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1.
Oncology ; 96(3): 147-155, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30282082

RESUMO

OBJECTIVES: Due to the rarity of breast carcinomas with neuroendocrine features (NEBC), the knowledge on their biology is very limited but the identification of their biology and prognostic factors is essential to evaluate both pathogenesis and possible targeted treatment options. We assessed the expression of the well-characterized prognostic factors of gastroenteropancreatic neuroendocrine tumors (GEP-NET) in NEBC. METHODS: We assessed the immunohistochemical expression of neuron-specific enolase (NSE), thymidylate synthase (TS), p27, CD56, menin, and somatostatin receptor type 2A (SSTR-2A) in a series of 36 NEBC and 45 invasive ductal carcinomas (IDC). RESULTS: Nuclear and cytoplasmic TS, nuclear and cytoplasmic NSE, and nuclear p27 had significant overexpression in NEBC compared with IDC (for all, p < 0.01). In NEBC, cytoplasmic SSTR-2A expression was associated with excellent distant disease-free survival (p = 0.013), cytoplasmic menin expression with poorer relapse-free survival (p = 0.022), and nuclear p27 with longer breast cancer-specific survival (p = 0.022). CONCLUSIONS: There is a striking similarity in GEP-NET and NEBC regarding prognostic factors. GEP-NET and NEBC also appear to show similar expression patterns of the studied markers, while there are notable differences compared to IDC. Due to the wide expression of SSTR-2A, the treatment option with somatostatin analogs in NEBC should be evaluated.


Assuntos
Neoplasias da Mama/metabolismo , Carcinoma Neuroendócrino/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/biossíntese , Neoplasias Intestinais/metabolismo , Tumores Neuroendócrinos/metabolismo , Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogênicas/biossíntese , Receptores de Somatostatina/biossíntese , Neoplasias Gástricas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/biossíntese , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Carcinoma Neuroendócrino/patologia , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Intestinais/patologia , Pessoa de Meia-Idade , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/patologia , Estudos Retrospectivos , Neoplasias Gástricas/patologia , Timidilato Sintase/biossíntese
2.
Sci Rep ; 8(1): 8968, 2018 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-29895834

RESUMO

We aimed to identify predictive clinicoradiologic characteristics of thymidylate synthase (TS) expression status in advanced non-squamous non-small cell lung cancer patients. We reviewed clinicoradiologic features of 169 patients stratified into TS-negative (n = 84) and TS-positive (n = 85) groups, including quantitative CT radiomic features of both primary lung and metastatic lesions from initial CT and PET. Clinical factors including age and smoking history were significantly associated with TS as well as radiomic features. The predictive performance for dichotomizing TS expression status was slightly higher when imaging features of primary lung lesions were added compared to the model based solely on the clinical features, but without statistical significance (10-fold cross-validated AUC = 0.619 and 0.581, respectively; P = 0.425). The predictive performance of clinicoradiologic parameters slightly increased with primary lung lesions only compared to the inclusion of metastatic lesions, but without statistical significance (10-fold cross-validated AUC = 0.619 and 0.554, respectively; P = 0.203). Overall survival was prolonged in the TS-negative group compared to the TS-positive group (P = 0.001). TS-negativity is a potential prognostic biomarker, and our study presents that although CT radiomic features have potential for predicting TS expression status, clinical significance is uncertain. The addition of radiomic features to clinical factors did not show significant improvement in predicting TS-negativity.


Assuntos
Adenocarcinoma de Pulmão , Biomarcadores Tumorais/biossíntese , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares , Proteínas de Neoplasias/biossíntese , Timidilato Sintase/biossíntese , Tomografia Computadorizada por Raios X , Adenocarcinoma de Pulmão/diagnóstico por imagem , Adenocarcinoma de Pulmão/enzimologia , Adenocarcinoma de Pulmão/mortalidade , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida
3.
Cancer ; 124(4): 688-697, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29211295

RESUMO

BACKGROUND: The authors hypothesized that patients with metastatic colorectal cancer (mCRC) who had tumors with low thymidylate synthase (TS-L) expression would have a higher response rate to combined 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) plus bevacizumab (FOLFOX/Bev) than those with high TS (TS-H) expression and that combined irinotecan and oxaliplatin (IROX) plus bevacizumab (IROX/Bev) would be more effective than FOLFOX/Bev in those with TS-H tumors. METHODS: TS protein expression was determined in mCRC tissue. Patients who had TS-L tumors received FOLFOX/Bev, and those who had TS-H tumors were randomly assigned to receive either FOLFOX/Bev or IROX/Bev. The primary endpoint was the response rate (complete plus partial responses). RESULTS: In total, 211 of 247 patients (70% TS-H) were registered to the treatment phase. Efficacy analyses included eligible patients who had started treatment (N = 186). The response rates for patients who received IROX/Bev (TS-H), FOLFOX/Bev (TS-H), and FOLFOX/Bev (TS-L) were 33%, 38%, and 49%, respectively (P = nonsignificant). The median progression-free survival (PFS) was 10 months (95% confidence interval [CI], 9-12 months; 10 months in the IROX/Bev TS-H group, 9 months in the FOLFOX/Bev TS-H group, and 13 months in the FOLFOX/Bev TS-L group). The TS-L group had improved PFS compared with the TS-H group that received FOLFOX/Bev (hazard ratio, 1.6; 95% CI, 1.0%-2.4%; P = .04; Cox regression). The median overall survival (OS) was 22 months (95% CI, 20 29 months; 18 months in the IROX/Bev TS-H group, 21 months in the FOLFOX/Bev TS-H group, and 32 months in the TS-L group). OS comparisons for the 2 TS-H arms and for the FOLFOX/Bev TS-H versus TS-L arms were not significantly different. CONCLUSIONS: TS expression was prognostic: Patients with TS-L tumors who received FOLFOX/Bev had a longer PFS than those with TS-H tumors, along with a trend toward longer OS. Patients with TS-H tumors did not benefit more from IROX/Bev than from FOLFOX/Bev. Cancer 2018;124:688-97. © 2017 American Cancer Society.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Timidilato Sintase/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Bevacizumab/administração & dosagem , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/patologia , Feminino , Fluoruracila/administração & dosagem , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Oxaliplatina/administração & dosagem , Prognóstico , Modelos de Riscos Proporcionais , Resultado do Tratamento
4.
Endocr Relat Cancer ; 24(7): 319-327, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28432084

