 2020 Aug 23.
Artigo em Chinês | MEDLINE | ID: mdl-32867464

RESUMO

Objective: To evaluate the efficacy and safety of polyethylene glycol liposome doxorubicin (PLD) in the treatment of osteosarcoma. Methods: This study was a single-center retrospective clinical study. Two hundreds and seventy-six classical osteosarcoma treated in Beijing Jishuitan Hospital from 2015 to 2016 were enrolled. There were 213 patients who received combined chemotherapy of high dose methotrexate, ifosfamide, cisplatin and doxorubicin (ADM) were classified in ADM group. Other 63 patients received the same types, doses and cycles of chemotherapy drugs except ADM replaced by PLD were identified as PLD group. Clinical and imaging evaluation and surgical treatment were performed after neoadjuvant chemotherapy. Tumor necrosis rate was examined according to Huvos method. The efficacy of neoadjuvant chemotherapy was evaluated based on 90% necrosis rate. The recurrence, metastasis and survival were followed up regularly after operation. The adverse reactions of hematology, hepatorenal toxicity, gastrointestinal reaction and cardiotoxicity were evaluated. Results: There were no significant differences between PLD group and ADM group in age, sex, location, stage and surgical margin (all P>0.05). There were no significant differences in clinical symptoms and imaging evaluation between PLD group and ADM group after preoperative chemotherapy (all P>0.05). The tumor necrosis rate was detected in 134 cases. Among 27 cases of PLD group, tumor necrosis rates more than 90% were 11 cases, while among 107 cases of ADM group, tumor necrosis rates more than 90% were 45 cases. No significant difference of tumor necrosis rate between this two group was observed (P=0.901). The recurrence rates of PLD group and ADM group were 7.8% (4/51) and 7.3% (12/164), the metastasis rates were 19.6% (10/51) and 16.5% (27/164), the median progression free survival (PFS) were 42 and 37 months, respectively, without significant differences (all P>0.05). The incidence of granulocytopenia and decrease degree of granulocytes in PLD group were significantly lower than those in ADM group (P<0.001). There were no significant differences in the incidences of thrombocytopenia, anemia, gastrointestinal reaction, liver function damage and stomatitis between two groups (all P>0.05). Conclusions: PLD and ADM have similar chemotherapeutic effects in osteosarcoma. The incidences of adverse reactions of PLD are lower, especially the hematological toxicity represented by granulocytopenia is significantly reduced. PLD has a better application prospect.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/terapia , Lipossomos/uso terapêutico , Osteossarcoma/tratamento farmacológico , Neoplasias Ósseas/patologia , Cisplatino/administração & dosagem , Doxorrubicina/administração & dosagem , Extremidades , Humanos , Ifosfamida/administração & dosagem , Metotrexato/administração & dosagem , Metotrexato/uso terapêutico , Recidiva Local de Neoplasia , Osteoblastos/efeitos dos fármacos , Osteoblastos/patologia , Osteossarcoma/patologia , Polietilenoglicóis , Prognóstico , Estudos Retrospectivos
2.
Int J Nanomedicine ; 15: 5131-5146, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764941

RESUMO

Background: Gene therapy is considered a novel way to treat osteosarcoma, and microRNAs are potential therapeutic targets for osteosarcoma. miR-214 has been found to promote osteosarcoma aggression and metastasis. Graphene oxide (GO) is widely used for gene delivery for the distinct physiochemical properties and minimal cytotoxicity. Methods: Polyethyleneimine (PEI)-functionalized GO complex was well-prepared and loaded with miR-214 inhibitor at different concentrations. The load efficacy was tested by gel retardation assay and the cy3-labeled fluorescence of cellular uptake. The experiments of wound healing, immunofluorescence staining, Western blot, qRT-PCR and immunohistochemical staining were performed to measure the inhibitory effect of the miR-214 inhibitor systematically released from the complexes against MG63, U2OS cells and xenograft tumors. Results: The systematic mechanistic elucidation of the efficient delivery of the miR-214 inhibitor by GO-PEI indicated that the inhibition of cellular miR-214 caused a decrease in osteosarcoma cell invasion and migration and an increase in apoptosis by targeting phosphatase and tensin homolog (PTEN). The synergistic combination of the GO-PEI-miR-214 inhibitor and CDDP chemotherapy showed significant cell death. In a xenograft mouse model, the GO-PEI-miR-214 inhibitor significantly inhibited tumor volume growth. Conclusion: This study indicates the potential of functionalized GO-PEI as a vehicle for miRNA inhibitor delivery to treat osteosarcoma with low toxicity and miR-214 can be a good target for osteosarcoma therapy.


