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1.
Anticancer Res ; 39(7): 3433-3442, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262867

RESUMO

BACKGROUND/AIM: DOG1 is a calcium-activated chloride channel that has gained attention as a promising drug target due to its involvement in several processes essential for tumor development and progression. DOG1 is overexpressed in >95% of gastrointestinal stromal tumors (GIST). The aim was to determine DOG1 inhibition antitumoral effects on GIST. MATERIALS AND METHODS: Human GIST (GIST-T1 and GIST882) cell lines were used to study the effect of DOG1 inhibitors on chloride currents, viability, colony formation, and cell cycle. RESULTS: CaCCinh-A01 decreased chloride currents. CaCCinh-A01 and T16inh-A01 reduced GIST cell viability and CaCCinh-A01 affected cell cycle distribution leading to G1 cell-cycle arrest. CaCCinh-A01 also increased the sub-G1 phase population, indicative of apoptosis, in GIST882. CaCCinh-A01 strongly reduced the colony forming ability of the cells, whereas T16inh-A01 did not. CONCLUSION: DOG1 inhibition has antitumoral effects in GIST cells in vitro, and could potentially serve as a target for GIST therapy.


Assuntos
Anoctamina-1/antagonistas & inibidores , Neoplasias Gastrointestinais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Proteínas de Neoplasias/antagonistas & inibidores , Anoctamina-1/fisiologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Gastrointestinais/fisiopatologia , Tumores do Estroma Gastrointestinal/fisiopatologia , Humanos , Proteínas de Neoplasias/fisiologia , Pirimidinas/farmacologia , Tiazóis/farmacologia , Tiofenos/farmacologia
2.
J Surg Oncol ; 120(4): 715-721, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31297829

RESUMO

INTRODUCTION: Rectal gastrointestinal stromal tumor (GIST) is rare and comprises about 3% of GIST. METHODS: Registry data was collected by the Life Raft Group June 1976 to November 2017. All patients had a histologic GIST diagnosis. Demographic, clinicopathologic, and clinical outcome data were patient reported. Recurrence-free survival (RFS) was analyzed using the Kaplan-Meier method and Cox regression analysis. RESULTS: Of 1798 patients in the database, 48 had localized rectal GIST (2.7%). Patients were frequently male (58.3%) and non-Hispanic whites (58.3%). Median age at diagnosis was 52 years. Most patients (77%) were diagnosed in the imatinib era (2001 to current). Over half (54.2%) of the cohort had mutation testing and all profiled tumors possessed KIT mutations (exon 9: 7.7%, exon 11: 88.5%, and exon 13: 3.8%). Most evaluable patients (26/28; 92.9%) had high-risk disease (modified NIH criteria) and nearly all patients (95.8%) received imatinib. Median follow-up was 8.8 years (range, 0.3-30.7) and overall RFS was 8.0 years (95% CI, 2.9-13.1). Thirty-two percent (12/37) of patients in the post-imatinib era developed recurrent disease. Diagnosis in the imatinib era was associated with improved RFS (HR = 0.22, 95% CI, 0.08-0.62; P = .004) in the multivariable model. CONCLUSION: We find that disease recurrence remains prevalent in one-third of patients treated during the imatinib-era.


Assuntos
Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/patologia , Mesilato de Imatinib/uso terapêutico , Recidiva Local de Neoplasia/patologia , Neoplasias Retais/patologia , Sistema de Registros/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Feminino , Seguimentos , Neoplasias Gastrointestinais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Humanos , Agências Internacionais , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Prognóstico , Estudos Prospectivos , Neoplasias Retais/tratamento farmacológico , Estudos Retrospectivos , Taxa de Sobrevida
3.
Eur J Radiol ; 116: 98-105, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31153581

