Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 8 de 8
Filtrar
1.
Cancer Prev Res (Phila) ; 14(1): 65-76, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-32917645

RESUMEN

Increased COX-2 and decreased 15-hydroxyprostaglandin dehydrogenase (15-HPGD) expression promote prostaglandin-mediated inflammation and colorectal carcinogenesis. Experimental studies suggest that vitamin D and calcium may inhibit these pathways, but their effects on colorectal tissue COX-2 and 15-HPGD expression in humans are unknown. We tested the effects of supplemental vitamin D (1,000 IU/day) and/or calcium (1,200 mg/day) on COX-2 and 15-HPGD expression in the morphologically normal rectal mucosa from 62 paients with colorectal adenoma in a placebo-controlled chemoprevention trial. We measured biomarker expression using automated IHC and quantitative image analysis at baseline and 1-year follow-up, and assessed treatment effects using mixed linear models. The primary outcome was the COX-2/15-HPGD expression ratio, because these enzymes function as physiologic antagonists. After 1 year of treatment, the mean COX-2/15-HPGD expression ratio in full-length crypts proportionately decreased 47% in the vitamin D group (P = 0.001), 46% in the calcium group (P = 0.002), and 34% in the calcium + vitamin D group (P = 0.03), relative to the placebo group. Among individuals with the functional vitamin D-binding protein isoform DBP2 (GC rs4588*A), the COX-2/15-HPDG ratio decreased 70% (P = 0.0006), 75% (P = 0.0002), and 60% (P = 0.006) in the vitamin D, calcium, and combined supplementation groups, respectively, relative to placebo. These results show that vitamin D and calcium favorably modulate the balance of expression of COX-2 and 15-HPGD-biomarkers of inflammation that are strongly linked to colorectal carcinogenesis-in the normal-appearing colorectal mucosa of patients with colorectal adenoma (perhaps especially those with the DBP2 isoform). PREVENTION RELEVANCE: Supplemental calcium and vitamin D reduce indicators of cancer-promoting inflammation in normal colorectal tissue in humans, thus furthering our understanding of how they may help prevent colorectal cancer.


Asunto(s)
Adenoma/prevención & control , Carbonato de Calcio/administración & dosificación , Neoplasias Colorrectales/prevención & control , Mucosa Intestinal/inmunología , Vitamina D/administración & dosificación , Adenoma/inmunología , Adenoma/patología , Anciano , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/metabolismo , Colon/efectos de los fármacos , Colon/enzimología , Colon/inmunología , Colon/patología , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/patología , Ciclooxigenasa 2/análisis , Ciclooxigenasa 2/metabolismo , Suplementos Dietéticos , Femenino , Estudios de Seguimiento , Humanos , Hidroxiprostaglandina Deshidrogenasas/análisis , Hidroxiprostaglandina Deshidrogenasas/metabolismo , Inflamación/diagnóstico , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Inflamación/patología , Mucosa Intestinal/enzimología , Mucosa Intestinal/patología , Masculino , Persona de Mediana Edad , Recto/efectos de los fármacos , Recto/enzimología , Recto/inmunología , Recto/patología , Resultado del Tratamiento
2.
Cancer Prev Res (Phila) ; 14(3): 393-402, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33229339