Assuntos
Grafite/química , MicroRNAs/antagonistas & inibidores , Terapia de Alvo Molecular , Osteossarcoma/tratamento farmacológico , PTEN Fosfo-Hidrolase/metabolismo , Polietilenoimina/química , Polietilenoimina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Neoplasias Ósseas/patologia , Morte Celular/efeitos dos fármacos , Morte Celular/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/genética , Terapia Combinada , Humanos , Camundongos , MicroRNAs/genética , Osteossarcoma/genética , Osteossarcoma/metabolismo , Osteossarcoma/patologia
3.
Anticancer Res ; 40(7): 3743-3749, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620613

RESUMO

BACKGROUND/AIM: The antiproliferative effects of cold atmospheric plasma (CAP) make it a promising application option in oncology. The aim of the present study was to examine whether short-term CAP treatment leads to an initial partial elimination of the treated cells or to long-term impairement and inhibition of cell growth. MATERIALS AND METHODS: Cells were treated with CAP and biostatistical modelling was used to estimate growth rates over the incubation time. Four cell lines (U2-OS and MNNG osteosarcoma cells, 3T3 fibroblasts, HaCaT keratinocytes) and three CAP sources (MiniJet-R, kINPen MED, Maxium) were used. RESULTS: The antiproliferative efficacy of CAP was due to a significant reduction in cell count during treatment and the long-lasting inhibition of growth rate in the remaining cells, detectable in all cell lines and after treatment using all three CAP devices. CONCLUSION: Induction of cell death and inhibition of cell growth are part of a general mechanism of biological CAP efficacy. However, data contradict the hypothesis that cancer cells respond more sensitively to CAP treatment compared to non-malignant cells.


Assuntos
Proliferação de Células/efeitos dos fármacos , Plasmócitos/patologia , Gases em Plasma/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Humanos , Cinética , Osteossarcoma/tratamento farmacológico , Osteossarcoma/patologia , Plasmócitos/efeitos dos fármacos
4.
PLoS One ; 15(7): e0236315, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32706791

RESUMO

The natural product nobiletin is a small molecule, widely studied with regard to its therapeutic effects, including in cancer cell lines and tumors. Recently, nobiletin has also been shown to affect circadian rhythms via their enhancement, resulting in protection against metabolic syndrome. We hypothesized that nobiletin's anti-oncogenic effects, such as prevention of cell migration and formation of anchorage independent colonies, are correspondingly accompanied by modulation of circadian rhythms. Concurrently, we wished to determine whether the circadian and anti-oncogenic effects of nobiletin differed across cancer cell lines. In this study, we assessed nobiletin's circadian and therapeutic characteristics to ascertain whether these effects depend on cell line, which here also varied in terms of baseline circadian rhythmicity. Three cell culture models where nobiletin's effects on cell proliferation and migration have been studied previously were evaluated: U2OS (bone osteosarcoma), which possesses robust circadian rhythms; MCF7 (breast adenocarcinoma), which has weak circadian rhythms; and MDA-MB-231 (breast adenocarcinoma), which is arrhythmic. We found that circadian, migration, and proliferative effects following nobiletin treatment were subtle in the U2OS and MCF7 cells. On the other hand, changes were clear in MDA-MB-231s, where nobiletin rescued rhythmicity and substantially reduced oncogenic features, specifically two-dimensional cell motility and anchorage-independent growth. Based on these results and those previously described, we posit that the effects of nobiletin are indeed cell-type dependent, and that a positive correlation may exist between nobiletin's circadian and therapeutic effects.


Assuntos
Antineoplásicos Fitogênicos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ritmo Circadiano/efeitos dos fármacos , Flavonas , Adenocarcinoma/tratamento farmacológico , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Flavonas/farmacologia , Flavonas/uso terapêutico , Humanos , Osteossarcoma/tratamento farmacológico
5.
Life Sci ; 256: 118011, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32592723