RESUMO

PURPOSE: Identification of prognostic CT-textural features in patients with gastrointestinal stromal tumors undergoing tyrosine kinase inhibitor (TKI) therapy. METHODS AND MATERIALS: We identified 25 GIST patients (mean age, 70.58 ± 9.7 years; range, 41.25-84.08 years; 20 males, 5 females) with a total of 123 scans, each examined with a standardized CT protocol between 1/2014-7/2018. 92 texture features, based on pyradiomics library, were extracted and correlated to response categories; evaluated with help of modified Choi criteria. All patients underwent therapy with imatinib in the first line and different tyrosine kinase inhibitors after disease progression. KIT and PDGFR-mutations were registered in all patients as well as the number of previous treatment regimens, patient's age as well as gender and the presence of contrast enhancement (vitality) in tumor. The lesion with the largest diameter was chosen and contoured using the spherical VOI tool. Inter-rater testing was performed by a second experienced radiologist. Regression and AUC analysis was performed. RESULTS: Ten variables could be confirmed to be significantly associated with disease progression. Of them, four textural parameters were significantly positively associated with disease progression and negatively with progression free survival (Glcm Id [grey-level co-occurrence matrix inverse difference], p = 0.012, HR 3.83; 95% CI 1.697-8.611, Glcm Idn [grey-level co-occurrence matrix inverse difference normalized], p = 0.045, HR 2.06, 95% CI 1.015-4.185, Glrlm [grey-level run length matrix] normalized, p = 0.005, HR 3.181; 95% CI 1.418-7.138 and Ngtdm [neighboring grey-tone difference matrix] coarseness, p < 0.001, HR 3.156, 95% CI 1.554-6.411). Single variables were shown to be significantly inferior to the combination of all variables. After 6 months, 90% of patients with 0-1 risk factors (group 1), 64.4% with 2-3 risk variables and 38.1% of patients presenting > 3 structural risk variables showed stable disease. Gclm Id, Gclm Idn and Glrlm non-uniformity were associated with the number of previous treatments, Glrlm non-uniformity also with tumor vitality (enhancement), whereas Gclm Idn and Ngtdm coarseness were associated with the number of tumor mutations. CONCLUSION: Some of the CT-textural features correlate with disease progression and the progressive free survival as well as with the number of gene mutations and the number of treatment regimens the patients were exposed to as well as with the tumor enhancement. All these features reflect tumor homogeneity.


Assuntos
Neoplasias Gastrointestinais/diagnóstico por imagem , Neoplasias Gastrointestinais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/diagnóstico por imagem , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Tomografia Computadorizada por Raios X/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/patologia , Trato Gastrointestinal/diagnóstico por imagem , Trato Gastrointestinal/patologia , Humanos , Mesilato de Imatinib/uso terapêutico , Masculino , Pessoa de Meia-Idade , Prognóstico , Resultado do Tratamento
4.
J Surg Oncol ; 120(2): 256-261, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31066052

RESUMO

BACKGROUND: The aim was to describe complicated tumor response (CTR) to tyrosine-kinase inhibitors (TKI) in gastrointestinal stromal tumors (GIST) patients. METHODS: From 2001 to 2017, data from patients with metastatic (group A) or locally advanced (group B) GIST who received TKI at our institution were collected. We defined CTR as bleeding, abscess, or perforation as surgical complications of TKI. Patients who had progressive disease were excluded. Clinical characteristics were assessed, and time of occurrence and mortality rate recorded. RESULTS: Among 470 patients, 30 developed CTR (6.4%), 26 in group A (6.8%) and four in group B (4.5%) (P = 0.43). Bleeding, abscess, and perforation, respectively, were observed in 17 (56.7%), 8 (26.7%), and 5 (16.7%) patients. A conservative approach was possible in 17 (56.7%) cases; four (13.3%) patients received percutaneous drainage, while nine (30%) underwent emergency surgery. The overall rate of mortality was 13.3%. CTR occurred after 1.6 months (median time) from the imatinib mesylate onset in group B and 14 months in group A. CONCLUSIONS: While the risk of CTR in early metastatic patients is virtually nil, patients with locally advanced disease should be monitored carefully. CTR as a consequence of TKI therapy do not prevent patients receiving a potentially curative surgery.


Assuntos
Neoplasias Gastrointestinais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Mesilato de Imatinib/efeitos adversos , Complicações Pós-Operatórias/terapia , Inibidores de Proteínas Quinases/efeitos adversos , Sunitinibe/efeitos adversos , Antineoplásicos/efeitos adversos , Feminino , Neoplasias Gastrointestinais/mortalidade , Neoplasias Gastrointestinais/cirurgia , Tumores do Estroma Gastrointestinal/mortalidade , Tumores do Estroma Gastrointestinal/cirurgia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Estudos Retrospectivos
5.
Molecules ; 24(9)2019 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-31058847