RESUMO

Topoisomerase II alpha (TOP2A) and thymidylate synthase (TS) are known prognostic parameters in several tumors and also predictors of efficacy of anthracyclines, topoisomerase inhibitors and fluoropirimidines, respectively. Expression of TOP2A and TS mRNA was assessed in 98 patients with adrenocortical carcinoma (ACC) and protein expression was assessed by immunohistochemistry in a subset of 39 tumors. Ninety-two patients were radically resected for stage II-III disease and 38 of them received adjuvant mitotane. Twenty-six patients with metastatic disease received the EDP-M (etoposide, doxorubicin, Adriamycin, cisplatin plus mitotane). TOP2A and TS expression in ACC tissue was directly correlated with the clinical data. Both markers were not associated with either disease free survival (DFS) or overall survival (OS) in multivariate analyses and failed to be associated to mitotane efficacy. Disease response or stabilization to EDP-M treatment was observed in 12/17 (71%) and 1/9 (11%) patients with high and low TOP2A expressing tumors (P = 0.0039) and 9/13 (69%) and 4/13 (31%) patients with high and low TS expressing ACC, respectively (P = 0.049). High TOP2A expression was significantly associated with longer time to progression (TTP) after EDP-M. TOP2A and TS proteins assessed by immunohistochemistry significantly correlated with mRNA expression. Immunohistochemical TOP2A expression was associated with a non-significant better response and longer TTP after EDP-M. TOP2A and TS were neither prognostic nor predictive of mitotane efficacy in ACC patients. The predictive role of TOP2A expression of EDP-M activity suggests a significant contribution of Adriamycin and etoposide for the efficacy of the EDP scheme.


Assuntos
Neoplasias do Córtex Suprarrenal/enzimologia , DNA Topoisomerases Tipo II/biossíntese , Timidilato Sintase/biossíntese , Adolescente , Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Neoplasias do Córtex Suprarrenal/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino/administração & dosagem , DNA Topoisomerases Tipo II/genética , Doxorrubicina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Mitotano/administração & dosagem , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Timidilato Sintase/genética , Adulto Jovem
5.
Tumour Biol ; 39(3): 1010428317695961, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28349820

RESUMO

Recurrence of breast cancer after radiotherapy may be partly explained by the presence of radioresistant cells. Thus, it would be desirable to develop an effective therapy against radioresistant cells. In this study, we demonstrated the intense antitumor activity of cytokine-induced killer cells against MCF-7 and radioresistant MCF-7 cells, as revealed by cytokine-induced killer-mediated cytotoxicity, tumor cell proliferation, and tumor invasion. Radioresistant MCF-7 cells were more susceptible to cytokine-induced killer cell killing. The stronger cytotoxicity of cytokine-induced killer cells against radioresistant MCF-7 cells was dependent on the expression of major histocompatibility complex class I polypeptide-related sequence A/B on radioresistant MCF-7 cells after exposure of cytokine-induced killer cells to sensitized targets. In addition, we demonstrated that cytokine-induced killer cell treatment sensitized breast cancer cells to chemotherapy via the downregulation of TK1, TYMS, and MDR1. These results indicate that cytokine-induced killer cell treatment in combination with radiotherapy and/or chemotherapy may induce synergistic antitumor activities and represent a novel strategy for breast cancer.