RESUMO

Melatonin is recognized as an anti-angiogenic agent, but its function in the tumor microenvironment especially in osteosarcoma remains uncertain. Among the selected miRNAs, miR-205, miR-424, miR-140, miR-106, and miR-519 were upregulated by melatonin in osteosarcoma cells. The functional role of miR-424-5p in osteosarcoma was further analyzed using miR-424-5p mimic/inhibitor. VEGFA mRNA and protein expression were altered by miR-424-5p mimic/inhibitor transfection with and without melatonin treatment and it was further identified that the VEGFA 3'UTR is directly targeted by miR-424-5p using the luciferase reporter gene system. The conditioned medium from SaOS2 and MG63 cells treated with melatonin and/or transfected with miR-424-5p mimic/inhibitor was exposed to endothelial cells, and cell proliferation and migration was analyzed. MG-63 and SaOS2 cells are also transfected with miR-424-5p inhibitors and positioned on CAM vascular bed to study the angiogenic activity at both morphological and molecular level under melatonin treatment. Our observations demonstrate for the first time that, melatonin upregulated the expression of miR-424-5p in osteosarcoma inhibiting VEGFA. Furthermore, it suppresses tumor angiogenesis, modulating surrounding endothelial cell proliferation and migration as well as the morphology of blood vessels, and angiogenic growth factors. These findings suggest that melatonin could play a pivotal role in tumor suppression via miR-424-5p/VEGFA axis.


Assuntos
Inibidores da Angiogênese/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Melatonina/farmacologia , Osteossarcoma/tratamento farmacológico , Animais , Neoplasias Ósseas/irrigação sanguínea , Linhagem Celular Tumoral , Galinhas , Gema de Ovo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Humanos , MicroRNAs/genética , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/patologia , Osteossarcoma/irrigação sanguínea , RNA Mensageiro/genética , Transdução de Sinais/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
6.
Adv Exp Med Biol ; 1257: 1-10, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32483726

RESUMO

Osteosarcoma was initially resistant to chemotherapy that worked for Ewing sarcoma and rhabdomyosarcoma as well as other chemotherapeutic agents available in the 1960s. In the early 1970s, responses of osteosarcoma to adriamycin were reported, and at about the same time, so were responses of osteosarcoma to high-dose methotrexate. These agents were introduced into adjuvant therapy due to the dire prognosis associated with apparently localized osteosarcoma. After initial questions regarding the role of chemotherapy delayed its uniform acceptance, there is now general agreement that chemotherapy is primarily responsible for the cure of patients with osteosarcoma when combined with surgical elimination of the primary tumor. Advances with combination chemotherapy later adding cisplatin and ifosfamide have improved ultimate survival. The history of the development of effective chemotherapy combinations at Memorial Sloan Kettering Cancer Center, UT MD Anderson Cancer Center, and the Rizzoli Institute are highlighted, and recent large cooperative group studies are reviewed in the context of those findings.


Assuntos
Neoplasias Ósseas , Quimioterapia Adjuvante , Terapia Neoadjuvante , Osteossarcoma , Protocolos de Quimioterapia Combinada Antineoplásica/história , Quimioterapia Adjuvante/história , História do Século XX , História do Século XXI , Humanos , Osteossarcoma/tratamento farmacológico
7.
Adv Exp Med Biol ; 1257: 45-53, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32483729

RESUMO

Although trace amounts of radioactivity are routinely used to detect osteosarcoma, the use of larger therapeutic amounts of radiation is often an unrecognized opportunity to treat metastatic osteosarcoma. This chapter will review a number of approaches to use ionizing radiation in the form of injectable radiopharmaceuticals. Since bone metastases are a common pattern of metastatic spread of cancer in general, a number of bone-seeking radiopharmaceuticals have been developed and FDA approved for treatment of bone metastases. Although osteosarcoma, a bone-forming cancer, would seem ideally suited to be treated with bone seekers, patterns of relapse involving non-ossifying metastases remain a major problem to be overcome. Thus, this review will not only describe experience using a number of bone-seeking radiopharmaceuticals such as 153-samarium-EDTMP, 153-samarium-DOTMP, and 223-radium against osteosarcoma, but also approaches to identify patients who may benefit as well as some means to the improve overall efficacy including combination therapy with routine agents and using nuclear imaging to develop best strategy for use. These include imaging with not only 99mTc-MDP standard bone scans, but also 99mTc-MDP bone scans with SPECT CT, bone-specific sodium fluoride PET-CT (Na18F), and 18FDG-PET-CT. Accurate knowledge of oligometastatic active disease can facilitate more effective use of combination therapy, including radiosensitizers and local control measures, for example, stereotactic body radiotherapy (SBRT) and/or cryoablation to reduce disease burden as well as manage and prevent micrometastatic disease from growing and metastasizing. Finally, a new tumor-specific radiopharmaceutical, CLR 131, may also provide another radiopharmaceutical to treat both osteoblastic and non-ossifying areas of osteosarcoma.