RESUMO

Due to changes in the dietary structure of individuals, the incidence of digestive tract tumors has increased significantly in recent years, causing a serious threat to the life and health of patients. This has in turn led to an increase in cancer prevention research. Many studies have shown that epigallocatechin-3-gallate (EGCG), an active ingredient in green tea, is in direct contact with the digestive tract upon ingestion, which allows it to elicit a significant antagonizing effect on digestive tract tumors. The main results of EGCG treatment include the prevention of tumor development in the digestive tract and the induction of cell cycle arrest and apoptosis. EGCG can be orally administered, is safe, and combats other resistances. The synergistic use of cancer drugs can promote the efficacy and reduce the anti-allergic properties of drugs, and is thus, favored in medical research. EGCG, however, currently possesses several shortcomings such as poor stability and low bioavailability, and its clinical application prospects need further development. In this paper, we have systematically summarized the research progress on the ability of EGCG to antagonize the activity and mechanism of action of digestive tract tumors, to achieve prevention, alleviation, delay, and even treat human gastrointestinal tract tumors via exogenous dietary EGCG supplementation or the development of new drugs containing EGCG.


Assuntos
Catequina/análogos & derivados , Ciclo Celular/efeitos dos fármacos , Neoplasias Gastrointestinais/tratamento farmacológico , Administração Oral , Disponibilidade Biológica , Catequina/administração & dosagem , Catequina/farmacocinética , Catequina/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Descoberta de Drogas , Humanos , Chá/química
6.
JAMA ; 321(14): 1361-1369, 2019 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-30964526

RESUMO

Importance: Randomized clinical trials of vitamin D supplementation for secondary prevention in patients with cancer are needed, given positive results of observational studies. Objective: To determine whether postoperative vitamin D3 supplementation can improve survival of patients with digestive tract cancers overall and in subgroups stratified by 25-hydroxyvitamin D (25[OH]D) levels. Design, Setting, and Participants: The AMATERASU trial, a randomized, double-blind, placebo-controlled trial conducted at a single university hospital in Japan. Enrollment began in January 2010 and follow-up was completed in February 2018. Patients aged 30 to 90 years with cancers of the digestive tract from the esophagus to the rectum, stages I to III, were recruited. Of 439 eligible patients, 15 declined and 7 were excluded after operation. Interventions: Patients were randomized to receive oral supplemental capsules of vitamin D (2000 IU/d; n = 251) or placebo (n = 166) from the first postoperative outpatient visit to until the end of the trial. Main Outcomes and Measures: The primary outcome was relapse-free survival time to relapse or death. The secondary outcome was overall survival time to death due to any cause. Subgroups analyzed had baseline serum 25(OH)D levels of 0 to less than 20 ng/mL, 20 to 40 ng/mL, and greater than 40 ng/mL; because of small sample size for the highest-baseline-level group, interactions were tested only between the low- and middle-baseline-level groups. Results: All 417 randomized patients (mean age, 66 years; male, 66%; esophageal cancer, 10%; gastric cancer, 42%; colorectal cancer, 48%) were included in the analyses. There was 99.8% follow-up over a median 3.5 (interquartile range, 2.3-5.3) years, with maximal follow-up of 7.6 years. Relapse or death occurred in 50 patients (20%) randomized to vitamin D and 43 patients (26%) randomized to placebo. Death occurred in 37 (15%) in the vitamin D group and 25 (15%) in the placebo group. The 5-year relapse-free survival was 77% with vitamin D vs 69% with placebo (hazard ratio [HR] for relapse or death, 0.76; 95% CI, 0.50-1.14; P = .18). The 5-year overall survival in the vitamin D vs placebo groups was 82% vs 81% (HR for death, 0.95; 95% CI, 0.57-1.57; P = .83). In the subgroup of patients with baseline serum 25(OH)D levels between 20 and 40 ng/mL, the 5-year relapse-free survival was 85% with vitamin D vs 71% with placebo (HR for relapse or death, 0.46; 95% CI, 0.24-0.86; P = .02; P = .04 for interaction). Fractures occurred in 3 patients (1.3%) in the vitamin D group and 5 (3.4%) in the placebo group. Urinary stones occurred in 2 patients (0.9%) in the vitamin D group and 0 in the placebo group. Conclusions and Relevance: Among patients with digestive tract cancer, vitamin D supplementation, compared with placebo, did not result in significant improvement in relapse-free survival at 5 years. Trial Registration: UMIN Identifier: UMIN000001977.