Assuntos
Neoplasias da Mama/radioterapia , Terapia Baseada em Transplante de Células e Tecidos , Células Matadoras Induzidas por Citocinas/metabolismo , Recidiva Local de Neoplasia/radioterapia , Subfamília B de Transportador de Cassetes de Ligação de ATP/biossíntese , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Células Matadoras Induzidas por Citocinas/imunologia , Citotoxicidade Imunológica/efeitos dos fármacos , Citotoxicidade Imunológica/efeitos da radiação , Feminino , Humanos , Células MCF-7 , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/patologia , Tolerância a Radiação , Timidina Quinase/biossíntese , Timidilato Sintase/biossíntese
6.
Regul Toxicol Pharmacol ; 81: 353-361, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27693704

RESUMO

Pemetrexed, a multitargeted antifolate agent, has demonstrated clinical activity in non-small cell lung cancer (NSCLC) cells. Increased expression of thymidylate synthase (TS) is thought to be associated with resistance to pemetrexed. Astaxanthin exhibits a wide range of beneficial effects including anti-cancer and anti-inflammatory properties. In this study, we showed that down-regulating of TS expression in two NSCLC cell lines, human lung adenocarcinoma H1650 and squamous cell carcinoma H1703 cells, with astaxanthin were associated with decreased MKK1/2-ERK1/2 activity. Enforced expression of constitutively active MKK1 (MKK1-CA) vector significantly rescued the decreased TS mRNA and protein levels in astaxanthin-treated NSCLC cells. Combined treatment with a MKK1/2 inhibitor (U0126 or PD98059) further decreased the TS expression in astaxanthin-exposed NSCLC cells. Knockdown of TS using small interfering RNA (siRNA) or inhibiting ERK1/2 activity enhanced the cytotoxicity and cell growth inhibition of astaxanthin. Combination of pemetrexed and astaxanthin resulted in synergistic enhancing cytotoxicity and cell growth inhibition in NSCLC cells, accompanied with reduced activation of phospho-MKK1/2, phopho-ERK1/2, and TS expression. Overexpression of MKK1/2-CA reversed the astaxanthin and pemetrexed-induced synergistic cytotoxicity. Our findings suggested that the down-regulation of MKK1/2-ERK1/2-mediated TS expression by astaxanthin is an important regulator of enhancing the pemetrexed-induced cytotoxicity in NSCLC cells.


Assuntos
Antineoplásicos/farmacologia , Regulação para Baixo/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Pemetrexede/farmacologia , Timidilato Sintase/biossíntese , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Relação Estrutura-Atividade , Timidilato Sintase/genética , Xantofilas/farmacologia
7.
Clin Pharmacokinet ; 55(10): 1205-1216, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27138786

RESUMO

BACKGROUND AND OBJECTIVE: 5-Fluorouracil plus cisplatin is the most commonly used chemotherapy regimen for nasopharyngeal carcinoma (NPC). The objective of this study was to establish an individualized 5-fluorouracil treatment model based on pharmacokinetic and pharmacodynamic analyses of 5-fluorouracil in East-Asian NPC patients. METHODS: A total of 122 NPC patients were administered 5-fluorouracil plus cisplatin treatment. Blood samples were collected to calculate the area under the concentration-time curve (AUC) for 5-fluorouracil, and expressions of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) at both protein and messenger RNA (mRNA) levels were analyzed in the tumor tissues from 73 patients in the same cohort. RESULTS: The results showed a wide (sevenfold) pharmacokinetic variability of 5-fluorouracil exposure (measured as AUC) based on body surface area (BSA) dosing. Pharmacokinetic analyses revealed that the 5-fluorouracil AUC range had a significant impact on the response of patients to 5-fluorouracil and related toxicities. Patients with 5-fluorouracil AUC <25 mg·h/L responded unsatisfactorily to 5-fluorouracil (overall response rate [ORR] 17.5 % lower than patients with AUC 25-35, p = 0.176; and 26.1 % lower than patients with AUC >35, p = 0.031). On the other hand, patients with 5-fluorouracil AUC >35 mg·h/L experienced more 5-fluorouracil-related toxicities (a grade 3 or higher toxicity rate 57.1 % higher than patients with AUC 25-35, p < 0.001; and 60.0 % higher than AUC >35, p < 0.001). The established 5-fluorouracil therapeutic window in head and neck cancer (HNC) [AUC 25-35 mg·h/L) was verified in our study. Pharmacodynamic analyses indicated a positive correlation between TS and DPD expression (p < 0.001) and, despite the pharmacokinetic influences, low expression of TS mRNA in tumor tended to have a better ORR (81.0 vs. 54.3 %, p = 0.051). No significant association was found between DPD expression and ORR. CONCLUSIONS: The therapeutic window of 5-fluorouracil for East-Asian NPC patients was verified as 25-35 mg·h/L based on lower toxicity and higher efficacy. TS mRNA expression showed potentially predictive value in 5-fluorouracil treatment, and personalized treatment based on pharmacokinetics and pharmacodynamics proved to be clinically beneficial and is worthy of further clinical studies.


Assuntos
Antimetabólitos Antineoplásicos/farmacocinética , Antimetabólitos Antineoplásicos/uso terapêutico , Carcinoma/tratamento farmacológico , Fluoruracila/farmacocinética , Fluoruracila/uso terapêutico , Neoplasias Nasofaríngeas/tratamento farmacológico , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/farmacologia , Área Sob a Curva , Grupo com Ancestrais do Continente Asiático , Cisplatino/administração & dosagem , Di-Hidrouracila Desidrogenase (NADP)/biossíntese , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos , Extremo Oriente , Feminino , Fluoruracila/efeitos adversos , Fluoruracila/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo , RNA Mensageiro/biossíntese , Timidilato Sintase/biossíntese
8.
Int J Biol Markers ; 31(2): e101-9, 2016 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-27012156