Assuntos
Antineoplásicos , Neoplasias Ósseas , Osteossarcoma , Compostos Radiofarmacêuticos , Antineoplásicos/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/radioterapia , Humanos , Recidiva Local de Neoplasia , Osteossarcoma/tratamento farmacológico , Osteossarcoma/radioterapia , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/uso terapêutico
8.
Adv Exp Med Biol ; 1257: 55-66, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32483730

RESUMO

In this chapter, we will review studies of HER2 in osteosarcoma and discuss the controversies that have existed in this field. Our present understanding of HER2 in the context of osteosarcoma is that it is expressed on a subset of patient samples, but that expression is not prognostic. We will review the two trials that have been conducted in osteosarcoma which have targeted HER2. Use of an antibody, trastuzumab, did not suggest activity, but a smaller study using HER2-targeted CAR T cells suggested activity may be present. A trial of an antibody-drug conjugate targeting HER2 for recurrent osteosarcoma is under consideration. Trials targeting other surface proteins for the treatment of osteosarcoma have occurred or are in development. Indeed, this leads us to discuss in a broader fashion therapeutic approaches to targeting surface proteins. It is hoped that some of these approaches will lead to new effective therapies for patients with osteosarcoma.


Assuntos
Neoplasias Ósseas , Osteossarcoma , Receptor ErbB-2 , Antineoplásicos/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Humanos , Recidiva Local de Neoplasia , Osteossarcoma/tratamento farmacológico , Receptor ErbB-2/metabolismo , Trastuzumab/uso terapêutico
9.
Adv Exp Med Biol ; 1257: 67-73, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32483731

RESUMO

Inhalation therapy remains a suitable approach to treat lung diseases including cancer. This approach has been used to deliver various therapies including chemotherapy. The rationale for using the inhalation route vs. the systemic route has been the fewer side effects encountered when drugs are administered via inhalation. Furthermore, this approach overcomes one of the major limitations of systemic chemotherapy that results from inability of the drug to reach high concentrations in the lungs. Local delivery overcomes this limitation and spares exposure of vital organs to the drug, resulting in a more effective delivery system.Pulmonary metastasis of osteosarcoma (OS) remains a major cause of death and is very difficult to treat. Using various OS mouse models, we demonstrated that aerosol chemotherapy causes regression of pulmonary metastases and improves survival of mice with OS. In these studies, we used gemcitabine, a nucleoside analog that is effective against various solid tumors. An initial phase I study done in Europe in patients with primary lung cancer demonstrated aerosol gemcitabine therapy to be feasible and safe. In this chapter, we describe different chemotherapeutic agents delivered by inhalation to treat lung diseases with an emphasis on an ongoing study of aerosolized gemcitabine for patients with solid tumors and lung metastases developed at the MD Anderson Cancer Center that uses a convenient approach to track patient lung health with the ultimate goal of implementing this therapy at home.


Assuntos
Antineoplásicos , Neoplasias Ósseas , Neoplasias Pulmonares , Osteossarcoma , Administração por Inalação , Animais , Antineoplásicos/administração & dosagem , Neoplasias Ósseas/tratamento farmacológico , Modelos Animais de Doenças , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Camundongos , Osteossarcoma/tratamento farmacológico
10.
Adv Exp Med Biol ; 1257: 75-83, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32483732

RESUMO

The prognosis for metastatic osteosarcoma (OS) is poor and has not changed in several decades. Therapeutic paradigms that target and exploit novel molecular pathways are desperately needed. Recent preclinical data suggests that modulation of the Fas/FasL pathway may offer benefit in the treatment of refractory osteosarcoma. Fas and FasL are complimentary receptor-ligand proteins. Fas is expressed in multiple tissues, whereas FasL is restricted to privilege organs, such as the lung. Fas expression has been shown to inversely correlate with the metastatic potential of OS cells; tumor cells which express high levels of Fas have decreased metastatic potential and the ones that reach the lung undergo cell death upon interaction with constitutive FasL in the lung. Agents such as gemcitabine and the HDAC inhibitor, entinostat/Syndax 275, have been shown to upregulate Fas expression on OS cells, potentially leading to decreased OS pulmonary metastasis and improved outcome. Clinical trials are in development to evaluate this combination as a potential treatment option for patients with refractory OS.


