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1.
Int J Cancer ; 146(2): 510-520, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31173656

RESUMO

Recent data suggest that rhabdomyosarcoma (RMS) cells might be vulnerable to oxidative stress-induced cell death. Here, we show that RMS are susceptible to cell death induced by Erastin, an inhibitor of the glutamate/cystine antiporter xc - that can increase reactive oxygen species (ROS) production via glutathione (GSH) depletion. Prior to cell death, Erastin caused GSH depletion, ROS production and lipid peroxidation. Importantly, pharmacological inhibitors of lipid peroxidation (i.e., Ferrostatin-1, Liproxstatin-1), ROS scavengers (i.e., α-Tocopherol, GSH) and the iron chelator Deferoxamine inhibited ROS accumulation, lipid peroxidation and cell death, consistent with ferroptosis. Interestingly, the broad-spectrum protein kinase C (PKC) inhibitor Bisindolylmaleimide I as well as the PKCα- and ß-selective inhibitor Gö6976 significantly reduced Erastin-induced cell death. Similarly, genetic knockdown of PKCα significantly protected RMS cells from Erastin-induced cell death. Furthermore, the broad-spectrum nicotinamide adenine dinucleotide phosphate-oxidase (NOX) inhibitor Diphenyleneiodonium and the selective NOX1/4 isoform inhibitor GKT137831 significantly decreased Erastin-stimulated ROS, lipid ROS and cell death. These data provide new insights into the molecular mechanisms of ferroptosis in RMS, contributing to the development of new redox-based treatment strategies.


Assuntos
Ferroptose/efeitos dos fármacos , Rabdomiossarcoma/tratamento farmacológico , Apoptose/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cicloexilaminas/metabolismo , Glutationa/metabolismo , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fenilenodiaminas/metabolismo , Piperazinas/metabolismo , Pirazóis/farmacologia , Piridinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Rabdomiossarcoma/metabolismo , alfa-Tocoferol/metabolismo
2.
Cancer Metastasis Rev ; 38(4): 683-694, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31797181

RESUMO

Wilms tumor (or nephroblastoma), rhabdomyosarcoma, and medulloblastoma, common embryonal tumors in children, can occasionally occur in adults, for whom survival is significantly inferior than pediatric patients. Available data on adults with Wilms tumor consist of case or case series reports. Among other factors, the unfamiliarity of adult oncologists and pathologists with nephroblastoma and consequent delays in initiating the appropriate risk-adapted chemotherapy may negatively influence outcomes. The survival decrement in adults with rhabdomyosarcoma has been attributed to the lack of centralized care, the inconsistent use of standard protocol-driven multimodal therapy, and lower chemotherapy tolerance in adult patients. In children with medulloblastoma, evidence from randomized clinical trials has led to risk-tailored therapies tuned on histology, extent of initial disease, and biological features. Such refinements are still missing for adults due to the lack of similar trials and studies that might provide the same or a different understanding regarding patients' individual prognosis, treatment morbidity, and quality of life. Recent experiences have suggested that applying or adjusting pediatric protocols to adult patients with these tumors is feasible and can improve survival. Here, we provide an evaluation of the current evidence for the management of Wilms tumor, rhabdomyosarcoma, and medulloblastoma arising in adults. This review aims to promote the referral of adolescents and adults with pediatric tumors to pediatric centers for inclusion into pediatric protocols, or into protocols and studies specifically designed for that age group with the cooperation between pediatric and adult oncologists.


Assuntos
Neoplasias Cerebelares/diagnóstico , Neoplasias Renais/diagnóstico , Meduloblastoma/diagnóstico , Rabdomiossarcoma/diagnóstico , Tumor de Wilms/diagnóstico , Adulto , Fatores Etários , Neoplasias Cerebelares/tratamento farmacológico , Humanos , Neoplasias Renais/tratamento farmacológico , Meduloblastoma/tratamento farmacológico , Rabdomiossarcoma/tratamento farmacológico , Tumor de Wilms/tratamento farmacológico
3.
Medicine (Baltimore) ; 98(52): e18344, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31876708