RESUMO

PURPOSE: To provide an assessment by meta-analysis of the relationship between the expression variations of 5-fluorouracil metabolic enzymes and clinical outcomes in patients with gastric cancer treated with S-1. METHOD: Databases were searched electronically from inception to April 19th, 2015. Studies in gastric cancer patients treated with S-1 investigating the expression variations of 5-fluorouracil metabolic enzymes were included after having been identified systematically. Pooled odds ratios (OR) for the objective response rate (ORR) and median survival ratio were calculated using the Review Manager 5.3 and Stata 12.0 software separately. RESULTS: A total of 555 patients in 10 studies met our inclusion criteria. There was a significant difference in ORR between patients with high/+ and low/- expression of orotate phosphoribosyl transferase (OPRT) (OR = 8.06; 95% CI, 4.06-16.02; p<0.001) and dihydropyrimidine dehydrogenase (DPD) (OR = 1.95; 95% CI, 1.21-3.13; p = 0.006). There was no significant difference in ORR between different expression levels of thymidylate synthase (TS) and thymidine phosphorylase (TP). Although patients with low/- TS expression, low/- TP expression and high/+ DPD expression showed a trend towards longer survival, no statistical significance was found. The median OS was significantly longer in patients with high/+ expression of OPRT (p = 0.076). CONCLUSIONS: OPRT and DPD expression can be treated as a potential predictive biomarker for S-1 response in gastric cancer patients. Further investigation is warranted.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/enzimologia , Biomarcadores Tumorais/biossíntese , Combinação de Medicamentos , Fluoruracila/metabolismo , Humanos , Orotato Fosforribosiltransferase/biossíntese , Ácido Oxônico/administração & dosagem , Tegafur/administração & dosagem , Timidina Fosforilase/biossíntese , Timidilato Sintase/biossíntese
9.
Int J Oncol ; 48(4): 1399-407, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26847426

RESUMO

Malignant pleural mesothelioma (MPM) is an incurable cancer with an increasing incidence. Currently, pemetrexed (PMX)-based chemotherapy is the mainstay of chemotherapy for MPM, however, the outcome of PMX-based chemotherapy in patients with MPM is dismal. RNA interference (RNAi) technology has been considered as an effective tool to substantially enhance the therapeutic efficacy of chemotherapeutic agents in many preclinical and clinical settings. In this study, therefore, we investigated whether non-viral anti-thymidylate synthase RNAi embedded liposome (TS shRNA lipoplex) would effectively guide the downregulation of TS in human malignant mesothelioma MSTO-211H cells. Consequently, it enhanced the antitumor effect of PMX both in vitro and in vivo. TS shRNA effectively enhanced the in vitro cell growth inhibition upon treatment with PMX via downregulating TS expression in the MSTO-211H cell line. In in vivo orthotopic tumor model, the combined treatment of PMX and TS shRNA lipoplex efficiently combated the progression of orthotopic thoracic tumors and as a result prolonged mouse survival, compared to each single treatment. Our findings emphasize the pivotal relevance of RNAi as an effective tool for increasing the therapeutic efficacy of PMX, a cornerstone in the treatment regimens of MPM, and thereby, raising the possibility for the development of a novel therapeutic strategy, combination therapy of TS-shRNA and PMX, that can surpass many of the currently applied, but less effective, therapeutic regimens against lethal MPM.


Assuntos
Terapia Genética , Neoplasias Pulmonares/tratamento farmacológico , Mesotelioma/tratamento farmacológico , Pemetrexede/administração & dosagem , Timidilato Sintase/biossíntese , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Terapia Combinada , Regulação Neoplásica da Expressão Gênica , Humanos , Lipossomos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mesotelioma/genética , Mesotelioma/patologia , Camundongos , Interferência de RNA , Timidilato Sintase/genética , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Neoplasma ; 63(2): 282-7, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26774151

RESUMO

Thymidylate synthase (TS) plays an essential role in the pathogenesis and development of cancer, and TS-targeting agents have been widely used against different types of cancers. However, it remains still unclear whether or not TS is expressed in malignant melanoma. We conducted the clinicopathological study to investigate the prognostic significance of TS expression in cutaneous malignant melanoma. Ninety-nine patients with surgically resected cutaneous malignant melanoma were assessed. Tumor sections were stained by immunohistochemistry for TS, Ki-67, and microvessel density (MVD) determined by CD34. TS was positively expressed in 26% (26 out of 99). The expression of TS was significantly associated with T factor, cell proliferation (Ki-67) and MVD (CD34). By Spearman's rank test, TS expression was significantly correlated with Ki67 and CD34. By univariate analysis, ulceration, disease stage, TS, Ki-67 and CD34 had a significant relationship with survival. Multivariate analysis confirmed that TS was an independent prognostic factor for poor prognosis of cutaneous malignant melanoma. The positive expression of TS could be a useful marker for predicting poor prognosis in patients with cutaneous malignant melanoma, and TS-targeting agents may be worth trying for the treatment of this dismal disease.