Assuntos
Colecalciferol/uso terapêutico , Suplementos Nutricionais , Neoplasias Gastrointestinais/tratamento farmacológico , Recidiva Local de Neoplasia/prevenção & controle , Vitaminas/uso terapêutico , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Colecalciferol/efeitos adversos , Intervalo Livre de Doença , Método Duplo-Cego , Feminino , Neoplasias Gastrointestinais/mortalidade , Neoplasias Gastrointestinais/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Cuidados Pós-Operatórios , Modelos de Riscos Proporcionais , Análise de Sobrevida , Resultado do Tratamento , Vitamina D/análogos & derivados , Vitamina D/sangue , Vitaminas/efeitos adversos
7.
Turk J Med Sci ; 49(2): 583-588, 2019 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-30997793

RESUMO

Background/aim: The purpose of this study was to determine sarcopenia, sarcopenic obesity and phase angle (PA) and the influence of chemotherapy (CT) on anthropometric measurements and and the PA in in geriatric patients with gastrointestinal (GI) cancer. Materials and methods: The anthropometric measurements, calf circumference (CC), upper midarm circumference (UMAC), and hand grip strength (HGS), have been measured to understand muscle function of 153 patients (mean age of 70.5 ± 5.6 years, 28.8% female, 71.2% male). Sarcopenia and PA measurements have been evaluated by bioelectrical impedance analyses. The same evaluations were checked again after 1 cycle of CT (min: 4, max: 6 weeks). Results: Patient population consisted of colorectal (51,6%), gastric (26.8%), pancreas (11.8%), liver (7.2%), and biliary tract cancer (2%). UMAC (28.5 ± 4.4 before, 28.1 ± 4.9, P = 0.034 after CT), and HGS measurements (27.5 ± 8.6 before, 26.8 ± 8.8 after CT, P = 0.007) have significantly decreased after CT. CC measurement < 31 cm at first visit was seen in 13.1% of patients, but the ratio raised to 20.3% after CT (χ², P = 0.003). Severe sarcopenia was determined in 33% of all patients, and 30.0% of them have been considered as sarcopenic obese. Conclusion: Sarcopenia and sarcopenic obesity were prevalent in this group patients. The CT caused a decrease in muscle functions, UMAC, and CC. Patients should be followed up carefully for sarcopenia, sarcopenic obesity, and nutritional aspect and it would be proper to intervene before sarcopenia has not occurred yet.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Gastrointestinais/complicações , Neoplasias Gastrointestinais/tratamento farmacológico , Avaliação Geriátrica , Músculo Esquelético/fisiopatologia , Obesidade/diagnóstico , Sarcopenia/diagnóstico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Impedância Elétrica , Feminino , Neoplasias Gastrointestinais/fisiopatologia , Força da Mão , Humanos , Masculino , Músculo Esquelético/efeitos dos fármacos , Obesidade/complicações , Obesidade/fisiopatologia , Prevalência , Estudos Prospectivos , Sarcopenia/etiologia , Sarcopenia/fisiopatologia
8.
Nutr Hosp ; 36(1): 5-12, 2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30829529

RESUMO

Introduction: Background and objective: malnutrition during cancer treatment is common in patients; therefore, nutritional intervention has an important role in cancer prognosis. Total parenteral nutrition is indicated for patients subjected to a major surgery with gastrointestinal complications. Nutritional support could be improved with glutamine (Gln). Therefore, in this work, the effect of parenteral glutamine in patients with gastrointestinal cancer undergoing surgery was studied. Material and methods: patients were classifi ed into two groups: non-supplemented and supplemented (Gln; 0.4 g/kg/day). Both groups received parenteral nutrition. One and seven days after surgery the nutritional status was evaluated. Hematic cytometry, protein metabolism and biochemical data were analyzed. A questionnaire was also applied to assess gastrointestinal function. Results: after the intervention, the nutritional status in both groups improved. However, the nutritional condition improved signifi cantly better (p = 0.008) in the supplemented group. According to the gastrointestinal function evaluation, the supplemented group changed from severe to mild dysfunction (p = 0.0001). The non-supplemented group progressed from moderate to severe dysfunction, but no changes in blood cell markers were observed. The supplemented group improved its concentration of lymphocytes (p = 0.014). The plasma albumin concentration did not change in groups, but prealbumin improved signifi cantly (p = 0.012) in the group that was supplemented with Gln. Conclusions: intravenous nutritional support supplemented with glutamine can improve gastrointestinal function, improving the absorption of nutrients, which leads to a better state of nutrition. It also has positive effects on plasma concentration of lymphocytes, monocytes and prealbumin.