RESUMEN

Gut barrier dysfunction promotes chronic inflammation, contributing to several gastrointestinal diseases, including colorectal cancer. Preliminary evidence suggests that vitamin D and calcium could prevent colorectal carcinogenesis, in part, by influencing gut barrier function. However, relevant human data are scarce. We tested the effects of supplemental calcium (1,200 mg/day) and/or vitamin D3 (1,000 IU/day) on circulating concentrations of biomarkers of gut permeability (anti-flagellin and anti-lipopolysaccharide IgA and IgG, measured via ELISA) from baseline to 1 and 3 or 5 years postbaseline among 175 patients with colorectal adenoma in a randomized, double-blinded, placebo-controlled clinical trial. We also assessed factors associated with baseline concentrations of these biomarkers. We found no appreciable effects of supplemental vitamin D3 and/or calcium on individual or aggregate biomarkers of gut permeability. At baseline, a combined permeability score (the summed concentrations of all four biomarkers) was 14% lower among women (P = 0.01) and 10% higher among those who consumed >1 serving per day of red or processed meats relative to those who consumed none (P trend = 0.03). The permeability score was estimated to be 49% higher among participants with a body mass index (BMI) > 35 kg/m2 relative to those with a BMI < 22.5 kg/m2 (P trend = 0.17). Our results suggest that daily supplemental vitamin D3 and/or calcium may not modify circulating concentrations of gut permeability biomarkers within 1 or 3-5 years, but support continued investigation of modifiable factors, such as diet and excess adiposity, that could affect gut permeability. PREVENTION RELEVANCE: Calcium and vitamin D may be involved in regulating and maintaining the integrity of the intestinal mucosal barrier, the dysfunction of which results in exposure of the host to luminal bacteria, endotoxins, and antigens leading to potentially cancer-promoting endotoxemia and chronic colon inflammation. While our results suggest that daily supplementation with these chemopreventive agents does not modify circulating concentrations of gut permeability biomarkers, they support continued investigation of other potential modifiable factors, such as diet and excess adiposity, that could alter gut barrier function, to inform the development of treatable biomarkers of risk for colorectal neoplasms and effective colon cancer preventive strategies.


Asunto(s)
Adenoma/tratamiento farmacológico , Biomarcadores de Tumor/sangre , Calcio de la Dieta/administración & dosificación , Neoplasias del Colon/tratamiento farmacológico , Suplementos Dietéticos , Tracto Gastrointestinal/efectos de los fármacos , Vitamina D/administración & dosificación , Adenoma/metabolismo , Adenoma/patología , Anciano , Calcio de la Dieta/sangre , Estudios de Casos y Controles , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Método Doble Ciego , Femenino , Estudios de Seguimiento , Tracto Gastrointestinal/metabolismo , Tracto Gastrointestinal/patología , Humanos , Masculino , Persona de Mediana Edad , Permeabilidad , Pronóstico , Vitamina D/sangre , Vitaminas/administración & dosificación , Vitaminas/sangre
3.
Mol Carcinog ; 58(7): 1279-1290, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-30938860

RESUMEN

The physical gut barrier, comprised of a thick mucus layer and the epithelium, plays an important role in defense against microbes and foreign antigens. Calcium and vitamin D may be involved in maintaining the integrity of the intestinal mucosal barrier, the dysfunction of which may lead to endotoxemia and inflammation, and contribute to colorectal carcinogenesis. We investigated supplemental calcium (1200 mg, daily) and/or vitamin D3 (1000 IU daily) effects on intestinal barrier function-related biomarkers in a subset of 105 participants from a large colorectal adenoma recurrence chemoprevention clinical trial. We assessed expression of the tight junction proteins claudin-1 (CLDN1), occludin (OCLD), and mucin-12 (MUC12) in the normal-appearing colorectal mucosa using standardized, automated immunohistochemistry and quantitative image analysis. Following 1 year of treatment, in the calcium relative to the no calcium group, the CLDN1, OCLD, and MUC12 expression increased by 14% (P = 0.17), 23% (P = 0.11), and 22% (P = 0.07), respectively. In secondary analyses, the estimated calcium treatment effects were greater among participants with baseline serum 25-OH-vitamin D concentrations below the median value of 22.69 ng/mL (CLDN1: 29%, P = 0.04; OCLD: 36%, P = 0.06; MUC12: 35%, P = 0.05). There were no biomarker expression changes in the vitamin D3 alone group; however, modest increases were found in the combined calcium/vitamin D3 group. At baseline, obesity, history of a sessile-serrated adenoma, colorectal MIB-1/Ki-67 expression, and a family history of colorectal cancer were associated with CLDN1, OCLD, and MUC12 expression. Our study supports continued investigation of factors that could affect intestinal mucosal barrier integrity relevant to colorectal carcinogenesis.