Assuntos
Benzamidas , Neoplasias Ósseas , Osteossarcoma , Piridinas , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/enzimologia , Proteína Ligante Fas/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Osteossarcoma/tratamento farmacológico , Osteossarcoma/enzimologia , Piridinas/farmacologia , Piridinas/uso terapêutico
11.
Adv Exp Med Biol ; 1257: 85-94, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32483733

RESUMO

Osteosarcoma relapses not only herald a very poor prognosis but also opportunities to treat this genetically diverse complex cancer in new ways. This review will attempt to show that the field is a rapidly evolving one in which not only cytotoxic agents but also local control strategies and the immune system can be harnessed to improve the prognosis of relapsed patients. The molecular heterogeneity and the difficulty of effectively treating most common patterns of relapse with surgery and/or radiation (lung and/or bone metastases) have been responsible for a wide variety of approaches to learning whether agents are active against osteosarcoma. This chapter will highlight past, current, and potential future approaches to provide more effective systemic therapy for the problem of recurrent metastases of osteosarcoma. These include single-agent trials with a wide variety of agents, radiopharmaceuticals, and immune therapies. Finally, how such efforts are integrated into more effective local control strategies is also discussed.


Assuntos
Neoplasias Ósseas , Osteossarcoma , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/radioterapia , Neoplasias Ósseas/cirurgia , Ensaios Clínicos como Assunto , Humanos , Recidiva Local de Neoplasia , Osteossarcoma/tratamento farmacológico , Osteossarcoma/radioterapia , Osteossarcoma/cirurgia
12.
Adv Exp Med Biol ; 1257: 133-139, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32483736

RESUMO

The recruitment of autologous macrophages to attack osteosarcoma represents a novel immunotherapy approach to the treatment of osteosarcoma. Muramyl tripeptide-phosphatidyl ethanolamine encapsulated in liposomes (L-MTP-PE) was derived as a compound with the ability to stimulate macrophages to destroy autologous osteosarcoma tumor cells. Preclinical studies including studies in dogs with spontaneously arising osteosarcoma showed the ability of L-MTP-PE to control microscopic metastatic disease in osteosarcoma. A pivotal clinical trial led to the approval of L-MTP-PE for the treatment of newly diagnosed osteosarcoma in over 40 countries.


Assuntos
Neoplasias Ósseas , Osteossarcoma , Acetilmuramil-Alanil-Isoglutamina , Animais , Neoplasias Ósseas/tratamento farmacológico , Ensaios Clínicos como Assunto , Cães , Humanos , Fatores Imunológicos/administração & dosagem , Lipossomos/administração & dosagem , Lipossomos/química , Osteossarcoma/tratamento farmacológico , Fosfatidiletanolaminas/administração & dosagem
13.
Adv Exp Med Biol ; 1257: 181-192, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32483740

RESUMO

Doxorubicin is an anthracycline and one of the more effective chemotherapy agents used in the treatment of children, adolescents, and adults with osteosarcoma. Despite its effectiveness, cardiotoxicity is a major late effect that compromises the survival and quality of life of survivors of this and other cancers. Cardiotoxicity is the inability of the heart to pump blood through the body effectively. Doxorubicin-induced cardiotoxicity is dose dependent. Additionally, the age of the patients plays a role in susceptibility with younger patients having a greater risk for cardiotoxicity and heart failure years after treatment is complete. The exact mechanism(s) responsible for doxorubicin-induced cardiotoxicity is poorly understood, and further research needs to be done to elucidate the mechanisms. This chapter summarizes the identified mechanisms that may play a role in anthracycline-induced cardiotoxicity. We will also summarize the types of cardiomyopathies that have been described in survivors treated with doxorubicin and the current recommendations for monitoring survivor for the development of cardiomyopathies. Included will be the important search for defining early biomarkers to identify patients and survivors at risk. Finally, we will summarize some of the interventions proposed for decreasing anthracycline-induced cardiotoxicity.