RESUMO

BACKGROUND: Approximately 80% to 90% of patients with low-risk rhabdomyosarcoma can be cured. However, cured patients often face long-term complications associated with the treatment. An important factor in the treatment plan is the dose of cyclophosphamide administered because the dose can have both acute and long-term side effects. It is therefore essential to investigate whether the dose can be reduced without a negative effect on treatment outcome. The ARST0331 trial revealed that drastically reducing the cyclophosphamide dose to 4.8 g/m negatively affected treatment outcomes. The current study aims to determine whether reducing the cyclophosphamide dose to 10.8 g/m while introducing a new drug, irinotecan, can prevent the negative effect on treatment outcome. We also aim to investigate whether the reduced cyclophosphamide dose results in a decrease in infertility, one of the long-term complications of this treatment. METHODS: The subjects are patients with stage 1 group III rhabdomyosarcoma (excluding those with orbital group III N0 and NX) or patients with stage 3 group I and II low-risk subset B embryonal rhabdomyosarcoma who will alternately undergo VAC 1.2 treatment (vincristine, actinomycin D, cyclophosphamide 1.2 g/m) and VI treatment (vincristine, irinotecan). The effectiveness and safety of this treatment regimen will be assessed. Data will be presented at international conferences and will be published in peer-reviewed journals. DISCUSSION: This study is significant because it aims to establish that the use of irinotecan in patients with low-risk subset B embryonal rhabdomyosarcoma (aged 30 or younger) allows the dose of cyclophosphamide to be reduced and is associated with few short-term adverse effects and long-term complications. The open-label and single-arm design of this study may be a limitation. TRIAL REGISTRATION AND ETHICAL APPROVAL: The trial registration number is jRCTs051180200 (Japan Registry of Clinical Trials). The study protocol was approved by the institutional review board at each of the participating centers and the data will be presented at international conferences and published in peer-reviewed journals.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/administração & dosagem , Dactinomicina/administração & dosagem , Irinotecano/administração & dosagem , Rabdomiossarcoma/tratamento farmacológico , Vincristina/administração & dosagem , Adulto , Protocolos Clínicos , Ciclofosfamida/uso terapêutico , Dactinomicina/uso terapêutico , Humanos , Irinotecano/uso terapêutico , Estadiamento de Neoplasias , Rabdomiossarcoma/patologia , Resultado do Tratamento , Vincristina/uso terapêutico
4.
Zhonghua Zhong Liu Za Zhi ; 41(11): 873-877, 2019 Nov 23.
Artigo em Chinês | MEDLINE | ID: mdl-31770858

RESUMO

Objective: This study aimed to investigate the clinicopathological characteristics and prognosis of adult rhabdomyosarcoma (RMS) patients. Methods: The clinical data of 34 adult RMS patients were retrospectively analyzed. Based on their intervention and treatment, patients were divided into operation group (n=7), chemotherapy group (n=8) and operation plus chemotherapy group (n=19). The clinical characteristics and treatment outcomes of the three groups were compared. Results: A statically significant difference was found in IRSG surgical-pathological stage among the three groups (P=0.026), while no significant difference existed in gender, age of disease onset, primary site, tumor size, pathological subtypes and IRSG risk group in the three groups (all P>0.05). In the operation group, three CR, one PR, one SD and two PD were achieved and one CR, one PR, one SD and five PD were obtained in the chemotherapy group. While in the chemotherapy plus operation group, four CR, twelve PR, one SD and two PD were achieved. A significant difference was found in response (P=0.043) and median overall survival (OS) (P=0.036) among the three groups, which were 44.7, 26.9 and 53.6 months, respectively. Conclusions: Pleomorphic RMS was the main histological subtype for adult RMS patients, and the prognosis for adult RMS was usually poorer than that for pediatric RMS patients. Single therapeutic approach could not achieve satisfactory outcomes, while multimodal treatment consisted of surgery, chemotherapy and radiotherapy are helpful to improve the prognosis of adult patients with RMS.


Assuntos
Rabdomiossarcoma/tratamento farmacológico , Rabdomiossarcoma/cirurgia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica , Terapia Combinada , Humanos , Prognóstico , Estudos Retrospectivos , Rabdomiossarcoma/classificação , Resultado do Tratamento
5.
BMC Cancer ; 19(1): 945, 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31610788

RESUMO

BACKGROUND: Biliary rhabdomyosarcoma (RMS) is the most common biliary tumor in children. The management of affected patients contains unique challenges because of the rarity of this tumor entity and its critical location at the porta hepatis, which can make achievement of a radical resection very difficult. METHODS: In a retrospective chart analysis we analysed children suffering from biliary RMS who were registered in three different CWS trials (CWS-96, CWS-2002P, and SoTiSaR registry). RESULTS: Seventeen patients (12 female, 5 male) with a median age of 4.3 years were assessed. The median follow-up was 42.2 months (10.7-202.5). The 5-year overall (OS) and event free survival (EFS) rates were 58% (45-71) and 47% (34-50), respectively. Patients > 10 years of age and those with alveolar histology had the worst prognosis (OS 0%). Patients with botryoid histology had an excellent survival (OS 100%) compared to those with non-botryoid histology (OS 38%, 22-54, p = 0.047). Microscopic complete tumor resection was achieved in almost all patients who received initial tumor biopsy followed by chemotherapy and delayed surgery. CONCLUSION: Positive predictive factors for survival of children with biliary RMS are age ≤ 10 years and botryoid tumor histology. Primary surgery with intention of tumor resection should be avoided.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Biliar/tratamento farmacológico , Neoplasias do Sistema Biliar/cirurgia , Rabdomiossarcoma/tratamento farmacológico , Rabdomiossarcoma/cirurgia , Adolescente , Sistema Biliar/patologia , Neoplasias do Sistema Biliar/patologia , Neoplasias do Sistema Biliar/radioterapia , Biópsia , Criança , Pré-Escolar , Terapia Combinada , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Lactente , Estimativa de Kaplan-Meier , Masculino , Complicações Pós-Operatórias , Recidiva , Estudos Retrospectivos , Rabdomiossarcoma/patologia , Rabdomiossarcoma/radioterapia
6.
Gulf J Oncolog ; 1(30): 22-28, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31242978