Asunto(s)
Poliposis Adenomatosa del Colon/patología , Calcio de la Dieta/uso terapéutico , Colecalciferol/uso terapéutico , Claudina-1/metabolismo , Neoplasias Colorrectales/patología , Mucinas/metabolismo , Ocludina/metabolismo , Anciano , Biomarcadores de Tumor/sangre , Suplementos Dietéticos , Conducta Alimentaria , Femenino , Humanos , Mucosa Intestinal/metabolismo , Masculino , Persona de Mediana Edad , Encuestas y Cuestionarios , Uniones Estrechas/fisiología
4.
Mol Carcinog ; 58(4): 511-523, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30499618

RESUMEN

Abnormal expression of the DNA mismatch repair protein MSH2 and autocrine/paracrine transforming growth factors TGFα (growth promoter) and TGFß1 (growth inhibitor) is common during colorectal carcinogenesis. To estimate vitamin D and calcium effects on these biomarkers in the normal-appearing colorectal mucosa of sporadic colorectal adenoma patients, we conducted a pilot, randomized, double-blinded, placebo-controlled, modified 2 × 2 factorial chemoprevention clinical trial (N = 104) of supplemental vitamin D3 (1000 IU daily) and calcium (1200 mg daily), alone and in combination, versus placebo over 1 year. The expression of the three biomarkers and Ki-67/mib-1 in colorectal crypts in biopsies of normal-appearing rectal mucosa were detected using automated immunohistochemistry and quantified using image analysis. In the vitamin D3 and vitamin D3 plus calcium groups, relative to their reference groups, in the upper 40% (differentiation zone) of crypts, it was estimated that, respectively, the MSH2/mib-1 ratio increased by 47% (P = 0.14) and 62% (P = 0.08), TGFß1 expression increased by 41% (P = 0.25) and 78% (P = 0.14), and the TGFα/TGFß1 ratio decreased by 25% (P = 0.31) and 44% (P = 0.13). Although not statistically significant, these results support further research into (i) whether supplemental vitamin D3 , alone or in combination with calcium, may increase DNA mismatch repair relative to proliferation, increase TGFß1 expression, and decrease autocrine/paracrine growth promotion relative to growth inhibition in the colorectal epithelium, all hypothesized to reduce risk for colorectal carcinogenesis; and (ii) the expression of MSH2 relative to mib-1, TGFß1 alone, and TGFα relative to TGFß1 in the normal-appearing rectal mucosa as potential modifiable, pre-neoplastic markers of risk for colorectal neoplasms.


Asunto(s)
Adenoma/metabolismo , Calcio/administración & dosificación , Neoplasias Colorrectales/metabolismo , Proteína 2 Homóloga a MutS/metabolismo , Factor de Crecimiento Transformador alfa/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Vitamina D/administración & dosificación , Adenoma/tratamiento farmacológico , Adenoma/patología , Biomarcadores de Tumor , Estudios de Casos y Controles , Colon/efectos de los fármacos , Colon/metabolismo , Colon/patología , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Suplementos Dietéticos , Método Doble Ciego , Femenino , Estudios de Seguimiento , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Pronóstico , Recto/efectos de los fármacos , Recto/metabolismo , Recto/patología , Vitaminas/administración & dosificación
5.
PLoS One ; 13(12): e0208762, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30557404