Assuntos
Biomarcadores Tumorais/metabolismo , Melanoma/mortalidade , Melanoma/patologia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Timidilato Sintase/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD34/metabolismo , Carcinogênese/genética , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Antígeno Ki-67/metabolismo , Masculino , Melanoma/genética , Pessoa de Meia-Idade , Neoplasias Cutâneas/genética , Timidilato Sintase/biossíntese , Timidilato Sintase/genética , Resultado do Tratamento
11.
Clin Cancer Res ; 22(5): 1243-55, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-26475334

RESUMO

PURPOSE: Chemoresistance is a major obstacle in cancer therapy. We found that fluorouracil (5-FU)-resistant esophageal squamous cell carcinoma cell lines, established through exposure to increasing concentrations of 5-FU, showed upregulation of Id1, IGF2, and E2F1. We hypothesized that these genes may play an important role in cancer chemoresistance. EXPERIMENTAL DESIGN: In vitro and in vivo functional assays were performed to study the effects of Id1-E2F1-IGF2 signaling in chemoresistance. Quantitative real-time PCR, Western blotting, immunoprecipitation, chromatin immunoprecipitation, and dual-luciferase reporter assays were used to investigate the molecular mechanisms by which Id1 regulates E2F1 and by which E2F1 regulates IGF2. Clinical specimens, tumor tissue microarray, and Gene Expression Omnibus datasets were used to analyze the correlations between gene expressions and the relationships between expression profiles and patient survival outcomes. RESULTS: Id1 conferred 5-FU chemoresistance through E2F1-dependent induction of thymidylate synthase expression in esophageal cancer cells and tumor xenografts. Mechanistically, Id1 protects E2F1 protein from degradation and increases its expression by binding competitively to Cdc20, whereas E2F1 mediates Id1-induced upregulation of IGF2 by binding directly to the IGF2 promoter and activating its transcription. The expression level of E2F1 was positively correlated with that of Id1 and IGF2 in human cancers. More importantly, concurrent high expression of Id1 and IGF2 was associated with unfavorable patient survival in multiple cancer types. CONCLUSIONS: Our findings define an intricate E2F1-dependent mechanism by which Id1 increases thymidylate synthase and IGF2 expressions to promote cancer chemoresistance. The Id1-E2F1-IGF2 regulatory axis has important implications for cancer prognosis and treatment.


Assuntos
Carcinoma de Células Escamosas/genética , Fator de Transcrição E2F1/biossíntese , Neoplasias Esofágicas/genética , Proteína 1 Inibidora de Diferenciação/biossíntese , Fator de Crescimento Insulin-Like II/biossíntese , Ligação Competitiva/efeitos dos fármacos , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Proteínas Cdc20/genética , Proteínas Cdc20/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Fator de Transcrição E2F1/genética , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago , Fluoruracila/administração & dosagem , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Proteína 1 Inibidora de Diferenciação/genética , Fator de Crescimento Insulin-Like II/genética , Proteólise/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Timidilato Sintase/biossíntese
12.
Oncotarget ; 6(32): 32622-33, 2015 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-26416450

RESUMO

5-fluorouracil (5-FU), one of the first-line chemotherapeutic agents for the treatment of gastrointestinal malignancies, has shown limited efficacy. The expression of thymidylate synthase (TYMS) has been reported to be associated with the resistance to 5-FU. Here, we demonstrate that the enhanced HSP90 function and subsequent activation of Src induce expression of TYMS and acquired resistance to 5-FU in colon cancer. We show that the persistent 5-FU treatment granted 5-FU-sensitive HCT116 colon cancer cells morphologic, molecular, and behavioral characteristic of the epithelial-mesenchymal transition (EMT), contributing to emergence of acquired resistance to 5-FU. HCT116/R, a HCT116 colon cancer cell subline carrying acquired resistance to 5-FU, showed increased expression and activation of HSP90's client proteins and transcriptional up-regulation of TYMS. Forced overexpression of HSP90 or constitutive active Src in HCT116 cells increased TYMS expression. Conversely, pharmacological blockade of HSP90 or Src in HCT116/R cells effectively suppressed the changes involved in 5-FU resistance in vitro and xenograft tumor growth, hematogenous spread, and metastatic tumor development in vivo. This study suggests a novel function of HSP90-Src pathway in regulation of TYMS expression and acquisition of 5-FU resistance. Thus, therapeutics targeting this pathway may be an effective clinical strategy to overcome 5-FU resistance in colon cancer.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Neoplasias do Colo/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Fluoruracila/farmacologia , Proteínas de Choque Térmico HSP90/metabolismo , Timidilato Sintase/biossíntese , Quinases da Família src/metabolismo , Animais , Neoplasias do Colo/enzimologia , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/genética , Indução Enzimática , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Proteínas de Choque Térmico HSP90/genética , Células HT29 , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/prevenção & controle , Neoplasias Pulmonares/secundário , Camundongos , Interferência de RNA , Transdução de Sinais/efeitos dos fármacos , Timidilato Sintase/genética , Fatores de Tempo , Transfecção , Carga Tumoral/efeitos dos fármacos , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto , Quinases da Família src/genética
13.
Tumour Biol ; 36(12): 9599-609, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26142736