RESUMO

INTRODUCTION: Paediatric soft tissue sarcoma treatments and outcomes have improved significantly in the last few decades. However, a significant number of patients still succumb to the disease. In low-middle income countries there are dual problems of advanced disease at presentation and financial burden leading to poor compliance to therapy. Hence, we designed a low-cost oral metronomic chemotherapy protocol for these patients and studied the responses and toxicities to therapy in a tertiary referral hospital. PATIENTS AND METHODS: This is retrospective, single institutional, observational study. We retrospectively reviewed data of patients with relapsed, refractory or metastatic soft tissue sarcoma (STS) [ Ewing Sarcoma (ES); Rhabdomyosarcoma (RMS) or other STS] who were treated with the metronomic protocol of oral Tamoxifen, Etoposide and Cyclophosphamide (TEC) during the period April 1998 to September 2013, at the Tata Memorial Hospital, Parel, Mumbai. Patients with ES and RMS were primarily treated on our Institutional protocols. The patients included in the analysis were those who had relapsed after the primary protocols and then treated with metronomic TEC protocol; or those with primary refractory or metastatic disease (RMS, ES) and received metronomic TEC therapy. RESULTS: 49 patients were enrolled. Among the 49 patients, 32 were diagnosed ES, 13 RMS and 4 other STS. For the whole cohort response rates (RR) were 59% and clinical benefit rate (CBR) was 79%. Patients in the study were grouped into the following subgroups. Systemic recurrent/relapsed disease (N=24), metastatic disease at presentation (N=15) and local disease (refractory/recurrent) (N=10). None of the patients required blood or platelet support or admission for supportive care. The PFS for the above groups were 16.8 months, 12.5 months and 126.68 months respectively. This compares favorably with other historical cohorts in a similar setting. CONCLUSIONS: This study provides a preliminary evidence efficacy and tolerability of metronomic chemotherapy in poor risk ES and RMS. It also demonstrates that with this low-cost low risk treatment few patients could go into long term remissions despite high disease burden.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Recidiva Local de Neoplasia/mortalidade , Rabdomiossarcoma/mortalidade , Terapia de Salvação , Sarcoma de Ewing/mortalidade , Sarcoma/mortalidade , Administração Metronômica , Adolescente , Adulto , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/patologia , Criança , Pré-Escolar , Ciclofosfamida/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Seguimentos , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Prognóstico , Estudos Retrospectivos , Rabdomiossarcoma/tratamento farmacológico , Rabdomiossarcoma/secundário , Sarcoma/tratamento farmacológico , Sarcoma/secundário , Sarcoma de Ewing/tratamento farmacológico , Sarcoma de Ewing/secundário , Taxa de Sobrevida , Tamoxifeno/administração & dosagem , Adulto Jovem
7.
Med Oncol ; 36(7): 59, 2019 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-31104202

RESUMO

Rhabdomyosarcoma (RMS) is rare in adults and it is generally characterized by poor outcome. In a previous retrospective study, we demonstrated a better prognosis in adults treated with multimodality approach resembling pediatric protocols. Thereafter, we developed specific recommendations based on the principles adopted in pediatric oncology. The present analysis reports the results in a subsequent prospective series. The study included 95 consecutive patients (age 18-77 years) treated from 2002 to 2015 for embryonal and alveolar RMS. As in the previous series, patients were stratified by the appropriateness of their treatment according to therapeutic guidelines for childhood RMS. The 5-year event-free survival (EFS) and overall survival (OS) rates were 33.6% and 40.3%, respectively. The 5-year EFS was 40.8% for patients with the highest treatment score, and 15% for those with lower score, while OS was 44.4% and 24.5%, respectively. The developing of specific recommendations enabled an increase in the number of patients treated with intensive multimodal treatment resembling pediatric strategy (69.7% vs. 39.1% in the retrospective series). This study reinforced the idea that adherence to the principles of pediatric protocols, improves adult RMS outcomes. However, treating adults with pediatric-type strategy is not enough to achieve the results obtained in children. Issues in compliance and a more aggressive biology of adult RMS might have a role in the different outcome according to age. Improving the collaboration between pediatric and adult oncologists in promoting specific clinical and biological research is crucial to improve the outcome for this patient population.