Assuntos
Neoplasias Gastrointestinais/terapia , Glutamina/administração & dosagem , Glutamina/uso terapêutico , Nutrição Parenteral , Adulto , Idoso , Contagem de Células Sanguíneas , Feminino , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/cirurgia , Trato Gastrointestinal/fisiopatologia , Humanos , Tempo de Internação , Estudos Longitudinais , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Estado Nutricional , Pré-Albumina/análise , Estudos Prospectivos
10.
Discov Med ; 27(146): 27-36, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30721649

RESUMO

Cyclin-dependent kinases (CDKs) play an important role in cell-cycle progression. CDKs are positively modulated by regulatory mitotic cyclins and negatively controlled by endogenous CDK inhibitors (CDKIs) cyclically as cells progress through different cell cycles of transitions. When activated by cyclins, cyclin-CDK complexes were able to facilitate the transition of cell cycle from one phase to the next, e.g., from G1 to S or from G2 to M. DNA damages may cause inhibition of CDKs leading to cell-cycle arrest, while unrepairable DNA damage causes cells to undergo apoptosis. Disruption of cell cycle progression is an important cancer hallmark to mediate uncontrolled cell proliferation, tumorigenesis, and metastasis. Aberrantly expressed CDKs are causally linked to the development of gastrointestinal cancers, and as such, CDKs may not only form a class of potential biomarkers for the diagnosis and therapy of gastrointestinal cancers. In this review article, we summarized the data from translational studies using CDKs as a target for gastrointestinal cancer treatment.


Assuntos
Antineoplásicos/uso terapêutico , Quinases Ciclina-Dependentes/uso terapêutico , Neoplasias Gastrointestinais/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Inibidores de Proteínas Quinases/uso terapêutico , Desenvolvimento de Medicamentos/tendências , Humanos , Terapia de Alvo Molecular/tendências , Pesquisa Médica Translacional
11.
Int J Clin Oncol ; 24(5): 596-601, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30607523

RESUMO

BACKGROUND: The purpose of this study was to detect background factors that might be associated with the therapeutic and curative outcome of chemotherapy in elderly cancer patients aged over 75 years. METHODS: A retrospective study was conducted for elderly cancer patients aged over 75 years who had received more than 2 courses of chemotherapy at our hospital. We analyzed the relationships between RECIST outcome and background factors, such as age, sex, clinical TNM stage, pre-treatment history, ECOG performance status, serum albumin, and Charlson comorbidity index using logistic regression analysis. RESULTS: A total of 103 cancer patients aged over 75 years were analyzed in this study, including 28 with hematological neoplasia, 36 with gastrointestinal tract cancers, 25 with breast cancers, and 14 with other malignancies originating in various tissues. Seventy-one patients (69.1%) had a positive clinical outcome including RECIST CR (complete response), PR (partial response) and SD (stable disease). Multivariate analysis showed that a high serum albumin level of more than 3.5 g/dl and a Charlson comorbidity index score of less than 2 points were positively correlated with a favorable therapeutic outcome. CONCLUSIONS: The results of the current study suggested that serum albumin level and comorbidity index are the principal clinical factors affecting therapeutic outcomes in elderly cancer patients receiving chemotherapy. In the future, these factors may make chemotherapy adaptations, continuity, and effectiveness easier to predict than GA screening.


