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1.
Cancers (Basel) ; 15(7)2023 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-37046763

RESUMO

After potentially curative treatment, colorectal cancer (CRC) patients remain at high risk for recurrence, second primary CRC, and high-risk adenomas. In combination with existing data, our previous findings provide a rationale for reducing tissue polyamines as tertiary prevention in non-metastatic CRC patients. The goal of this study was to demonstrate rectal tissue polyamine reduction in optimally treated stage I-III CRC patients after intervention with daily oral aspirin + dietary arginine restriction. A single-institution phase IIa clinical trial was conducted. Patients were treated with aspirin 325 mg/day and an individualized dietary regimen designed to reduce arginine intake by ≥30% over a 12-week study period. Dietary intake, endoscopy with rectal biopsies, and phlebotomy were performed pre- and post-intervention. The primary endpoint was to demonstrate ≥50% decrease in rectal tissue putrescine levels from baseline as a measure of polyamine reduction in the target tissue. Twenty eligible patients completed the study. After study intervention, mean dietary arginine intake decreased from 3.7 g/day ± 1.3 SD to 2.6 g/day ± 1.2 SD (29.7% decrease, p < 0.02 by Sign test). Mean plasma arginine levels decreased from 46.0 ng/mL ± 31.5 SD at baseline to 35 ng/mL ± 21.7 SD (p < 0.001). Rectal tissue putrescine levels were 0.90 nMol/mg-protein pre-intervention and 0.99 nMol/mg-protein post-intervention (p < 0.64, NS). No significant differences were observed for the other tissue polyamines investigated: spermidine (p < 0.13), spermine (p < 0.21), spermidine:spermine ratio (p < 0.71). Among CRC survivors, treatment with daily oral aspirin and an individualized dietary arginine restriction intervention resulted in lower calculated dietary arginine intake and plasma arginine levels but did not affect rectal tissue polyamine levels.

2.
Cancer Prev Res (Phila) ; 13(2): 203-212, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31818851

RESUMO

Obesity is associated with risk of colorectal adenoma (CRA) and colorectal cancer. The signaling pathway activated by metformin (LKB1/AMPK/mTOR) is implicated in tumor suppression in ApcMin/+ mice via metformin-induced reduction in polyp burden, increased ratio of pAMPK/AMPK, decreased pmTOR/mTOR ratio, and decreased pS6Ser235/S6Ser235 ratio in polyps. We hypothesized that metformin would affect colorectal tissue S6Ser235 among obese patients with recent history of CRA. A phase IIa clinical biomarker trial was conducted via the U.S. National Cancer Institute-Chemoprevention Consortium. Nondiabetic, obese subjects (BMI ≥30) ages 35 to 80 with recent history of CRA were included. Subjects received 12 weeks of oral metformin 1,000 mg twice every day. Rectal mucosa biopsies were obtained at baseline and end-of-treatment (EOT) endoscopy. Tissue S6Ser235 and Ki-67 immunostaining were analyzed in a blinded fashion using Histo score (Hscore) analysis. Among 32 eligible subjects, the mean baseline BMI was 34.9. Comparing EOT to baseline tissue S6Ser235 by IHC, no significant differences were observed. Mean (SD) Hscore at baseline was 1.1 (0.57) and 1.1 (0.51) at EOT; median Hscore change was 0.034 (P = 0.77). Similarly, Ki-67 levels were unaffected by the intervention. The adverse events were consistent with metformin's known side-effect profile. Among obese patients with CRA, 12 weeks of oral metformin does not reduce rectal mucosa pS6 or Ki-67 levels. Further research is needed to determine what effects metformin has on the target tissue of origin as metformin continues to be pursued as a colorectal cancer chemopreventive agent.


Assuntos
Adenoma/patologia , Pólipos do Colo/patologia , Neoplasias Colorretais/prevenção & controle , Metformina/administração & dosagem , Obesidade/complicações , Adenoma/complicações , Administração Oral , Idoso , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/metabolismo , Biópsia , Índice de Massa Corporal , Pólipos do Colo/complicações , Colonoscopia , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/patologia , Feminino , Humanos , Mucosa Intestinal/diagnóstico por imagem , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Intestino Grosso/diagnóstico por imagem , Intestino Grosso/efeitos dos fármacos , Intestino Grosso/patologia , Masculino , Metformina/efeitos adversos , Pessoa de Meia-Idade , Obesidade/diagnóstico , Proctoscopia , Reto/diagnóstico por imagem , Reto/efeitos dos fármacos , Reto/patologia
4.
Int J Mol Med ; 26(1): 121-5, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20514431