Assuntos
Rabdomiossarcoma/terapia , Adulto , Fatores Etários , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Combinada , Dactinomicina/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Humanos , Ifosfamida/administração & dosagem , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Rabdomiossarcoma/tratamento farmacológico , Rabdomiossarcoma/radioterapia , Rabdomiossarcoma/cirurgia , Taxa de Sobrevida , Vincristina/administração & dosagem , Adulto Jovem
8.
J Exp Clin Cancer Res ; 38(1): 118, 2019 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-30850026

RESUMO

BACKGROUND: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children with poor survival. New treatment approaches are urgently needed to improve treatment efficacy in RMS patients. DMAMCL is a novel agent from Asteraceae family that has been tested in phase I clinical trials in adult glioma in Australia. METHODS: Five RMS cell lines (RD, RH18, RH28, RH30 and RH41) were used. The in vitro anti-tumor effect of DMAMCL, alone or in combination with VCR or Epirubicin, was studied using MTS assay or IncuCyte-Zoom cell confluency assay, and further validated by xenograft-mouse model in vivo. Changes in caspase-3/7 activity, cell-cycle progression and generation of ROS after DMAMCL treatment were investigated. Bim mRNA expression was measured by RT-qPCR, and protein expressions of Bim and phosphorylated-NF-κB(p65) by Western blotting. Small interfering RNAs (siRNA) of Bim were used to study the role of Bim in DMAMCL-induced cell death. RESULTS: In vitro, DMAMCL treatment induced a dose-dependent increase in cell death that could be blocked by pan-caspase-inhibitor-Z-VAD-fmk in five RMS cell lines. The percent of cells in SubG1 phase and activities of caspase-3/7 increased after DMAMCL treatment; The combination of DMAMCL with VCR or Epirubicin significantly increased cell death compared to each reagent alone. In vivo, DMAMCL(75 mg/kg or 100 mg/kg) inhibited tumor growth and prolonged survival of mice bearing xenograft RMS tumors (RD, RH18, RH30, RH41). Compared to treatment with DMAMCL or VCR, a combination of two reagents caused significant inhibition of tumor growth (RD, RH41), even after treatment termination. The expression of Bim increased at protein level after DMAMCL treatment both in vitro and in vivo. The expression of p-NF-κB(p65) had a transient increase and the generation of ROS increased after DMAMCL treatment in vitro. Transfection of Bim siRNA into RMS cells blocked the DMAMCL-induced increase of Bim and partially attenuated the DMAMCL-induced cell death. CONCLUSION: DMAMCL had an anti-tumor growth effect in vitro and in vivo that potentially mediated by Bim, NF-κB pathway and ROS. A combination of DMAMCL with chemotherapeutic drugs significantly increased the treatment efficacy. Our study supports further clinical evaluation of DMAMCL in combination with conventional chemotherapy.


Assuntos
Proliferação de Células/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Rabdomiossarcoma/tratamento farmacológico , Sesquiterpenos de Guaiano/administração & dosagem , Adulto , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Criança , Pré-Escolar , Humanos , Camundongos , Rabdomiossarcoma/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Gen Thorac Cardiovasc Surg ; 67(12): 1089-1092, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30806970

RESUMO

Rhabdomyosarcoma is a well-known neoplasm in children that frequently occurs in the extremities, the head and neck region, and the genitourinary tract. To the best of our knowledge, pulmonary primary rhabdomyosarcoma in adults is exceedingly rare, and few resected cases have been reported. We report a case of pulmonary primary rhabdomyosarcoma that was surgically resected then treated with adjuvant chemotherapy (vincristine, actinomycin-D and cyclophosphamide). At 9 months after surgery, the patient is free from disease. Although the prognosis of rhabdomyosarcoma is unfavorable, surgical resection and adjuvant therapy could be a potential treatment strategy for pulmonary primary rhabdomyosarcoma.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Pulmonares/diagnóstico , Rabdomiossarcoma/diagnóstico , Idoso , Terapia Combinada , Ciclofosfamida/administração & dosagem , Dactinomicina/administração & dosagem , Diagnóstico Diferencial , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/cirurgia , Rabdomiossarcoma/diagnóstico por imagem , Rabdomiossarcoma/tratamento farmacológico , Rabdomiossarcoma/cirurgia , Tomografia Computadorizada por Raios X , Vincristina/administração & dosagem
10.
BMC Cancer ; 19(1): 126, 2019 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-30732578