Assuntos
Neoplasias/tratamento farmacológico , Albumina Sérica Humana/análise , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/epidemiologia , Estudos de Casos e Controles , Comorbidade , Feminino , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/epidemiologia , Humanos , Masculino , Neoplasias/epidemiologia , Estudos Retrospectivos , Resultado do Tratamento
12.
Drug Saf ; 42(2): 159-179, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30649744

RESUMO

Angiogenesis is an essential process for tumor growth and metastasis. Inhibition of angiogenesis as an anticancer strategy has shown significant results in a plethora of tumors. Anti-angiogenic agents are currently part of many standard-of-care options for several metastatic gastrointestinal cancers. Bevacizumab, aflibercept, ramucirumab, and regorafenib have significantly improved both progression-free and overall survival in different lines of treatment in metastatic colorectal cancer. Second-line ramucirumab and third-line apatinib are effective anti-angiogenic treatments for patients with metastatic gastric cancer. Unfortunately, the anti-angiogenic strategy has major practical limitations: resistance inevitably develops through redundancy of signaling pathways and selection for subclonal populations adapted for hypoxic conditions. Anti-angiogenic agents may be more effective in combination therapies, with not only cytotoxics but also other emerging compounds in the anti-angiogenic class or in the separate class of the so-called vascular-disrupting agents. This review aims to provide an overview of the approved and "under development" anti-angiogenic compounds as well as the vascular-disrupting agents in the treatment of gastrointestinal cancers, focusing on the actual body of knowledge available on therapy challenges, pharmacodynamic and pharmacokinetic mechanisms, safety profiles, promising predictive biomarkers, and future perspectives.


Assuntos
Inibidores da Angiogênese/administração & dosagem , Antineoplásicos/administração & dosagem , Neoplasias Gastrointestinais/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores da Angiogênese/metabolismo , Animais , Antineoplásicos/metabolismo , Desenvolvimento de Medicamentos/métodos , Neoplasias Gastrointestinais/metabolismo , Humanos , Neovascularização Patológica/metabolismo , Ligação Proteica/fisiologia , Inibidores de Proteínas Quinases/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
13.
Expert Opin Pharmacother ; 20(4): 399-409, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30649964

RESUMO

INTRODUCTION: Capecitabine is an oral prodrug of 5-fluorouracil (5-FU) which is converted to 5FU by a series of reactions catalyzed by different enzymes, the last of the enzymes being thymidine phosphorylase (TP). TP is found to be elevated in tumor cells in comparison to normal cells, which consequently tumor-localizes the production of 5-FU, thereby limiting its systemic toxicity. Today, capecitabine is extensively used for the treatment of many solid malignancies, with a particular focus in breast and gastrointestinal tumors, but also in pancreatic cancer. Areas covered: This review summarizes the pharmacology and the clinical evidence relevant to the use of capecitabine in the treatment of pancreas cancer. The authors provide, furthermore, provide their expert perspectives on its use. Expert opinion: Capecitabine has the advantage over other therapeutics in so much that it has both convenient oral administration and a favorable toxicity profile. Current data has promised the use of capecitabine in all stages of pancreatic cancer. However, predictive markers for outcome and toxicity remain to be validated.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Capecitabina/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Neoplasias Gastrointestinais/tratamento farmacológico , Humanos , Pró-Fármacos , Timidina Fosforilase/metabolismo
14.
Drugs ; 79(1): 1-10, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30604292

RESUMO

Immune checkpoint blockade has revolutionised the treatment of multiple cancers including melanoma, non-small cell lung cancer, urothelial and renal cell cancers. For patients with chemorefractory gastroesophageal cancer, treatment with anti-PD-1 therapy results in modest benefits in overall survival; nivolumab and pembrolizumab have been licenced in Japan and the USA, respectively, for this indication. However, initial enthusiasm has been tempered by the results of several large negative trials; immune checkpoint blockade is not superior to chemotherapy in the second-line setting or beyond in unselected or low PD-L1-expressing patients. Microsatellite instability is uncommon in patients with metastatic gastric cancer; however, it is associated with response rates of more than 50% and long-term survival benefit. Combining anti-PD-1 with cytotoxic chemotherapy and targeted therapies also shows promise to extend the benefit of immune checkpoint blockade to a larger proportion of gastroesophageal cancer patients. In this review we discuss recently reported and ongoing clinical research in immunotherapy for gastroesophageal cancer, and consider molecular biology associated with sensitivity and resistance to immune checkpoint blockade in gastroesophageal cancer patients.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Gastrointestinais/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Neoplasias Gastrointestinais/imunologia , Humanos , Imunoterapia , Terapia de Alvo Molecular , Nivolumabe/uso terapêutico , Receptor de Morte Celular Programada 1/imunologia
15.
Gastroenterology ; 156(4): 890-903, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30578781

