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1.
Artigo em Chinês | MEDLINE | ID: mdl-31550757

RESUMO

Objective: Using propensity score matching method (PSM) to investigate the clinical effect of postoperative adjuvant radiotherapy and postoperative concurrent chemoradiotherapy for locally advanced hypopharyngeal squamous cell carcinoma. Methods: From July 2007 to July 2018,174 postoperative patients with locally advanced hypopharyngeal squamous cell carcinoma were enrolled in pre-PSM cohort, including 168 males and 6 females, the median age was 60 years old (ranged from 37 to 79 years old).Loco-regional control (LRC),progression-free survival (PFS) and overall survival (OS) were compared and analyzed between the patients treated with postoperative adjuvant radiotherapy and postoperative concurrent chemoradiotherapy (cisplatin was given in a dose of 80 mg/m(2) on days 1, 22, and 43). After the propensity score matching (PSM), 61 sub-pairs of 122 patients were generated in post-PSM cohort. Survival rate were assessed with Kaplan-Meier method and Log-rank test. Results: After the propensity score matching(PSM), 61 sub-pairs of 122 patients were generated in post-PSM cohort.The patients were followed up for 3-135 months, the median follow-up was 42 months. No significant differences in 3-year and 5-year LRC, PFS, OS were observed between the two groups (P>0.05) . For postoperative patients who had high-risk factors (extracapsular extension of nodal disease, and/or vascular embolism, and/or lymph node metastasis≥2, and/or positive surgical margin, and/or perineural infiltration),there were significant differences between the two groups in 3-year PFS (60.99% vs 84.49%,P<0.05), 5-year PFS (35.47% vs 56.97%,P<0.05) and 5-year LRC (41.02% vs 68.50%, P<0.05), but no significant difference was found in OS between the two groups (P>0.05). Conclusion: Postoperative concurrent chemoradiotherapy was more efficacious than postoperative radiotherapy alone in terms of loco-regional control and PFS for high-risk postoperative patients with locally advanced hypopharyngeal squamous cell carcinoma.


Assuntos
Carcinoma de Células Escamosas , Quimiorradioterapia , Neoplasias Hipofaríngeas , Radioterapia Adjuvante , Adulto , Idoso , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/radioterapia , Estudos de Coortes , Feminino , Humanos , Neoplasias Hipofaríngeas/tratamento farmacológico , Neoplasias Hipofaríngeas/radioterapia , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida
2.
Life Sci ; 235: 116798, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31472149

RESUMO

Lung cancer is the leading cause for cancer death due to refractory nature to current treatment strategies, understanding the regulatory mechanism of therapy resistance of lung cancer is important for lung cancer therapy. Here, we aimed to study the role of SHCBP1 in lung cancer cisplatin resistance, we found SHCBP1 was upregulated in lung cancer tissues and cells, patients with high SHCBP1 had poor prognosis. SHC binding and spindle associated 1 (SHCBP1) overexpression promoted cisplatin induced apoptosis resistance, migration and invasion determined by apoptosis assay and transwell assay with or without Matrigel, while SHCBP1 knockdown inhibited cisplatin induced apoptosis resistance, migration and invasion. Wnt pathway promoted lung cancer progression, we found SHCBP1 activated Wnt pathway, characterized by promoting ß-catenin nuclear translocation. Inhibition of Wnt pathway in SHCBP1 overexpression cells reversed the effect of SHCBP1 overexpression, confirming SHCBP1 promoted lung cancer progression through activating Wnt pathway. We also found SHCBP1 expression was positively corrected with Wnt pathway activity in lung cancer samples. In summary, we found SHCBP1 promoted cisplatin induced apoptosis resistance, migration and invasion through activating Wnt pathway, providing a potential target for lung cancer therapy.