RESUMO

BACKGROUND: Insulin-like Growth Factor Receptor-1 (IGF1R) system sustains the genesis of rhabdomyosarcoma through IGF2 autocrine overexpression. While several IGF1R-targeted strategies have been investigated to interphere with rhabdomyosarcoma growth, no attempt to neutralize IGF2 has been reported. We therefore studied the possibility to hamper rhabdomyosarcoma growth with passive and active immune approaches targeting IGF2. METHODS: A murine model developing IGF2-overexpressing pelvic rhabdomyosarcoma, along with IGF2-independent salivary carcinoma, was used to investigate the efficacy and specificity of passive anti-IGFs antibody treatment. Active vaccinations with electroporated DNA plasmids encoding murine or human IGF2 were performed to elicit autochthonous anti-IGF2 antibodies. Vaccinated mice received the intravenous injection of rhabdomyosarcoma cells to study the effects of anti-IGF2 antibodies against developing metastases. RESULTS: Passive administration of antibodies neutralizing IGFs delayed the onset of IGF2-overexpressing rhabdomyosarcoma but not of IGF2-independent salivary carcinoma. A DNA vaccine against murine IGF2 did not elicit antibodies, even when combined with Treg-depletion, while a DNA vaccine encoding the human IGF2 gene elicited antibodies crossreacting with murine IGF2. Mice with anti-IGF2 antibodies were partially protected against the metastatic growth of IGF2-addicted rhabdomyosarcoma cells. CONCLUSIONS: Immune targeting of autocrine IGF2 inhibited rhabdomyosarcoma genesis and metastatic growth.


Assuntos
Comunicação Autócrina , Imunomodulação , Fator de Crescimento Insulin-Like II/metabolismo , Rabdomiossarcoma/imunologia , Rabdomiossarcoma/metabolismo , Animais , Animais Geneticamente Modificados , Anticorpos Monoclonais/farmacologia , Antineoplásicos Imunológicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Feminino , Humanos , Fator de Crescimento Insulin-Like II/antagonistas & inibidores , Fator de Crescimento Insulin-Like II/genética , Masculino , Camundongos , Ratos , Rabdomiossarcoma/tratamento farmacológico , Rabdomiossarcoma/patologia , Resultado do Tratamento
11.
Mol Cancer Res ; 17(3): 794-805, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30610105

RESUMO

Methyl 2-trifluoromethyl-3,11-dioxo-18ß-olean-1,12-dien-3-oate (CF3DODA-Me) is derived synthetically from glycyrrhetinic acid, a major component of licorice, and this compound induced reactive oxygen species (ROS) in RD and Rh30 rhabdomyosarcoma (RMS) cells. CF3DODA-Me also inhibited growth and invasion and induced apoptosis in RMS cells, and these responses were attenuated after cotreatment with the antioxidant glutathione, demonstrating the effective anticancer activity of ROS in RMS. CF3DODA-Me also downregulated expression of specificity protein (Sp) transcription factors Sp1, Sp3, and Sp4 and prooncogenic Sp-regulated genes including PAX3-FOXO1 (in Rh30 cells). The mechanism of CF3DODA-Me-induced Sp-downregulation involved ROS-dependent repression of c-Myc and cMyc-regulated miR-27a and miR-17/20a, and this resulted in induction of the miRNA-regulated Sp repressors ZBTB4, ZBTB10, and ZBTB34. The cell and tumor growth effects of CF3DODA-Me further emphasize the sensitivity of RMS cells to ROS inducers and their potential clinical applications for treating this deadly disease. IMPLICATIONS: CF3DODA-Me and HDAC inhibitors that induce ROS-dependent Sp downregulation could be developed for clinical applications in treating rhabdomyosarcoma.


Assuntos
Espécies Reativas de Oxigênio/metabolismo , Rabdomiossarcoma/tratamento farmacológico , Fatores de Transcrição Sp/genética , Triterpenos/uso terapêutico , Animais , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Humanos , Camundongos , Camundongos Nus , Rabdomiossarcoma/patologia , Transfecção , Triterpenos/farmacologia
12.
Cancer ; 125(2): 290-297, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30351457

RESUMO

BACKGROUND: The outcome for patients with metastatic rhabdomyosarcoma (RMS) remains poor. A previous Children's Oncology Group (COG) study (ARST0431) for patients with metastatic RMS produced no improvement in outcome using multiple cytotoxic agents in a dose-intensive manner. The authors report results from the subsequent COG study (ARST08P1), which evaluated the feasibility and efficacy of adding cixutumumab (insulin-like growth factor-1 monoclonal antibody) or temozolomide to the ARST0431 intensive chemotherapy backbone. METHODS: Two nonrandomized pilot studies were conducted in patients with metastatic RMS, initially to determine feasibility, and both pilots were expanded to assess efficacy. All patients received 54 weeks of chemotherapy, including vincristine/irinotecan, interval-compressed vincristine/doxorubicin/cyclophosphamide alternating with ifosfamide/etoposide, and vincristine/dactinomycin/cyclophosphamide. In pilot 1, patients received intravenous cixutumumab (3, 6, or 9 mg/kg) once weekly throughout therapy. In pilot 2, patients received oral temozolomide (100 mg/m2 ) daily for 5 days with irinotecan. All patients received radiation to the primary tumor and to metastatic sites. RESULTS: One hundred sixty-eight eligible patients were enrolled (97 on pilot 1 and 71 on pilot 2). Most patients were aged ≥10 years (73%), with alveolar histology (70%), and had bone and/or bone marrow metastases (59%). Toxicities observed in each pilot were similar to those reported on ARST0431. With a median follow-up of 2.9 years, the 3-year event-free survival rate was 16% (95% confidence interval, 7%-25%) with cixutumumab and 18% (95% confidence interval, 2%-35%) with temozolomide. CONCLUSIONS: The addition of cixutumumab or temozolomide to intensive multiagent chemotherapy for metastatic RMS was safe and feasible. Neither agent improved outcome compared with the same chemotherapy that was used on ARST0431.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Rabdomiossarcoma/tratamento farmacológico , Adolescente , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Projetos Piloto , Rabdomiossarcoma/mortalidade , Rabdomiossarcoma/patologia , Taxa de Sobrevida , Temozolomida/administração & dosagem , Resultado do Tratamento
13.
Cancer Lett ; 442: 341-350, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30447254