RESUMO

Mismatch repair (MMR) gene is closely related to the pathogenesis of colon cancer. This study aimed to evaluate the association between MMR status and efficacy of irinotecan-based chemotherapy. As a target of 5-FU, thymidylate synthase (TS) expression level might be influenced by irinotecan. Understanding whether this influence of TS is related with MMR status is helpful to the further exploration of the mechanism of irinotecan sensitivity in metastatic colon cancer with different MMR status. One hundred eighty-four patients with metastatic colon cancer receiving irinotecan-based chemotherapy for the first-line treatment were included. Correlations between MMR and clinicopathological characteristics and prognosis were determined. Two pairs of colon cancer cell lines (HCT-116-hMLH1(Vector) (deficient MMR, dMMR) versus HCT-116-hMLH1(+) (proficient MMR, pMMR); SW480-shRNA-hMLH1 (dMMR) versus SW480-shRNA-Control (pMMR)) were established by regulating MMR status. Sensitivity of these cell lines to irinotecan was determined by MTT assay. Regulation of TS by irinotecan was evaluated by western blotting and quantitative real-time PCR assay. dMMR accounted for 18.5 % and was related with proximal colon cancer (p = 0.005), poorly differentiated tumors (p = 0.018) and favorable efficacy with a higher disease control rate (DCR), a longer progression-free survival (PFS) and a trend of longer overall survival (OS). dMMR colon cancer cells were more sensitive to irinotecan. TS expression level was reduced more in dMMR cells after irinotecan treatment (p < 0.05). Our study favors an increased sensitivity of irinotecan in colon cancer with dMMR status. MMR status may be a predictive biomarker of response to irinotecan-based chemotherapy in metastatic colon cancer.


Assuntos
Camptotecina/análogos & derivados , Neoplasias do Colo/tratamento farmacológico , Reparo de Erro de Pareamento de DNA/genética , Timidilato Sintase/biossíntese , Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Proteínas Adaptadoras de Transdução de Sinal/genética , Idoso , Camptotecina/administração & dosagem , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HCT116 , Humanos , Irinotecano , Masculino , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL , Proteína 2 Homóloga a MutS/biossíntese , Proteína 2 Homóloga a MutS/genética , Proteínas Nucleares/biossíntese , Proteínas Nucleares/genética , Prognóstico , Timidilato Sintase/genética , Resultado do Tratamento
14.
Medicine (Baltimore) ; 94(27): e1091, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26166093

RESUMO

Allelic imbalance of thymidylate synthase (TYMS) is attributed to polymorphisms in the 5'- and 3'-untranslated region (UTR). These polymorphisms have been related to the risk of suffering different cancers, for example leukemia, breast or gastric cancer, and response to different drugs, among which are methotrexate glutamates, stavudine, and specifically 5-fluorouracil (5-FU), as TYMS is its direct target. A vast literature has been published in relation to 5-FU, even suggesting the sole use of these polymorphisms to effectively manage 5-FU dosage. Estimates of the extent to which these polymorphisms influence in TYMS expression have in the past been based on functional analysis by luciferase assays and quantification of TYMS mRNA, but both these studies, as the association studies with cancer risk or with toxicity or response to 5-FU, are very contradictory. Regarding functional assays, the artificial genetic environment created in luciferase assay and the problems derived from quantitative polymerase chain reactions (qPCRs), for example the use of a reference gene, may have distorted the results. To avoid these sources of interference, we have analyzed the allelic imbalance of TYMS by allelic-specific analysis in peripheral blood mononuclear cells (PBMCs) from patients.Allelic imbalance in PBMCs, taken from 40 patients with suspected myeloproliferative haematological diseases, was determined by fluorescent fragment analysis (for the 3'-UTR polymorphism), Sanger sequencing and allelic-specific qPCR in multiplex (for the 5'-UTR polymorphisms).For neither the 3'- nor the 5'-UTR polymorphisms did the observed allelic imbalance exceed 1.5 fold. None of the TYMS polymorphisms is statistically associated with allelic imbalance.The results acquired allow us to deny the previously established assertion of an influence of 2 to 4 fold of the rs45445694 and rs2853542 polymorphisms in the expression of TYMS and narrow its allelic imbalance to 1.5 fold, in our population. These data circumscribe the influence of these polymorphisms in the clinical outcome of 5-FU and question their use for establishing 5-FU dosage, above all when additional genetic factors are not considered.


Assuntos
Desequilíbrio Alélico , Fluoruracila/uso terapêutico , Neoplasias/genética , Timidilato Sintase/biossíntese , Timidilato Sintase/genética , Regiões 3' não Traduzidas , Regiões 5' não Traduzidas , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Feminino , Genótipo , Humanos , Leucócitos Mononucleares , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Polimorfismo Genético
15.
Clin Transl Oncol ; 17(11): 876-83, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26055341

RESUMO

PURPOSE: The response rate of first-line fluoropyrimidine-based regimens for metastatic colorectal cancer (mCRC) is generally less than 50 %. The down-regulation of miR-197 in colorectal cancer cells after exposure to 5-fluorouracil might be related to the mechanism of resistance to fluoropyrimidine-based chemotherapy. So we investigated the regulatory mechanism of miR-197 on 5-FU sensitivity. METHODS: Dual luciferase reporter gene construct and dual luciferase reporter assay were used to identify the target of miR-197. TYMS expression was evaluated by immunohistochemistry staining. 5-Fu resistance of colorectal cancer cell lines was detected by MTS assay. The expression of miR-197 was detected by real time PCR. RESULTS: A luciferase assay and western blot analysis confirmed that miR-197 directly binds to and negatively regulates TYMS expression. Overexpressing miR-197 could increase the sensitivity of colorectal cancer cells to 5-fluorouracil (5-FU). The expression of miR-197 negatively correlated with TYMS expression in cancerous tissues from patients with stage IV colorectal cancer. CONCLUSION: miR-197 mediates the response of colorectal cancer cells to 5-FU by regulating TYMS expression.