Assuntos
Apoptose , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares/patologia , Proteínas Adaptadoras da Sinalização Shc/metabolismo , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Movimento Celular , Proliferação de Células , Células Cultivadas , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Invasividade Neoplásica , Prognóstico , Proteínas Adaptadoras da Sinalização Shc/genética , Taxa de Sobrevida , Proteínas Wnt/genética , Via de Sinalização Wnt , beta Catenina/genética
3.
Shanghai Kou Qiang Yi Xue ; 28(3): 225-230, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31489406

RESUMO

PURPOSE: To investigate the mechanism of ANXA1 in TPF chemotherapy of oral squamous cell carcinoma (OSCC). METHODS: ANXA1 overexpression and low-expression cell lines were constructed. The role of ANXA1 in TPF chemotherapy was analyzed by cell proliferation, cytotoxicity test, real-time PCR and Western blot, and the mechanism of ANXA1 in TPF chemotherapy through EMT (epithelial-mesenchymal transition) pathway was discussed. The data were analyzed with SPSS 18.0 software package. RESULTS: After overexpression of ANXA1, cell growth rate decreased, cell cycle slowed down, sensitivity to TPF-induced drugs decreased, and EMT occurred in OSCC. After underexpression of ANXA1, cell growth rate increased, cell cycle accelerated, sensitivity to TPF chemotherapeutic drugs increased, and reverse EMT occurred in OSCC. CONCLUSIONS: In TPF chemotherapy of OSCC, overexpression of ANXA1 results in EMT of cells, which leads to decreased chemosensitivity.


Assuntos
Anexina A1 , Antineoplásicos , Carcinoma de Células Escamosas , Transição Epitelial-Mesenquimal , Neoplasias Bucais , Anexina A1/metabolismo , Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/genética
4.
Drugs Today (Barc) ; 55(8): 485-494, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31461085

RESUMO

Cutaneous squamous cell carcinoma (cSCC) is the second most frequent type of malignancy in Caucasians worldwide. Several factors have been correlated with aggressiveness and likelihood of recurrence and distant metastases, which are challenging to control. Metastatic disease has a dismal prognosis, and standard chemotherapy has failed to significantly improve outcomes. Recently, it has been recognized that cSCCs are highly mutated tumors with a denoting potential likelihood of response to immune checkpoint blockade. Cemiplimab is an anti-programmed cell death protein 1 (PD-1) antibody recently approved for the treatment of unresectable locally advanced or metastatic cSCC by the U.S. Food and Drug Administration (FDA) and the European Commission with a compelling response rate and an acceptable safety profile.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Cutâneas/tratamento farmacológico , Humanos , Recidiva Local de Neoplasia
5.
Cancer Sci ; 110(10): 3215-3224, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432603

RESUMO

Patient-derived xenograft (PDX) models are a useful tool in cancer biology research. However, the number of lung cancer PDX is limited. In the present study, we successfully established 10 PDX, including three adenocarcinoma (AD), six squamous cell carcinoma (SQ) and one large cell carcinoma (LA), from 30 patients with non-small cell lung cancer (NSCLC) (18 AD, 10 SQ, and 2 LA), mainly in SCID hairless outbred (SHO) mice (Crlj:SHO-Prkdcscid Hrhr ). Histology of SQ, advanced clinical stage (III-IV), status of lymph node metastasis (N2-3), and maximum standardized uptake value ≥10 when evaluated using a delayed 18 F-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) scan was associated with successful PDX establishment. Histological analyses showed that PDX had histology similar to that of patients' surgically resected tumors (SRT), whereas components of the microenvironment were replaced with murine cells after several passages. Next-generation sequencing analyses showed that after two to six passages, PDX preserved the majority of the somatic mutations and mRNA expressions of the corresponding SRT. Two out of three PDX with AD histology had epidermal growth factor receptor (EGFR) mutations (L858R or exon 19 deletion) and were sensitive to EGFR tyrosine kinase inhibitors (EGFR-TKI), such as gefitinib and osimertinib. Furthermore, in one of the two PDX with an EGFR mutation, osimertinib resistance was induced that was associated with epithelial-to-mesenchymal transition. This study presented 10 serially transplantable PDX of NSCLC in SHO mice and showed the use of PDX with an EGFR mutation for analyses of EGFR-TKI resistance.