RESUMO

In the recent few years, significant efforts have been undertaken for the development of different immunotherapeutic approaches against cancer. In this context, immune checkpoint inhibitors (ICIs), a novel class of immunotherapeutic drugs with the potential to unleash the immune system, have emerged as authentic game-changers for managing patients with various cancers, including gastrointestinal malignancies. Although the majority of gastrointestinal cancers are generally considered poorly immunogenic, basic research findings and data from clinical trials have proven that subset(s) of patients with various digestive tract cancers are highly responsive to ICI-based therapy. In this context, a better understanding on the role of various DNA repair pathway alterations, especially the evidence supporting the significant importance of DNA mismatch repair deficiencies and the efficacy of the anti-programmed cell death 1 drugs, have led to US Food and Drug Administration approval of 2 anti-programmed cell death 1 antibodies (pembrolizumab and nivolumab) for the treatment of patients with microsatellite instability. This review aims to provide a comprehensive and up-to-date summary for the role of DNA mismatch repair deficiency in cancer, and its importance in the development of ICI therapy. In addition, we provide insights into the spectrum of various genetic alterations underlying ICI resistance, together with the important influence that the tumor microenvironment plays in mediating the therapeutic response to this new class of drugs. Finally, we provide a comprehensive yet succinct glimpse into the most exciting preclinical discoveries and ongoing clinical trials in the field, highlighting bench-to-beside translational impact of this exciting area of research.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Reparo de Erro de Pareamento de DNA , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/genética , Instabilidade de Microssatélites , Anticorpos Monoclonais Humanizados/uso terapêutico , Biomarcadores Tumorais , Resistencia a Medicamentos Antineoplásicos , Microbioma Gastrointestinal , Humanos , Ipilimumab/uso terapêutico , Nivolumabe/uso terapêutico
16.
Anticancer Res ; 39(1): 159-165, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30591453

RESUMO

BACKGROUND/AIM: L-type amino acid transporter 1 (LAT1) is a promising molecular target for cancer therapy. The present study aimed to characterize the anti-cancer effects of JPH203, an LAT1-selective inhibitor, on gastrointestinal cancer cells. MATERIALS AND METHODS: Three esophageal, two gastric, and two colon cancer cell lines were used. Cytotoxic effects of JPH203 were assessed by a WST-8 assay. LAT1 mRNA levels were determined by quantitative PCR. The inhibitory property of JPH203 against LAT1 function was examined by a transport assay. RESULTS: JPH203 treatment significantly reduced the viability of all gastric and colon cancer cells. While LAT1 expression levels and inhibitory potencies of JPH203 on LAT1 functions were comparable among the cells, all the esophageal cells were resistant to JPH203. CONCLUSION: JPH203 was effective in reducing gastric and colon cancer cells. To clarify its cell type-dependent efficacy, identification of the causal factors for JPH203 resistance will be needed.


Assuntos
Benzoxazóis/farmacologia , Neoplasias do Colo/tratamento farmacológico , Neoplasias Gastrointestinais/tratamento farmacológico , Transportador 1 de Aminoácidos Neutros Grandes/genética , Tirosina/análogos & derivados , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Tirosina/farmacologia
17.
Iran J Allergy Asthma Immunol ; 17(4): 318-325, 2018 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-30537795

RESUMO

Mir-22-3p is associated with many important biological processes, including neuroprotection, tumorigenesis, and various other tumor progressions. Our study aimed to investigate the roles of Mir-22-3p in chemosensitivity of gastrointestinal stromal tumor (GIST-T1) cells to cisplatin and explore its underlying mechanisms. Mir-22-3p high-expressing cell line was established by transfecting GIST-T1 cell line cells with Mir-22-3p mimic. After treatment with cisplatin (10 µM), Cell counting kits-8 (CCK-8) method was used to detect the cell viability. Flow cytometry was applied to measure the degree of cell apoptosis. Scratch wound healing test was used to detect the migration ability of cells. The protein and mRNA levels of the phosphatase and tensin homolog deleted on chromosome ten (PTEN)/phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) pathway-related factors were analyzed by Western blot and qRT-PCR. The mRNA level of Mir-22-3p was increased in transfected GIST-T1 cells compared with that in control cells. The survival rate and Bcl-2/Bax ratio of GIST-T1 cells treated with both Mir-22-3p analogue and cisplatin were significantly decreased, while the apoptosis rate and protein level of caspase-3 were significantly increased (p<0.05). In addition, the mRNA and protein levels of PTENwere significantly increased in cells treated with both Mir-22-3p analogue and cisplatin (p<0.05), while the expression levels of PI3K and Akt were significantly decreased (p<0.05). Mir-22-3p overexpression can increase the chemosensitivity of cisplatin in human gastrointestinal stromal tumor cells by PTEN/PI3K/Akt pathway.