RESUMO

Overactivation of the Hedgehog (HH) signaling pathway is implicated in many cancers. In this study, we demonstrate that the small molecule RITA, a p53 activator, effectively downregulates HH signaling in human medulloblastoma and rhabdomyosarcoma cells irrespective of p53. This is mediated by a ROS-independent activation of the MAP kinase JNK. We also show that in vitro RITA sensitized cells to the GLI antagonist GANT61, as co-administration of the two drugs had more pronounced effects on cell proliferation and apoptosis. In vivo administration of RITA or GANT61 suppressed rhabdomyosarcoma xenograft growth in nude mice; however, co-administration did not further enhance tumor suppression, even though cell proliferation was decreased. RITA was more potent than GANT61 in downregulating HH target gene expression; surprisingly, this suppressive effect was almost completely eliminated when the two drugs were administered together. Notably, RNA-seq demonstrated a broader response of pathways involved in cancer cell growth in the combination treatment, providing a plausible interpretation for tumor reduction in the absence of HH signaling downregulation.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Cerebelares/tratamento farmacológico , Furanos/farmacologia , Proteínas Hedgehog/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Meduloblastoma/tratamento farmacológico , Rabdomiossarcoma/tratamento farmacológico , Proteína Supressora de Tumor p53/metabolismo , Proteína GLI1 em Dedos de Zinco/metabolismo , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias Cerebelares/enzimologia , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/patologia , Feminino , Proteínas Hedgehog/genética , Humanos , Meduloblastoma/enzimologia , Meduloblastoma/genética , Meduloblastoma/patologia , Camundongos Nus , Piridinas/farmacologia , Pirimidinas/farmacologia , Rabdomiossarcoma/enzimologia , Rabdomiossarcoma/genética , Rabdomiossarcoma/patologia , Transdução de Sinais/efeitos dos fármacos , Carga Tumoral/efeitos dos fármacos , Proteína Supressora de Tumor p53/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína GLI1 em Dedos de Zinco/análise , Proteína GLI1 em Dedos de Zinco/genética
14.
J Craniofac Surg ; 30(2): e113-e116, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30550438

RESUMO

OBJECTIVE: The aim of the study was to explore an optimal surgery way for head and neck rhabdomyosarcoma (HNRMS) children who have failed primary chemotherapy. METHODS: A total of 51 HNRMS children who have failed primary chemotherapy were retrospectively analyzed from April 2005 to May 2017. Surgery was performed in 2 ways, widely radical resection (22 patients) and conservative resection (29 patients). Multivariate analysis was performed to identify the various variables related to overall survival (OS). RESULTS: The estimated 5-year OS was 53%. Embryonic RMS enjoyed a favorable outcome than those nonembryonic RMS (P = 0.03). Head and neck rhabdomyosarcoma children who received partial remission (PR) after primary chemotherapy enjoyed a better outcome than those only achieved stable disease (SD) (P = 0.006). A total of 22 children accepted widely radical resection, whereas 29 patients got conservative resection. Interestingly, the 2 groups did not have a statistical significance (P = 0.86). However, the latter group children have conserved more important organs, such as eyeball, facial nerves, and enough mandible or maxilla bones, and have enjoyed a better life quality. CONCLUSION: Primary chemotherapy is most important for HNRMS children, which influences the prognosis of HNRMS widely. Conservative resection is an optimal surgery way for HNRMS, bringing a better life quality for these children.


Assuntos
Dissecação , Neoplasias de Cabeça e Pescoço , Quimioterapia de Indução/métodos , Complicações Pós-Operatórias , Qualidade de Vida , Rabdomiossarcoma , Adolescente , Criança , Pré-Escolar , China/epidemiologia , Dissecação/efeitos adversos , Dissecação/métodos , Feminino , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/cirurgia , Humanos , Masculino , Análise Multivariada , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/psicologia , Prognóstico , Indução de Remissão/métodos , Estudos Retrospectivos , Rabdomiossarcoma/tratamento farmacológico , Rabdomiossarcoma/mortalidade , Rabdomiossarcoma/patologia , Rabdomiossarcoma/cirurgia , Análise de Sobrevida
15.
Oncol Rep ; 41(1): 643-649, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30365145