Assuntos
Adenocarcinoma de Pulmão/patologia , Carcinoma de Células Grandes/patologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/patologia , Neoplasias Pulmonares/patologia , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Idoso , Idoso de 80 Anos ou mais , Animais , Carcinoma de Células Grandes/tratamento farmacológico , Carcinoma de Células Grandes/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Masculino , Camundongos , Camundongos Pelados , Camundongos SCID , Pessoa de Meia-Idade , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Artigo em Chinês | MEDLINE | ID: mdl-31434372

RESUMO

Objective: To analyze the clinical characteristics of two groups(vascular classification declines or not in narrow band imaging (NBI) of patients with advanced hypopharyngeal carcinoma after induced chemotherapy, to follow-up and compare the survival differences between the two groups, and to explore the effect of vascular changes on clinical prognosis after induced chemotherapy in patients with advanced hypopharyngeal carcinoma. Methods: Clinical data of 56 patients with advanced hypopharyngeal carcinoma from August 2014 to September 2016 in Beijing Tongren Hospital, Capital Medical University were collected. The patients were divided into two groups according to NBI vascular classification declines or not after induced chemotherapy. The survival of patients and the impact of different factors on the prognosis were retrospectively analyzed. SPSS 24.0 statistical software was used for analysis. Frequency data were compared between the two groups using χ(2) test. Kaplan-Meier method and Cox regression analysis were employed for survival analysis and Log-Rank test was used for inter-group comparison, P<0.05 was statistically significant. Results: There was significant difference in overall survival rate(OS) between two groups of patients with advanced hypopharyngeal carcinoma after induced chemotherapy (P<0.05). Multivariate analysis showed that NBI vascular classification changes after induced chemotherapy was the impact factor for prognosis of advanced hypopharyngeal carcinoma after induced chemotherapy. Conclusion: In addition to recurrence and metastasis, NBI vascular classification changes is the important impact factor for prognosis of advanced hypopharyngeal carcinoma after induced chemotherapy. Patients with NBI vascular classification declines have significant survival benefit. The patients with advanced hypopharyngeal carcinoma should be checked with NBI examination before and after induced chemotherapy. NBI should be included in the routine screening indicators for prognosis of advanced hypopharyngeal carcinoma.


Assuntos
Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Hipofaríngeas/tratamento farmacológico , Imagem de Banda Estreita , Veias/efeitos dos fármacos , Veias/diagnóstico por imagem , Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas/diagnóstico por imagem , Carcinoma de Células Escamosas/patologia , Humanos , Neoplasias Hipofaríngeas/diagnóstico por imagem , Neoplasias Hipofaríngeas/patologia , Quimioterapia de Indução , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida
7.
Cancer Invest ; 37(8): 339-354, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31412717

RESUMO

Squamous cell carcinoma (SCC) of skin has no standard treatment regimen, resulting in recurrences/metastasis. Although, doxorubicin (Dox), an anthracycline antibiotic has demonstrated some degree of efficacy. Molecular imaging can help in assessment of treatment response and prognosis of SCCs. MRI data showed that spin-spin relaxation (T2) time was longer (138 ± 2 msec) in Dox treated Test-II and there is no significant difference in spin-lattice relaxation (T1) time with respective controls. These findings further corroborated with the histology, proliferation index, apoptotic index, and HMGA1 protein expression. Thus, MRI may be a useful tool for monitoring treatment response noninvasively for skin tumor prognosis.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Doxorrubicina/farmacologia , Imagem por Ressonância Magnética , Imagem Molecular/métodos , Neoplasias Cutâneas/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Biomarcadores/metabolismo , Carcinoma de Células Escamosas/diagnóstico por imagem , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Proteínas HMGA/genética , Proteínas HMGA/metabolismo , Camundongos , Valor Preditivo dos Testes , Neoplasias Cutâneas/diagnóstico por imagem , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Fatores de Tempo , Carga Tumoral/efeitos dos fármacos
8.
Nat Methods ; 16(9): 866-869, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31451765

RESUMO

Auxin-inducible degron technology allows rapid and controlled protein depletion. However, basal degradation without auxin and inefficient auxin-inducible depletion have limited its utility. We have identified a potent auxin-inducible degron system composed of auxin receptor F-box protein AtAFB2 and short degron miniIAA7. The system showed minimal basal degradation and enabled rapid auxin-inducible depletion of endogenous human transmembrane, cytoplasmic and nuclear proteins in 1 h with robust functional phenotypes.