Assuntos
Antineoplásicos/uso terapêutico , Cisplatino/uso terapêutico , Neoplasias Gastrointestinais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , MicroRNAs/genética , Apoptose , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/metabolismo , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/metabolismo , Humanos , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais
18.
Crit Rev Oncol Hematol ; 130: 13-26, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30196908

RESUMO

The use of immune checkpoint inhibitors constitutes an emerging therapeutic field for the therapy of gastrointestinal (GI) malignancies following the recent FDA approvals of PD-1 inhibitors for esophago-gastric adenocarcinoma, hepatocellular carcinoma and for microsatellite-instable tumors, which are mainly colorectal cancers. This paper reviews the clinical evidence end of 2017 and discusses the clinical development programs of atezolizumab, avelumab, durvalumab, nivolumab and pembrolizumab in GI-tract cancers. Since 2014, these antagonists of the PD-1/PD-L1 axis have gained approval for use in numerous other tumors. Phase II trials and phase I expansion cohorts demonstrate clinical activity in patients with oesophageal, gastric, colorectal, anal and hepatic cancer. Signals of outstanding efficacy are particularly observed in biomarker selected populations and for certain combination regimen. Comprehensive phase III development programs have been initiated in oesophageal and gastric cancer, with randomized trials ongoing in hepatocellular and colorectal cancer as well.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Neoplasias Gastrointestinais/tratamento farmacológico , Imunoterapia/métodos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Gastrointestinais/imunologia , Humanos
19.
Crit Rev Oncol Hematol ; 130: 78-91, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30196915

RESUMO

KRAS mutations are common in pancreatic and colorectal cancers and are associated with lack of response to anti-epidermal growth factor receptor therapy. Ras is an established therapeutic target that has long eluded efforts to develop specific inhibitors, while targeting downstream signaling pathways has proven largely ineffective, highlighting a need for rational combination strategies to overcome resistance. Recently, renewed interest in directly targeting Ras has led to the development of several small-molecule inhibitors that bind directly to K-Ras or its effector proteins, downregulation of K-Ras expression using therapeutic antisense oligonucleotides or siRNAs, and targeting scaffold proteins such as kinase suppressor of Ras. Indirect approaches to inhibiting K-Ras include combining inhibitors of the mitogen-activated protein kinase pathway with novel targeted agents. Immunotherapy in early studies has also shown clinical promise. This review summarizes the current evidence for each of these approaches.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Gastrointestinais/tratamento farmacológico , Terapia de Alvo Molecular , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/metabolismo , Humanos , Prognóstico
20.
Expert Opin Pharmacother ; 19(13): 1451-1463, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30161003

RESUMO

INTRODUCTION: Metronomic chemotherapy (mCT) is endowed with various properties, ranging from antiangiogenic to immunomodulation, and may revert tumor resistance to conventional drug administration. A variety of antineoplastic agents displayed activity when administered with metronomic schedules in preclinical models of gastrointestinal cancers. However, most of the field is still unexplored. Areas covered: Herein, the authors review the existing literature from PubMed, concerning the use of mCT in gastrointestinal oncology. Expert opinion: A mounting body of evidence is emerging in support of mCT as a treatment option for gastrointestinal tumors, but the frequent signs of clinical activity inconsistently translate into a benefit for survival. Research in this field should focus on providing high-quality evidence on the safety and efficacy of mCT, with more prospective, comparative trials; identifying the subgroups of patients for whom mCT would be the best approach; establishing standardized protocols based on mCT pharmacokinetics and pharmacodynamics; developing drug activity biomarkers. mCT is also potentially suitable for combinations with targeted antiangiogenic drugs and may be incorporated with conventional administration into dual regimens.


Assuntos
Inibidores da Angiogênese/administração & dosagem , Antineoplásicos/administração & dosagem , Neoplasias Gastrointestinais/tratamento farmacológico , Inibidores da Angiogênese/uso terapêutico , Animais , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Humanos
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