RESUMO

Rhabdomyosarcoma (RMS) is an aggressive pediatric cancer of musculoskeletal origin. Despite multidisciplinary approaches, such as surgical resection, irradiation, and intensive chemotherapy, adopted for its treatment, the prognosis of patients with high­risk RMS remains poor. Thus, molecularly targeted therapies are required to improve patient survival and minimize side effects. Histone deacetylases (HDACs) modify transcription by deacetylation of the lysine residues in chromatin histone tails and several non­histone proteins. HDAC inhibitors, classes of compounds targeted to various HDAC proteins, are being studied for their roles in several types of cancers in a rigorous manner. This study aimed to investigate the potential of a novel HDAC inhibitor, OBP­801, as a therapeutic agent for the treatment of RMS. We used 8 RMS cell lines in this study. Protein expression patterns, cell proliferation, cell cycle status, and apoptosis in RMS cells after OBP­801 treatment in vitro were investigated. We also studied the antitumor activity of OBP­801 in an in vivo xenograft mouse model. We observed cell cycle arrest at the M­phase and apoptosis in all RMS cell lines after exposure to pharmacological levels of OBP­801 for 24 h. Immunofluorescence staining revealed that OBP­801 may induce mitotic catastrophe via chromosome misalignment and reduced survivin expression, ultimately leading to apoptosis. Our results demonstrated that the novel HDAC inhibitor OBP­801 was an effective inhibitor of RMS cell line proliferation and may be a potent therapeutic option for RMS.


Assuntos
Apoptose/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Rabdomiossarcoma/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Proteínas Inibidoras de Apoptose/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transcrição Genética/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
16.
Tumori ; 105(2): 138-143, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30131003

RESUMO

INTRODUCTION: From 2002 to 2011, the Italian Soft Tissue Sarcoma Committee explored a combination of topotecan and carboplatin as a second-line strategy for children with resistant or relapsing rhabdomyosarcoma. METHODS: Patients received two blocks of topotecan 2 mg/m2 on days 1, 2, and 3, and carboplatin 250 mg/m2 on days 4 and 5, followed by alternating blocks of topotecan-cyclophosphamide and carboplatin-etoposide for a total of six courses with 3-week intervals. Tumor response was assessed after two cycles, and local control was implemented when feasible. RESULTS: A total of 38 patients were included in this study: 18/38 had alveolar rhabdomyosarcoma (RMS), 10/38 had metastatic disease at diagnosis, 8/38 had tumor progression during first-line chemotherapy, 21/38 had locoregional relapses, and 9/38 had distant relapses. Thirty-two patients could be assessed for tumor response to topotecan-carboplatin, and 9 (28%) showed a complete or partial response. Twenty-four patients experienced grade IV hematologic toxicity, while transient grade 1 tubulopathy, grade 3 mucositis, transient grade 2 nephrotoxicity, and a grade 2 decline in cardiac function occurred in one patient each. The 5-year overall and progression-free survival rates were 17% and 14%, respectively. CONCLUSION: the prognosis for children with resistant or relapsing RMS remains unsatisfactory. The topotecan-carboplatin regimen was well-tolerated. Though in case of late relapse the response rate was similar to those reported for other regimes, the result achieved remains unsatisfactory. New approaches, possibly including target agents, seem more attractive for future studies.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/administração & dosagem , Rabdomiossarcoma/tratamento farmacológico , Topotecan/administração & dosagem , Adolescente , Criança , Pré-Escolar , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Lactente , Estimativa de Kaplan-Meier , Masculino , Recidiva Local de Neoplasia/tratamento farmacológico , Rabdomiossarcoma/mortalidade , Adulto Jovem
17.
Cancer Lett ; 440-441: 126-134, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30312727

RESUMO

Multidrug resistance (MDR) in cancer patients undergoing chemotherapy is preventing effective treatment of multiple cancer types including pediatric tumors. Resistance to chemotherapeutic drugs in cancer cells is frequently associated with high expression of p-glycoprotein, a transporter in the plasma membrane that can mediate cellular drug export. Here, we generated pediatric cancer cells with acquired resistance to the chemotherapeutic drug vincristine (VCR). In these cells, acquired resistance is associated with increased expression of p-glycoprotein. VCR-resistant cells display an MDR phenotype and have acquired resistance to multiple other chemotherapeutic drugs including doxorubicin (DOXO) and etoposide (ETO). Notably, we discovered that these cells also display cross-resistance with several Smac mimetics, a novel class of experimental cancer therapeutics designed to induce apoptosis by inhibiting Inhibitor of Apoptosis (IAP) proteins. Resistance to Smac mimetics is reversible in the presence of p-glycoprotein inhibitors, highlighting Smac mimetics as novel substrates for p-glycoprotein. The identification of Smac mimetics as substrates for p-glycoproteins may influence the design of future clinical trials to prevent usage of Smac mimetics in the context of MDR or, alternatively, combine Smac mimetics with p-glycoprotein inhibitors to maximize their efficiency.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Materiais Biomiméticos/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Mitocondriais/metabolismo , Neuroblastoma/tratamento farmacológico , Rabdomiossarcoma/tratamento farmacológico , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Proteínas Reguladoras de Apoptose , Linhagem Celular Tumoral , Dipeptídeos/farmacologia , Doxorrubicina/farmacologia , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Etoposídeo/farmacologia , Humanos , Indóis/farmacologia , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Oligopeptídeos/farmacologia , Rabdomiossarcoma/metabolismo , Rabdomiossarcoma/patologia , Tiazóis/farmacologia , Regulação para Cima , Vincristina/farmacologia
18.
Urol Int ; 102(1): 118-121, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-28427078