Assuntos
Antraciclinas , Cardiotoxicidade , Osteossarcoma , Antraciclinas/efeitos adversos , Antibióticos Antineoplásicos/efeitos adversos , Cardiotoxicidade/etiologia , Cardiotoxicidade/prevenção & controle , Humanos , Neoplasias/tratamento farmacológico , Osteossarcoma/tratamento farmacológico , Qualidade de Vida
14.
Bone Joint J ; 102-B(6): 795-803, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32475245

RESUMO

AIMS: To assess the correlation between the histological response to preoperative chemotherapy and event-free survival (EFS) or overall survival (OS) in patients with high-grade localized osteosarcoma. METHODS: Out of 625 patients aged ≤ 40 years treated for primary high-grade osteosarcoma between 1997 and 2016, 232 patients without clinically detectable metastases at the time of diagnosis and treated with preoperative high-dose methotrexate, adriamycin and cisplatin (MAP) chemotherapy and surgery were included. Associations of chemotherapy-induced necrosis in the resected specimen and EFS or OS were assessed using Cox model and the Pearson's correlation coefficients (r). Time-dependent receiver operating characteristic analysis was applied to determine the optimal cut-off value of chemotherapy-induced necrosis for EFS and OS. RESULTS: OS was 74% (95% confidence interval (CI) 67 to 79) at five years. Median chemotherapy-induced necrosis was 85% (interquartile range (IQR) 50% to 97%). In multivariate Cox model, chemotherapy-induced necrosis was significantly associated with EFS and OS (hazard ratio (HR) = 0.99 (95% CI 0.98 to 0.99); p < 0.001 and HR = 0.98 (95% CI 0.97 to 0.99); p < 0.001, respectively). Positive correlation was observed between chemotherapy-induced necrosis and five-year EFS and five-year OS (r = 0.91; p < 0.001, and r = 0.85; p < 0.001, respectively). The optimal cut-off value of chemotherapy-induced necrosis for five-year EFS and five-year OS was 85% and 72%, respectively. CONCLUSION: Chemotherapy-induced necrosis in the resected specimen showed positive correlation with EFS and OS in patients with high-grade localized osteosarcoma after MAP chemotherapy. In our analysis, optimal cut-off values of MAP chemotherapy-induced necrosis in EFS and OS were lower than the commonly used 90%, suggesting the need for re-evaluation of the optimal cut-off value through larger, international collaborative research. Cite this article: Bone Joint J 2020;102-B(6):795-803.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/cirurgia , Cisplatino/administração & dosagem , Doxorrubicina/administração & dosagem , Metotrexato/administração & dosagem , Osteossarcoma/tratamento farmacológico , Osteossarcoma/cirurgia , Adolescente , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/patologia , Criança , Correlação de Dados , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Necrose/induzido quimicamente , Terapia Neoadjuvante , Osteossarcoma/mortalidade , Osteossarcoma/patologia , Período Pré-Operatório , Estudos Retrospectivos , Taxa de Sobrevida , Adulto Jovem
15.
DNA Cell Biol ; 39(7): 1172-1180, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32584170

RESUMO

Osteosarcoma is one of the most common primary malignant tumors of the bone and tends to develop in teenage years. Although multitreatments for the diagnosis and therapy of osteosarcoma have been developed, there are still needs of new methods to prevent and treat the osteosarcoma. Here, we performed bioinformatic analysis to screen for the key genes, molecules, and pathways involved in osteosarcoma survival. Four microarray data sets (GSE99671, GSE87624, GSE65071, and GSE28423), which include data from human bone and osteosarcoma samples, were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed mRNAs and miRNAs were identified. Kyoto Encyclopedia of Genes and Genomes enriched pathways, miRNA-mRNA target, gene/disease relationship, and overall survival was elucidated using related websites and software according to bioinformatic analysis protocols. We found three critical genes miR-29c, blood vessel epicardial substance (BVES), and proteasome 20S subunit beta 2 (PSMB2) through the GEO database and predicting miRNA-mRNA target. Among these genes, BVES and PSMB2 presented a high expression level in osteosarcoma based on GSE99671 and GSE87624 data sets, while miR-29c showed a low expression level in osteosarcoma based on GSE65071 and GSE28423 data sets. Furthermore, we found that the high expression level of miR-29c and BVES associated with better prognosis, while highly expressed PSMB2 associated with poor prognosis. The abnormally expressed mRNAs and miRNAs, which were identified by integrated bioinformatic analysis, provided insights into the molecular mechanisms of osteosarcoma. Notably, we found three critical genes that could be used as novel therapeutic targets for preventing or diagnosing osteosarcoma. Finally, PSMB2 may be the target of miR-29c.