Assuntos
Proteínas de Arabidopsis/metabolismo , Carcinoma de Células Escamosas/metabolismo , Ácidos Indolacéticos/farmacologia , Proteólise/efeitos dos fármacos , Receptores de Superfície Celular/metabolismo , Neoplasias Cutâneas/metabolismo , Fatores de Transcrição/metabolismo , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Colesterol/metabolismo , Citoplasma/metabolismo , Células HEK293 , Humanos , Reguladores de Crescimento de Planta/farmacologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Células Tumorais Cultivadas
9.
Chem Biol Interact ; 312: 108799, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31433961

RESUMO

Black seed (Nigella sativa) oil has been used in various dermatological applications, and its major constituent, thymoquinone (TQ) has been shown to exhibit antiproliferative activity against various cancer cells. In this study, we tried to provide a mechanistic basis of apoptosis induced by TQ. Skin squamous carcinoma A431 cells were treated with TQ to monitor the apoptosis induced by TQ. Western blot analysis was performed to detect expression of apoptotic or anti-apoptotic proteins. Cell viability and apoptosis were measured by using the MTT test and FACS analysis, respectively. The induction of intracellular reactive oxygen species (ROS) by TQ was evaluated by 2',7'-dichlorofluorescein diacetate staining. In vivo xenograft study was followed to confirm the antiproliferative effect of TQ. Treatment of A431 cells with TQ-induced apoptosis, which was associated with the induction of p53 and Bax, inhibition of Mdm2, Bcl-2, and Bcl-xl expression, and activation of caspase-9, -7, and -3. TQ inhibited the constitutive phosphorylation and DNA binding activity of signal transducer and activator of transcription-3 (STAT3) in A431 cells by blocking the phosphorylation of the upstream kinase, Src. Moreover, the expression of STAT3 target gene products, cyclin D1 and survivin, was attenuated by TQ treatment. The generation of ROS was increased during TQ-induced apoptosis, and the pretreatment of N-acetyl cysteine, a ROS scavenger, reversed the apoptotic effect of TQ. In vivo study with NOD scid gamma (NSG) mice confirmed the inhibitory effect of TQ on the growth of A431 cells. Our results provide the first demonstration that TQ induces the apoptosis of A431 cells through generation of ROS and inhibition of STAT3 signaling.


Assuntos
Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Benzoquinonas/farmacologia , Regulação para Baixo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Antineoplásicos/uso terapêutico , Benzoquinonas/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Humanos , Camundongos , Camundongos Endogâmicos NOD , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transplante Heterólogo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
10.
Rev Med Liege ; 74(7-8): 436-440, 2019 Jul.
Artigo em Francês | MEDLINE | ID: mdl-31373461

RESUMO

The treatment of locally advanced or metastatic cutaneous squamous cell carcinoma (cSCC) essentially relies on surgery and eventually radiotherapy of the treated site and afferent lymph nodes. Unfortunately, some cases are no candidates for surgery or radiotherapy and a systemic treatment may be indicated. Chemotherapies are only partially efficacious and associated with potential toxicities. A recent study evaluating the efficacy and tolerance of cemiplimab, a PD1 antagonist for locally advanced and metastatic cSCC demonstrated an objective response rate of 49 % and 47 % for locally advanced and metastatic cSCC, while maintaining a response of at least 6 months of 63 % and 60 %, respectively. We present a clinical case of a patient with a locally advanced cSCC of the forehead with bone resorption and cervical lymphadenopathies. After failure of multiple surgical interventions and radiotherapies, he responded partially to cemiplimab immunotherapy with a good safety profile.


Assuntos
Anticorpos Monoclonais , Carcinoma de Células Escamosas , Neoplasias Cutâneas , Anticorpos Monoclonais/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Humanos , Masculino , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia
11.
Anticancer Res ; 39(8): 4129-4136, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366497

RESUMO

BACKGROUND/AIM: 5-Aza-2-deoxycytidine (5-Aza-CdR) enhances the sensitivity to 5-fluorouracil (5-FU), but the molecular mechanism is not fully understood. The aim of this study was to investigate the molecular mechanism that enhances the sensitivity to 5-FU treated with 5-Aza-CdR via thymidine phosphorylase (TP). MATERIALS AND METHODS: The sensitivity to drugs was determined on several cancer cell lines by the MTT assay. Protein and mRNA levels were examined by immunoblot and RT-PCR, respectively. Gene silencing, binding of Sp1 to DNA and methylation of DNA was performed by siRNA, ChIP assay and sodium bisulfate genomic sequencing, respectively. RESULTS: Sp1-binding sites in the TP promoter were methylated in epidermoid carcinoma. 5-Aza-CdR demethylated Sp1-binding sites and enhanced sensitivity to 5-FU. CONCLUSION: Demethylation of Sp1-binding sites by 5-Aza-CdR was a key factor enhancing 5-FU sensitivity, which may enable more effective treatments for cancer patients with the combination of 5-Aza-CdR and 5-FU.


Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Metilação de DNA/genética , Resistencia a Medicamentos Antineoplásicos/genética , Fator de Transcrição Sp1/genética , Timidina Fosforilase/genética , Sítios de Ligação/efeitos dos fármacos , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Metilação de DNA/efeitos dos fármacos , Proteínas de Ligação a DNA/genética , Decitabina/metabolismo , Fluoruracila/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inativação Gênica , Humanos , Regiões Promotoras Genéticas/efeitos dos fármacos , RNA Mensageiro/genética , Timidina Fosforilase/química
12.
Anticancer Res ; 39(8): 4137-4142, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366498

RESUMO

BACKGROUND: P53 is a key regulator of genomic stability and function, acting as a tumor suppressor protein. Our aim was to correlate P53 expression with murine double minute 2 (MDM2), a proto-oncogene that interacts with P53 and forms an auto-regulatory pathway, in laryngeal squamous cell carcinoma (LSCC). MATERIALS AND METHODS: A total of 50 LSCC cases were included in the study. Immunohistochemistry was applied by using antibodies to P53 and MDM2 in the corresponding tissue sections. Protein expression levels for both molecules were measured by implementing a digital image analysis assay (immunostaining intensity levels, densitometric evaluation). RESULTS: Overexpression of P53 protein was observed in 16/50 (32%) LSCC cases, while 22/50 (44%) cases strongly expressed MDM2 protein. Interestingly, in 13/50 (26%) cases, combined overexpression of P53/MDM2 was detected. Overall P53 was strongly positively correlated with MDM2 expression (p=0.001). Both P53 and MDM2 overexpression were significantly correlated with advanced stage of LSCC (p=0.032 and p=0.001, respectively). Additionally, MDM2 was found to be associated with poorer survival of patients (p=0.046). CONCLUSION: Aberrant co-expression of P53 and MDM2 is associated with advanced stage in LSCC. Furthermore, MDM2 overexpression is a frequent and critical genetic event in LSCC and seems to negatively affect survival.


Assuntos
Carcinoma de Células Escamosas/diagnóstico por imagem , Neoplasias Laríngeas/diagnóstico por imagem , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteína Supressora de Tumor p53/genética , Idoso , Animais , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imuno-Histoquímica , Neoplasias Laríngeas/tratamento farmacológico , Neoplasias Laríngeas/genética , Neoplasias Laríngeas/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Anticancer Res ; 39(8): 4337-4342, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366527

RESUMO

BACKGROUND: Induction therapy with docetaxel, cisplatin and fluorouracil (TPF) is a treatment option for locally advanced head and neck cancer (LAHNC), but it is not known which patients are appropriate for TPF. PATIENTS AND METHODS: We retrospectively reviewed the records of patients with LAHNC who underwent induction TPF, and evaluated factors predictive of the completion of TPF treatment (defined as ≥3 cycles administered). RESULTS: Of the total 93 enrolled patients, 73 (78.5%) achieved therapy completion. In a multivariate analysis, hypolaryngeal/ laryngeal primary tumor site was a negative predictive factor (hazard ratio(HR)=0.32, 95% confidence interval(CI)=0.11-0.96, p=0.041) and body mass index ≥22 kg/m2 was a positive predictive factor (hazard ratio=3.51, 95% confidence intervaI=1.04-11.83, p=0.043) of TPF completion. CONCLUSION: For patients with LAHNC, oropharyngeal primary tumor site and high body mass index can be used to predict TPF completion and may contribute to decisions on the indications for TPF in terms of safety and tolerability.


Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Prognóstico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células Escamosas/patologia , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Intervalo Livre de Doença , Docetaxel/administração & dosagem , Docetaxel/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Quimioterapia de Indução/métodos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia
14.
Cancer Sci ; 110(10): 3288-3295, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31348586

RESUMO

Cisplatin (CDDP) is an important drug for chemotherapy in patients with head and neck squamous cell carcinoma. Nephrotoxicity and lack of an effect on bone invasion are limitations of CDDP. To increase its antitumor effect on bone invasion and reduce toxicity problems, anionic Pt complex (3Pt) has been developed. The present study aimed to characterize the basis of the cytotoxicity of the novel platinum complex 3Pt in comparison with that of CDDP for oral squamous cell carcinoma. The ionic platinum complex was prepared to increase solubility and avoid platinum nephrotoxicity. Furthermore, 3Pt was designed to target bone hydroxyapatite and has germinal bisphosphonate moieties for drug delivery. In vitro antitumor activity was assayed in two oral squamous cell carcinoma cell lines. To investigate the antitumor and nephrotoxic effects of 3Pt, nude mice with OSC-19 were given 3Pt and CDDP. The in vitro growth-inhibitory effect of 3Pt was significantly less than that of CDDP. However, both 3Pt and CDDP showed equivalent antitumor effects in vivo. Mice injected with CDDP developed renal cell apoptosis; however, those injected with 3Pt were almost free of renal cell injury. In addition to similar in vivo antitumor effects, 3Pt decreased the volume of bone resorption compared to that with CDDP in a bone invasion model using OSC-19. In conclusion, considering the potential advantages in terms of noticeable antitumor activity on bone invasion and reduced nephrotoxicity, 3Pt represents a significant improvement in the development of bone-targeting platinum drugs.


Assuntos
Antineoplásicos/administração & dosagem , Reabsorção Óssea/epidemiologia , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Bucais/tratamento farmacológico , Compostos Organoplatínicos/administração & dosagem , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Reabsorção Óssea/induzido quimicamente , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Humanos , Masculino , Camundongos , Camundongos Nus , Compostos Organoplatínicos/efeitos adversos , Compostos Organoplatínicos/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Nat Med ; 25(8): 1251-1259, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31359002

RESUMO

Immunotherapies that block inhibitory checkpoint receptors on T cells have transformed the clinical care of patients with cancer1. However, whether the T cell response to checkpoint blockade relies on reinvigoration of pre-existing tumor-infiltrating lymphocytes or on recruitment of novel T cells remains unclear2-4. Here we performed paired single-cell RNA and T cell receptor sequencing on 79,046 cells from site-matched tumors from patients with basal or squamous cell carcinoma before and after anti-PD-1 therapy. Tracking T cell receptor clones and transcriptional phenotypes revealed coupling of tumor recognition, clonal expansion and T cell dysfunction marked by clonal expansion of CD8+CD39+ T cells, which co-expressed markers of chronic T cell activation and exhaustion. However, the expansion of T cell clones did not derive from pre-existing tumor-infiltrating T lymphocytes; instead, the expanded clones consisted of novel clonotypes that had not previously been observed in the same tumor. Clonal replacement of T cells was preferentially observed in exhausted CD8+ T cells and evident in patients with basal or squamous cell carcinoma. These results demonstrate that pre-existing tumor-specific T cells may have limited reinvigoration capacity, and that the T cell response to checkpoint blockade derives from a distinct repertoire of T cell clones that may have just recently entered the tumor.


Assuntos
Carcinoma Basocelular/tratamento farmacológico , Linfócitos do Interstício Tumoral/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Linfócitos T/imunologia , Carcinoma Basocelular/imunologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/imunologia , Humanos , Imunoterapia , Receptores de Antígenos de Linfócitos T/fisiologia , Análise de Sequência de RNA , Fator 1 de Transcrição de Linfócitos T/fisiologia
16.
Gan To Kagaku Ryoho ; 46(6): 1027-1031, 2019 Jun.
Artigo em Japonês | MEDLINE | ID: mdl-31273169