RESUMO

A 32-year-old man visited our hospital due to urinary retention. Prostate-specific antigen was 13.7 ng/mL. Imaging examinations showed a large prostatic tumor and lung and internal iliac lymph node metastases. Transrectal biopsy confirmed embryonal rhabdomyosarcoma of the prostate classified as cT2bN1M1 (stage IV) by the International Rhabdomyosarcoma Study (IRS) Group staging system. Systemic chemotherapy was started according to the IRS III regimen 36, which consisted of 16 weeks of induction chemotherapy with radiation. After 20 weeks, magnetic resonance imaging showed the disappearance of metastases, and the prostate tumor shrunk markedly. Moreover, prostatic re-biopsy showed no viable tumor cells. Maintenance chemotherapy, excluding vincristine because of severe peripheral nerve disorder, was performed for 2 years. There has been no recurrence for 49 months after the termination of maintenance chemotherapy. To the best of our knowledge, this is the longest surviving case of adult-onset metastatic rhabdomyosarcoma of the prostate reported in the literature.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/radioterapia , Rabdomiossarcoma/tratamento farmacológico , Rabdomiossarcoma/radioterapia , Adulto , Terapia Combinada , Ciclofosfamida/administração & dosagem , Dactinomicina/administração & dosagem , Doxorrubicina/administração & dosagem , Humanos , Masculino , Recidiva Local de Neoplasia/tratamento farmacológico , Próstata/patologia , Neoplasias da Próstata/patologia , Rabdomiossarcoma/patologia , Vincristina/administração & dosagem
19.
J Pediatr Hematol Oncol ; 41(1): e41-e43, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29877907

RESUMO

Vincristine (VCR) is a common chemotherapeutic agent used in the treatment of multiple types of pediatric tumors. VCR's adverse effects are well documented and commonly involve peripheral neuropathy via axonal degeneration. Neuropathic severity is dose-dependent, with sensory deficits occurring with as little as 4 mg cumulative dose. Severe peripheral neuropathy is generally rare, but its effects become additive when given to patients with undiagnosed hereditary peripheral neuropathy such as Charcot-Marie-Tooth. We report a case of an effect of VCR administration given to a patient who developed grade 4 neuropathy and was found to be a carrier of Charcot-Marie-Tooth disease type 4.


Assuntos
Doença de Charcot-Marie-Tooth , Heterozigoto , Neoplasias Mandibulares , Rabdomiossarcoma , Vincristina/efeitos adversos , Doença de Charcot-Marie-Tooth/induzido quimicamente , Doença de Charcot-Marie-Tooth/diagnóstico , Doença de Charcot-Marie-Tooth/genética , Criança , Humanos , Masculino , Neoplasias Mandibulares/diagnóstico , Neoplasias Mandibulares/tratamento farmacológico , Neoplasias Mandibulares/genética , Rabdomiossarcoma/diagnóstico , Rabdomiossarcoma/tratamento farmacológico , Rabdomiossarcoma/genética , Vincristina/administração & dosagem
20.
Obstet Gynecol ; 132(6): 1486-1490, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30399094

RESUMO

BACKGROUND: Embryonal rhabdomyosarcoma of the cervix is a rare and aggressive malignancy that usually affects children and young adults. CASE: We describe a 2-year-old patient who presented with a mass protruding through the vaginal introitus. Preoperative investigations including vaginoscopy, hysteroscopy, magnetic resonance imaging, and biopsies confirmed embryonal rhabdomyosarcoma, botryoid subtype, arising from the cervix. She was successfully treated with neoadjuvant chemotherapy and interval laparoscopic radical trachelectomy to achieve remission. CONCLUSION: Collaboration between the pediatric and adult surgical and medical oncology teams was critical to implement this fertility-sparing treatment strategy in such a young girl having this rare tumor.


Assuntos
Rabdomiossarcoma/cirurgia , Traquelectomia/métodos , Neoplasias do Colo do Útero/cirurgia , Quimioterapia Adjuvante , Pré-Escolar , Feminino , Preservação da Fertilidade , Humanos , Laparoscopia , Terapia Neoadjuvante , Equipe de Assistência ao Paciente , Rabdomiossarcoma/tratamento farmacológico , Neoplasias do Colo do Útero/tratamento farmacológico
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