RESUMO

This study was undertaken to define whether differences in the expression of Wnt pathway components are present between normal colonic mucosa, early (tubular) adenomas and villous adenomas which have a higher malignant potential. Normal mucosa, tubular adenomas and villous adenomas were obtained from twelve patients. RNA was isolated and utilized for Wnt pathway-specific membrane array expression analysis. Quantitative real-time polymerase chain reaction (qRT-PCR) and fluorescent immunohistochemistry (IHC) were utilized for confirmatory analyses. Fifteen Wnt pathway-related genes showed differential expression between villous adenomas and normal mucosa and villous and tubular adenomas at a significance level of p<0.01. Genes involved in canonical Wnt (beta-catenin) signaling with increased expression in villous adenomas included wnt1, fz2, csnk2A2, pygo2, pygo1, frat2 and myc, the latter confirmed by qRT-PCR and IHC. Myc protein expression was confined primarily to stromal components of villous adenomas. Genes involved in non-canonical Wnt signaling with increased expression in villous adenomas included rho-u, daam1, damm2, cxxc4 and nlk. Successive increases in the expression of ctnnb1 (beta-catenin) from normal to tubular adenomas to villous adenomas was seen. The Wnt pathway gene expression profile can differentiate between tubular and villous adenomas. These data suggest that Wnt signaling regulation changes during the progression from normal mucosa to tubular adenomas to villous adenomas. Expression of Myc in adenoma stroma suggests a dynamic signaling network within adenomas between mucosal and stromal elements. Inhibition of the Wnt pathway may provide a novel approach for cancer prevention in patients with benign tubular adenomas.


Assuntos
Adenoma Viloso/genética , Adenoma/genética , Neoplasias do Colo/genética , Perfilação da Expressão Gênica , Transdução de Sinais/genética , Adenoma/diagnóstico , Adenoma/metabolismo , Adenoma Viloso/diagnóstico , Adenoma Viloso/metabolismo , Neoplasias do Colo/diagnóstico , Neoplasias do Colo/metabolismo , Diagnóstico Diferencial , Humanos , Imuno-Histoquímica , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteínas Wnt/genética , Proteínas Wnt/metabolismo
5.
Dig Dis Sci ; 53(4): 1013-9, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17939044

RESUMO

The purpose of this study was to examine the expression of Wnt pathway-related genes in patients with ulcerative colitis (UC). RNA from colonoscopic biopsies from noninflammatory bowel disease (non-IBD) subjects and UC patients were obtained and examined with a Wnt-specific microarray for the expression of Wnt pathway-related genes. Paired samples from uninflamed and inflamed areas of the colon were obtained for the UC patients. WNT2B, WNT3A, WNT5B, WNT6, WNT7A, WNT9A, and WNT11 exhibited significantly increased expression in UC compared to non-IBD patients. Frizzled 3 (FZD3) and FZD4 exhibited significantly increased expression, and FZD1 and FZD5 exhibited significantly decreased expression in UC patients. Genes with increased expression in inflamed mucosa included DKK4, DVL2, SOX17, and COL1A1. There was no difference in the expression of a panel of Wnt target genes. The expression of inducible nitric oxide synthase (INOS) was variably influenced by inflammation. Significant differences in extracellular and cell-surface components of the Wnt pathway exist in the colonic mucosa of patients with UC compared with non-IBD patients, which may influence the strength or specificity of Wnt signaling. In inflammation, inhibitory components of the Wnt pathway exhibit increased expression, but no changes in Wnt pathway target gene expression are seen. The role and complex regulation of Sox17 and iNOS in IBD warrant further investigation.


Assuntos
Colite Ulcerativa/metabolismo , Receptores Frizzled/metabolismo , Transdução de Sinais/fisiologia , Proteínas Wnt/metabolismo , Estudos de Casos e Controles , Colite Ulcerativa/etiologia , Colite Ulcerativa/patologia , Feminino , Receptores Frizzled/genética , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , RNA Mensageiro/metabolismo , Proteínas Wnt/genética
6.
Cancer Prev Res (Phila) ; 1(1): 32-8, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18841250

RESUMO

Preclinical studies of chemoprevention drugs given in combination at low doses show remarkable efficacy in preventing adenomas with little additional toxicities, suggesting a strategy to improve risk to benefit ratios for preventing recurrent adenomas. Three hundred seventy-five patients with history of resected (> or =3 mm) adenomas were randomly assigned to receive oral difluoromethylornithine (DFMO) 500 mg and sulindac 150 mg once daily or matched placebos for 36 months, stratified by use of low-dose aspirin (81 mg) at baseline and clinical site. Follow-up colonoscopy was done 3 years after randomization or off-study. Colorectal adenoma recurrence was compared among the groups with log-binomial regression. Comparing the outcome in patients receiving placebos to those receiving active intervention, (a) the recurrence of one or more adenomas was 41.1% and 12.3% (risk ratio, 0.30; 95% confidence interval, 0.18-0.49; P < 0.001); (b) 8.5% had one or more advanced adenomas, compared with 0.7% of patients (risk ratio, 0.085; 95% confidence interval, 0.011-0.65; P < 0.001); and (c) 17 (13.2%) patients had multiple adenomas (>1) at the final colonoscopy, compared with 1 (0.7%; risk ratio, 0.055; 0.0074-0.41; P < 0.001). Serious adverse events (grade > or =3) occurred in 8.2% of patients in the placebo group, compared with 11% in the active intervention group (P = 0.35). There was no significant difference in the proportion of patients reporting hearing changes from baseline. Recurrent adenomatous polyps can be markedly reduced by a combination of low oral doses of DFMO and sulindac and with few side effects.


Assuntos
Adenoma/prevenção & controle , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/prevenção & controle , Eflornitina/administração & dosagem , Sulindaco/administração & dosagem , Adenoma/diagnóstico , Adulto , Idoso , Algoritmos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Colonoscopia , Neoplasias Colorretais/diagnóstico , Método Duplo-Cego , Eflornitina/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Placebos , Sulindaco/efeitos adversos , Resultado do Tratamento
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