RESUMO

BACKGROUND: In our department, patients with oral squamous cell carcinoma(OSCC)received preoperative chemotherapy containing S-1 to prevent the growth and dissemination of tumors during the waiting time before definitive surgery. We retrospectively evaluated the usefulness of this treatment. PATIENTS AND METHODS: One hundred and five patients comprising stages T1(26), T2(64), T3(7), and T4(8 cases)were enrolled in this study from July 2001 to June 2013. In principle, patients were administered S-1(80mg/m / 2/day, days 1-14)and followed by a drug holiday(days 15-21), continuing until 1 week before surgery. RESULTS: The median administration period was 14 days(256 days). Ninety-eight patients underwent definitive surgery, but 7 patients who revealed clinical CR underwent only biopsy and showed histological CR. The histological responses of all patients were CR(24), PR(22), and NC(59), and the response rate was 43.8%. Almost all adverse effects were Grade 1 or 2, except 1 case of neutropenia(Grade 3)and 1 case of urticaria(Grade 3). The 5-year overall survival rates were 86.7% in all cases, 95.3% in CR/PR cases, and 79.7% in NC cases. CONCLUSION: Preoperative S-1 administration during the waiting time was a safe and very effective method and was considered beneficial for patients with OSCC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas , Neoplasias Bucais , Carcinoma de Células Escamosas/tratamento farmacológico , Combinação de Medicamentos , Humanos , Neoplasias Bucais/tratamento farmacológico , Ácido Oxônico , Estudos Retrospectivos , Tegafur , Listas de Espera
17.
Gan To Kagaku Ryoho ; 46(7): 1171-1173, 2019 Jul.
Artigo em Japonês | MEDLINE | ID: mdl-31296824

RESUMO

Case 1: 83 years old man. For left upper lobe lungs squamous cell carcinoma infiltrating left main pulmonary artery. After 2 courses went of carboplatin(CBDCA)(AUC: 6)+weekly nab-paclitaxel(nab-PTX)(AUC: 6)+, left upper lobectomy and ND2 lymph nodes dissection. Tumor disappeared in pathology and diagnosed of Ef. 3. Case 2: 81 years old man. Right upper lobe lungs squamous cell carcinoma in #4R lymph node metastasis with the superior vena cava invasion. After 2 courses went of CBDCA(AUC: 6)+weekly nab-PTX(100mg/m2), left upper lobectomy and ND2 lymph nodes dissection. Tumor disappeared in pathology and diagnosed of Ef. 3. Nab-PTX may be considered a preoperative chemotherapeutic agent of choice for squamous cell carcinoma.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Idoso de 80 Anos ou mais , Albuminas , Carboplatina , Humanos , Masculino , Estadiamento de Neoplasias , Paclitaxel
18.
Anticancer Res ; 39(7): 3507-3518, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262875

RESUMO

BACKGROUND/AIM: Very few studies of anticancer activity of azulene amides led us to investigate the cytotoxicity of 21 N-alkylazulene-1-carboxamides introduced either with 3-methyl [1-7], 7-isopropyl-3-methyl [8-14] or 2-methoxy group [15-21] Materials and Methods: Tumor-specificity (TS) was calculated by the ratio of mean 50% cytotoxic concentration (CC50) against three normal human oral mesenchymal cells to that against four human oral squamous cell carcinoma (OSCC) cell lines. Potency-selectivity expression (PSE) was calculated by dividing TS value by CC50 value against OSCC cell lines. Apoptosis-inducing activity was evaluated by caspase-3 activation and appearance of subG1 cell population. RESULTS: [8-14] showed higher TS and PSE values, than [1-7] and [15-21] The most active compound [8-14] induced apoptosis in C9-22 OSCC cells at 4-times higher CC50 Quantitative structure-activity relationship analysis of [1-14] demonstrated that their tumor-specificity was correlated with chemical descriptors that explain the molecular shape and hydrophobicity. CONCLUSION: 7-Isopropyl-3-methyl-N-propylazulene-1-carboxamide [8] can be a potential candidate of lead compound for manufacturing new anticancer drug.