Assuntos
Neoplasias Colorretais/genética , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/genética , MicroRNAs/genética , Timidilato Sintase/biossíntese , Antimetabólitos Antineoplásicos/uso terapêutico , Western Blotting , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/enzimologia , Fluoruracila/uso terapêutico , Humanos , Imuno-Histoquímica , RNA Interferente Pequeno , Reação em Cadeia da Polimerase em Tempo Real , Transfecção
16.
Cancer Chemother Pharmacol ; 75(4): 861-7, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25732635

RESUMO

PURPOSE: Recent clinical trials showed that expression of excision repair cross-complementation group 1 (ERCC1), ribonucleotide reductase M1 (RRM1), and thymidylate synthase (TS) proteins was able to predict the effects of non-small cell lung cancer (NSCLC) to chemotherapy. However, it remains unknown whether the adjuvant chemotherapy based on expression of the three proteins has survival significance in Chinese NSCLC patients. METHODS: We investigated 128 Chinese patients receiving chemotherapy after tumor resection for expression of these proteins using immunohistochemistry. Based on protein expression, patients were assigned to two groups for different adjuvant chemotherapy regimes. The disease-free survival (DFS) data were collected and analyzed using Kaplan-Meier curves and Cox models. RESULTS: We found that DFS of these patients with carboplatin and a third-generation agent (gemcitabine or pemetrexed) stratified by protein expression showed no statistical difference between individual treatment versus non-individuation treatment analyzed using Kaplan-Meier method (P = 0.143, median 23.9 vs. 30.8 months). Furthermore, the multivariate analysis showed that histology and tumor stages were independent predictors for DFS in these patients. CONCLUSIONS: The results suggest that chemotherapy based on ERCC1, RRM1, and TS expression did not have significant impact on DFS of patients with resection of NSCLC.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas , Proteínas de Ligação a DNA/biossíntese , Endonucleases/biossíntese , Neoplasias Pulmonares , Timidilato Sintase/biossíntese , Proteínas Supressoras de Tumor/biossíntese , Idoso , Antineoplásicos/administração & dosagem , Biomarcadores Tumorais/metabolismo , Carboplatina/administração & dosagem , Carboplatina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Quimioterapia Adjuvante , China , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Intervalo Livre de Doença , Esquema de Medicação , Glutamatos/administração & dosagem , Glutamatos/uso terapêutico , Guanina/administração & dosagem , Guanina/análogos & derivados , Guanina/uso terapêutico , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/cirurgia , Masculino , Pemetrexede , Medicina de Precisão , Valor Preditivo dos Testes , Estudos Prospectivos , Ribonucleosídeo Difosfato Redutase
17.
Oncotarget ; 6(10): 8377-87, 2015 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-25762627

RESUMO

Thymidylate synthase (TYMS) plays a role in DNA synthesis and is a target for 5-fluorouracil. In this study TYMS was analyzed by immunohistochemistry on a tissue microarray containing 11,152 prostate cancers. TYMS expression was higher in neoplastic than in normal prostate epithelium and was detectable in 72.9% of 10,223 interpretable cancers. It was considered strong in 21.9%, moderate in 33.4% and weak in 17.6% of tumors. TYMS overexpression was associated with deletions at 5q21 (p < 0.0001), 6q15 (p < 0.0001) and 3p13 (p = 0.0083) and gradually increased with the total number of these deletions present in the respective cancer sample (p < 0.0001). TYMS expression was unrelated to PTEN deletions (p = 0.9535) but tightly linked to high Gleason grade, advanced pathological tumor stage and early PSA recurrence (p < 0.0001). The prognostic value of TYMS was independent from the ERG status and deletions at 3p13, 5q21, and 6q15. In multivariate analyses the prognostic role of TYMS expression was independent of Gleason grade, pT stage, preoperative PSA, pN stage, or resection margins. TYMS expression analysis might result in clinically useful information in prostate cancer. The striking link to some but not all chromosomal aberrations might suggest a mechanistical link with specific types of DNA damage.


Assuntos
Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/patologia , Timidilato Sintase/biossíntese , Humanos , Imuno-Histoquímica , Calicreínas , Masculino , Recidiva Local de Neoplasia/enzimologia , Recidiva Local de Neoplasia/patologia , Prognóstico , Antígeno Prostático Específico , Prostatectomia/métodos , Neoplasias da Próstata/cirurgia , Análise Serial de Tecidos/métodos
18.
Biochemistry ; 54(5): 1287-93, 2015 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-25581782