Assuntos
Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/genética , Biologia Computacional , Terapia de Alvo Molecular , Osteossarcoma/tratamento farmacológico , Osteossarcoma/genética , Neoplasias Ósseas/diagnóstico , Bases de Dados Genéticas , Ontologia Genética , Humanos , Osteossarcoma/diagnóstico , Prognóstico , Transcriptoma
16.
Jpn J Clin Oncol ; 50(8): 948-952, 2020 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-32463097

RESUMO

The prognosis of patients with relapsed osteosarcoma is extremely poor and the optimal treatment remains to be identified. Here, we retrospectively analysed the clinical outcomes of nine patients with relapsed osteosarcoma treated with temozolomide/etoposide. Of the two patients who received temozolomide/etoposide as palliative therapy for unresectable tumours, one remained alive with stable disease for >4 years. The remaining seven patients received temozolomide/etoposide as adjuvant therapy following resection of relapsed metastatic disease; of these, one was free from disease for 41 months. Potentially beneficial effects were observed in two of three O6-methylguanine-DNA methyltransferase protein-negative patients, whereas all five O6-methylguanine-DNA methyltransferase-positive patients experienced subsequent relapse. None of the patients experienced severe adverse effects requiring hospitalization. Temozolomide/etoposide is a feasible candidate as salvage therapy for relapsed osteosarcoma. Further studies are needed to verify the utility of O6-methylguanine-DNA methyltransferase protein expression as a biomarker for predicting the response to this treatment.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Etoposídeo/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Osteossarcoma/tratamento farmacológico , Temozolomida/uso terapêutico , Adolescente , Adulto , Antineoplásicos Alquilantes/uso terapêutico , Criança , Feminino , Humanos , Masculino , Prognóstico , Estudos Retrospectivos , Adulto Jovem
17.
J Cancer Res Clin Oncol ; 146(7): 1693-1700, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32333142

RESUMO

PURPOSE: Osteosarcoma is the most common bone tumor, mainly affecting adolescents and young adults, and metastatic disease has poor outcomes with a dismal overall survival. Currently, chemotherapy is the standard of care with limited results, finding that new therapies could improve these outcomes. Preclinical and clinical studies have suggested a possible important role of ErbB pathway aberrations in osteosarcoma etiology. The present study shows the effect of afatinib, an irreversible ErbB family blocker in osteosarcoma cell lines. METHODS: Within a panel of human osteosarcoma cell lines, we addressed cell viability assay using afatinib at increasing concentrations. Motility was measured in wound-healing assays and invasion capacity was assessed in Transwell chamber assays. Finally, to monitor ErbB pathway modulation by afatinib and related compounds, we used Western blot analyses. RESULTS: Cell viability inhibition, as well as a reduction of motility and migration of osteosarcoma cell line were observed after treatment with afatinib. Likewise, in the HOS cell line, afatinib decreased phosphorylation of key components in the ErbB signaling pathway. CONCLUSIONS: Afatinib shows relevant antitumor effect in several osteosarcoma cell lines, as it causes a significant impact on cell viability, motility, and migration with a significant decrease in the activation of ErbB pathway activity.


Assuntos
Afatinib/farmacologia , Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Osteossarcoma/tratamento farmacológico , Osteossarcoma/genética , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
18.
PLoS One ; 15(4): e0231762, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32348319

RESUMO

Canine osteosarcoma (OSA), the most common canine primary bone malignancy, has a highly aggressive biologic behavior. Despite current standard of care therapies, including amputation and adjuvant chemotherapy, most dogs still succumb to metastatic disease. Further investigations into molecular mechanisms and pathways driving OSA are needed to improve therapeutic options. The Hedgehog (HH) cell-signaling pathway has demonstrated involvement in human OSA. Several studies in canine OSA have found changes in expression of some HH pathway genes and demonstrated a role for HH transcription factors. However, the role of this pathway as well as the translational value of its targeting in canine OSA are still undefined. The objectives of this study were to determine the expression of HH components directly in canine OSA tissues and to evaluate the biologic impact of HH signaling inhibition in canine OSA cells. In situ hybridization was used to detect HH family mRNA expression in archived canine OSA tissues and revealed variable expression levels of these mRNAs in canine OSA tissues. The effect of a commercially available Smoothened inhibitor, vismodegib, was studied in established canine OSA cell lines. Alterations in cellular growth as well as assessment of downstream HH targets were evaluated. Although changes in cell growth were noted following Smoothened inhibition, inconsistent decreases in target gene expression were found. While treatment with vismodegib had a negative impact on canine OSA cell growth and viability, the mechanism remains unclear. Further studies are warranted to evaluate the clinical significance of canonical HH signaling in canine OSA.