Assuntos
Amidas/farmacologia , Antineoplásicos/farmacologia , Azulenos/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Bucais/tratamento farmacológico , Amidas/química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Azulenos/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Relação Quantitativa Estrutura-Atividade
19.
Anticancer Res ; 39(7): 3519-3529, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262876

RESUMO

BACKGROUND/AIM: Although adrenergic agonists have been used in dental treatments and oral surgery for general anesthesia, their cytotoxicity against human oral malignant and non-malignant cell has not been well- understood. The present study was undertaken to investigate the cytotoxicity of five adrenergic agonists against human oral squamous cell carcinoma (OSCC), glioblastoma, promyelocytic leukemia, and normal oral mesenchymal cells (gingival fibroblast, pulp cell, periodontal ligament fibroblast) and normal epidermal keratinocytes. MATERIALS AND METHODS: Tumor-specificity (TS) was calculated by the ratio between the mean 50% cytotoxic concentration against normal cells to that of tumor cells. Internucleosomal DNA fragmentation was detected using agarose gel electrophoresis. Caspase-3 activity was measured by substrate cleavage. RESULTS: Both cytotoxicity and tumor-specificity of adrenergic agonists against OSCC cell lines was in the order of isoprenaline>dexmedetomidine> adrenaline>clonidine and phenylephrine. Isoprenaline and dexmedetomidine did not induce apoptosis markers, such as internucleosomal DNA fragmentation and caspase-3 activation, but induced a smear pattern of DNA fragmentation in OSCC cell lines. Their cytotoxicity was not reduced by pretreatment with autophagy inhibitors, or by adrenoceptors antagonists. Addition of superoxide dismutase and catalase significantly reduced the cytotoxicity of isoprenaline, but not that of dexmedetomidine. CONCLUSION: Isoprenaline and dexmedetomidine induce non-apoptotic cell death by different mechanisms.


Assuntos
Agonistas Adrenérgicos/farmacologia , Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Morte Celular/efeitos dos fármacos , Neoplasias Bucais/tratamento farmacológico , Catalase/farmacologia , Células Cultivadas , Criança , Clonidina/farmacologia , Fragmentação do DNA , Dexmedetomidina/farmacologia , Epinefrina/farmacologia , Humanos , Isoproterenol/farmacologia , Fenilefrina/farmacologia , Superóxido Dismutase/farmacologia
20.
Anticancer Res ; 39(7): 3757-3765, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262902

RESUMO

BACKGROUND/AIM: The study focused on identifying the mechanisms or drugs that might sensitize resistant KBV20C human oral squamous carcinoma cells overexpressing P-glycoprotein (P-gp) to antimitotic drug treatment. MATERIALS AND METHODS: Five HIV protease inhibitors (atazanavir, nelfinavir, darunavir, lopinavir, and ritonavir) were tested to identify drugs that could be used at a relatively low dose for sensitizing antimitotic drug-resistant KBV20C cells. Fluorescence-activated cell sorting, annexin V analyses, and rhodamine uptake tests were performed to further investigate the mechanism of action. RESULTS: Co-treatment with nelfinavir or lopinavir had a high sensitizing effect on vincristine-treated KBV20C cells. Nelfinavir and lopinavir reduced cell viability, increased G2 phase arrest, and up-regulated apoptosis when used as a co-treatment with vincristine. We also demonstrated that eribulin co-treatment with nelfinavir and lopinavir similarly increased sensitization of KBV20C cells. Only lopinavir was found to have a high P-gp-inhibitory activity (similar to verapamil). Interestingly, nelfinavir had very low P-gp-inhibitory activity, suggesting that vincristine-nelfinavir sensitization is independent of the P-gp-inhibitory effect of nelfinavir. We also demonstrated this same combination mainly caused sensitization due to late apoptosis in P-gp-overexpressing drug-resistant KBV20C cells. CONCLUSION: Highly antimitotic drug-resistant KBV20C cells can be sensitized by co-treatment with the repositioned HIV protease inhibitors nelfinavir and lopinavir. In particular, the sensitizing effect of co-treatment with nelfinavir on antimitotic drug-resistant cancer cells was found to be strong and independent of P-gp-inhibitory activity. As P-gp inhibition can be toxic to normal cells, selecting nelfinavir may be safer for normal cells in patients with drug-resistant cancer.


Assuntos
Antimitóticos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Furanos/farmacologia , Inibidores da Protease de HIV/farmacologia , Cetonas/farmacologia , Lopinavir/farmacologia , Nelfinavir/farmacologia , Vincristina/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Sinergismo Farmacológico , Flufenazina/farmacologia , Humanos , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/metabolismo , Ritonavir/farmacologia
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