RESUMO

The development of cancer-specific probes for imaging by positron emission tomography (PET) is gaining impetus in cancer research and clinical oncology. One of the hallmarks of most cancer cells is incessant DNA replication, which requires the continuous synthesis of nucleotides. Thymidylate synthase (TSase) is unique in this context because it is the only enzyme in humans that is responsible for the de novo biosynthesis of the DNA building block 2'-deoxy-thymidylate (dTMP). TSase catalyzes the reductive methylation of 2'-deoxy-uridylate (dUMP) to dTMP using (R)-N(5),N(10)-methylene-5,6,7,8-tetrahydrofolate (MTHF) as a cofactor. Not surprisingly, several human cancers overexpress TSase, which makes it a common target for chemotherapy (e.g., 5-fluorouracil). We envisioned that [(11)C]-MTHF might be a PET probe that could specifically label cancerous cells. Using stable radiotracer [(14)C]-MTHF, we had initially found increased uptake by breast and colon cancer cell lines. In the current study, we examined the uptake of this radiotracer in human pancreatic cancer cell lines MIAPaCa-2 and PANC-1 and found predominant radiolabeling of cancerous versus normal pancreatic cells. Furthermore, uptake of the radiotracer is dependent on the intracellular level of the folate pool, cell cycle phase, expression of folate receptors on the cell membrane, and cotreatment with the common chemotherapeutic drug methotrexate (MTX, which blocks the biosynthesis of endogenous MTHF). These results point toward [(11)C]-MTHF being used as PET probe with broad specificity and being able to control its signal through MTX co-administration.


Assuntos
Neoplasias Pancreáticas , Tomografia por Emissão de Pósitrons/métodos , Traçadores Radioativos , Timidina Monofosfato/biossíntese , Timidilato Sintase/biossíntese , Isótopos de Carbono , Ácido Fólico/análogos & derivados , Ácido Fólico/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Marcação por Isótopo , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/metabolismo , Radiografia , Timidina Monofosfato/metabolismo , Uridina Monofosfato/metabolismo
19.
Asian Pac J Cancer Prev ; 15(10): 4153-8, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24935362

RESUMO

BACKGROUND: This study was aimed to establish a novel method to simultaneously detect expression of four genes, ribonucleotide reductase subunit M1(RRM1), X-ray repair cross-complementing gene 1 (XRCC1), thymidylate synthase (TS) and class III ß-tubulin (TUBB3), and to assess their application in the clinic for prediction of response of non-small cell lung cancer (NSCLC) to chemoradiotherapy. MATERIALS AND METHODS: We have designed four gene molecular beacon (MB) probes for multiplex quantitative real-time polymerase chain reactions to examine RRM1, XRCC1, TUBB3 and TS mRNA expression in paraffin-embedded specimens from 50 patients with advanced or metastatic carcinomas. Twenty one NSCLC patients receiving cisplatin- based first-line treatment were analyzed. RESULTS: These molecular beacon probes could specially bind to their target genes in homogeneous solutions. Patients with low RRM1 and XRCC1 mRNA levels were found to have apparently higher response rates to chemoradiotherapy compared with those with high levels of RRM1 and XRCC1 expression (p<0.05). The TS gene expression level was not significantly associated with chemotherapy response (p>0.05). CONCLUSIONS: A method of simultaneously detecting four molecular markers was successfully established and applied for evaluation of chemoradiotherapy response. It may be a useful tool in personalized cancer therapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Proteínas de Ligação a DNA/biossíntese , Timidilato Sintase/biossíntese , Tubulina (Proteína)/biossíntese , Proteínas Supressoras de Tumor/biossíntese , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Quimiorradioterapia , Quimiorradioterapia Adjuvante , Cisplatino/uso terapêutico , Proteínas de Ligação a DNA/genética , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/radioterapia , Masculino , Pessoa de Meia-Idade , Ribonucleosídeo Difosfato Redutase , Timidilato Sintase/genética , Resultado do Tratamento , Tubulina (Proteína)/genética , Proteínas Supressoras de Tumor/genética , Proteína 1 Complementadora Cruzada de Reparo de Raio-X
20.
Oncol Res ; 21(5): 281-6, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24854104

RESUMO

Histone deacetylase (HDAC) inhibitors have been shown to enhance the effects of 5-fluorouracil (5-FU) against various cancer cells; however, no report has shown that an HDAC inhibitor may enhance the effects of 5-FU with radiation. Therefore, we investigated whether the novel HDAC inhibitor OBP-801/YM753 could enhance the effects of 5-FU with radiation on esophageal squamous carcinoma KYSE170 cells. The inhibition of the cell growth was significantly stronger with the combination of OBP-801/YM753 with 5-FU than with the 5-FU treatment only. Furthermore, inhibition of the colony formation was the most effective with the combined treatment of OBP-801/YM753, 5-FU, and radiation. Western blot analysis showed that OBP-801/YM753 suppressed the expression of thymidylate synthase induced by 5-FU. Therefore, this three-combined therapy is promising for patients with esophageal squamous carcinoma.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/radioterapia , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/radioterapia , Fluoruracila/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Peptídeos Cíclicos/farmacologia , Processos de Crescimento Celular/efeitos dos fármacos , Processos de Crescimento Celular/efeitos da radiação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Quimiorradioterapia , Sinergismo Farmacológico , Indução Enzimática/efeitos dos fármacos , Carcinoma de Células Escamosas do Esôfago , Fluoruracila/administração & dosagem , Inibidores de Histona Desacetilases/administração & dosagem , Humanos , Peptídeos Cíclicos/administração & dosagem , Timidilato Sintase/biossíntese
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