Assuntos
Anilidas/farmacologia , Neoplasias Ósseas/patologia , Proteínas Hedgehog/metabolismo , Osteossarcoma/patologia , Piridinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Anilidas/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/veterinária , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cães , Perfilação da Expressão Gênica , Proteínas Hedgehog/genética , Osteossarcoma/tratamento farmacológico , Osteossarcoma/veterinária , Piridinas/uso terapêutico , RNA Mensageiro/isolamento & purificação , RNA Mensageiro/metabolismo , Receptor Smoothened/antagonistas & inibidores , Receptor Smoothened/metabolismo
19.
Cancer Sci ; 111(6): 1899-1909, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32232912

RESUMO

Tumor-infiltrating immune cells play a crucial role in tumor progression and response to treatment. However, the limited studies on infiltrating immune cells have shown inconsistent and even controversial results for osteosarcoma (OS). In addition, the dynamic changes of infiltrating immune cells after neoadjuvant chemotherapy are largely unknown. We downloaded the RNA expression matrix and clinical information of 80 OS patients from the TARGET database. CIBERSORT was used to evaluate the proportion of 22 immune cell types in patients based on gene expression data. M2 macrophages were found to be the most abundant immune cell type and were associated with improved survival in OS. Another cohort of pretreated OS samples was evaluated by immunohistochemistry to validate the results from CIBERSORT analysis. Matched biopsy and surgical samples from 27 patients were collected to investigate the dynamic change of immune cells and factors before and after neoadjuvant chemotherapy. Neoadjuvant chemotherapy was associated with increased densities of CD3+ T cells, CD8+ T cells, Ki67 + CD8+ T cells and PD-L1+ immune cells. Moreover, HLA-DR-CD33+ myeloid-derived suppressive cells (MDSC) were decreased after treatment. We determined that the application of chemotherapy may activate the local immune status and convert OS into an immune "hot" tumor. These findings provide rationale for investigating the schedule of immunotherapy treatment in OS patients in future clinical trials.


Assuntos
Neoplasias Ósseas/imunologia , Linfócitos do Interstício Tumoral/imunologia , Osteossarcoma/imunologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Adolescente , Adulto , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/patologia , Quimioterapia Adjuvante/métodos , Criança , Feminino , Humanos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Células Supressoras Mieloides/efeitos dos fármacos , Células Supressoras Mieloides/imunologia , Terapia Neoadjuvante/métodos , Osteossarcoma/tratamento farmacológico , Osteossarcoma/patologia
20.
Nat Commun ; 11(1): 1141, 2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-32111827

RESUMO

Osteosarcoma, an aggressive malignant cancer, has a high lung metastasis rate and lacks therapeutic target. Here, we reported that chromobox homolog 4 (CBX4) was overexpressed in osteosarcoma cell lines and tissues. CBX4 promoted metastasis by transcriptionally up-regulating Runx2 via the recruitment of GCN5 to the Runx2 promoter. The phosphorylation of CBX4 at T437 by casein kinase 1α (CK1α) facilitated its ubiquitination at both K178 and K280 and subsequent degradation by CHIP, and this phosphorylation of CBX4 could be reduced by TNFα. Consistently, CK1α suppressed cell migration and invasion through inhibition of CBX4. There was a reverse correlation between CK1α and CBX4 in osteosarcoma tissues, and CK1α was a valuable marker to predict clinical outcomes in osteosarcoma patients with metastasis. Pyrvinium pamoate (PP) as a selective activator of CK1α could inhibit osteosarcoma metastasis via the CK1α/CBX4 axis. Our findings indicate that targeting the CK1α/CBX4 axis may benefit osteosarcoma patients with metastasis.


Assuntos
Caseína Quinase Ialfa/metabolismo , Ligases/antagonistas & inibidores , Ligases/metabolismo , Osteossarcoma/patologia , Proteínas do Grupo Polycomb/antagonistas & inibidores , Proteínas do Grupo Polycomb/metabolismo , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Caseína Quinase Ialfa/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Ligases/genética , Camundongos , Mutação , Metástase Neoplásica , Osteossarcoma/tratamento farmacológico , Osteossarcoma/genética , Osteossarcoma/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas do Grupo Polycomb/genética , Regiões Promotoras Genéticas , Compostos de Pirvínio/farmacologia , Compostos de Pirvínio/uso terapêutico , Análise de Sobrevida , Fator de Necrose Tumoral alfa/farmacologia , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação/efeitos dos fármacos , Fatores de Transcrição de p300-CBP/metabolismo
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