RESUMEN

To clarify the roles of vitamin D and calcium as potential chemopreventive agents against colorectal cancer in humans, and to develop "treatable", pre-neoplastic, phenotypic biomarkers of risk for colorectal neoplasms, we estimated the effects of supplemental vitamin D3 (1,000 IU/day [25 µg/day]) and calcium (1,200 mg/day), alone and in combination, on biomarkers of proliferation (mib-1), differentiation (p21), and apoptosis (bax [apoptosis-promoting] and bcl-2 [apoptosis-inhibiting]), in the normal-appearing rectal mucosa in a subsample of participants (n = 104) in a larger randomized, double-blind, placebo-controlled clinical trial among colorectal adenoma patients. The biomarkers were measured in rectal biopsies at baseline and after one year of follow up, using automated immunohistochemistry and quantitative image analysis. In the vitamin D plus calcium group relative to control, in the crypt differentiation zone (upper 40% of crypts), mib-1 expression decreased 24% (P = 0.28); p21 expression alone and relative to mib-1 expression increased 29% (P = 0.06) and 73% (P = 0.06), respectively; and bax expression relative to mib-1 expression increased 58% (P = 0.21). The estimated vitamin D alone treatment effects were similar but of lesser magnitudes, and those for calcium alone were mixed. All estimated treatment effects on bcl-2 expression were close to the null. These pilot study results support further investigation of whether 1) vitamin D and calcium promote colorectal epithelial cell differentiation, reduce proliferation, and promote apoptosis in the normal-appearing human colorectal mucosa, 2) vitamin D and calcium act as chemopreventive agents against colorectal neoplasms, and 3) mib-1, p21, and bax are potential "treatable", pre-neoplastic, biomarkers of risk for colorectal neoplasms.


Asunto(s)
Adenoma/terapia , Calcio/uso terapéutico , Neoplasias Colorrectales/terapia , Suplementos Dietéticos , Mucosa Intestinal/fisiopatología , Vitamina D/uso terapéutico , Adenoma/patología , Adenoma/fisiopatología , Anciano , Apoptosis , Biomarcadores de Tumor/metabolismo , Diferenciación Celular , Proliferación Celular , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/fisiopatología , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Método Doble Ciego , Femenino , Estudios de Seguimiento , Humanos , Mucosa Intestinal/patología , Antígeno Ki-67/metabolismo , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/prevención & control , Proyectos Piloto , Proteína X Asociada a bcl-2/metabolismo
6.
Cancer Prev Res (Phila) ; 11(11): 707-716, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30209117

RESUMEN

Chronic inflammation in the colorectum, a significant contributor to colorectal carcinogenesis, can be triggered by the activation of proinflammatory signaling pathways such as those initiated by Toll-like receptors (TLR) and nuclear factor κB (NF-κB). Although experimental evidence supports calcium and vitamin D potentially modifying these proinflammatory pathways in the colorectum, human data in these regards are scarce. We investigated supplemental calcium (1,200 mg daily) and/or vitamin D3 (1,000 IU daily) effects on inflammatory signaling pathway-related biomarkers in a subset of 105 participants from a colorectal adenoma recurrence chemoprevention clinical trial. We assessed expression of TLR4 and TLR5, which recognize the bacterial components lipopolysaccharides and flagellin, respectively, and phospho-IKKα/ß (pIKKα/ß), a biomarker of inflammation, in the normal-appearing rectal crypt epithelium and stroma using standardized, automated immunohistochemistry and quantitative image analysis. Following 1 year of treatment, TLR4, TLR5, and pIKKα/ß expression in the rectal mucosa did not statistically significantly change with vitamin D or calcium supplementation, taken alone or in combination. Several baseline participant characteristics, including body mass index, history of sessile serrated adenomas, high red/processed meat intake, and high levels of rectal epithelial cell proliferation (as measured by MIB-1/Ki-67), were associated with higher baseline expression of TLRs or pIKKα/ß. Our findings suggest that vitamin D and calcium may have no substantial effect on the investigated biomarkers. However, several modifiable lifestyle factors may be associated with TLRs and pIKKα/ß expression in the normal rectal mucosa, supporting their future investigation as potentially treatable, preneoplastic risk factors for colorectal neoplasms. Cancer Prev Res; 11(11); 707-16. ©2018 AACR.


Asunto(s)
Calcio/administración & dosificación , Suplementos Dietéticos , Proctitis/dietoterapia , Vitamina D/administración & dosificación , Adenoma/patología , Adenoma/prevención & control , Anciano , Biomarcadores/análisis , Biomarcadores/metabolismo , Biopsia , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/prevención & control , Femenino , Estudios de Seguimiento , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Quinasa I-kappa B/inmunología , Quinasa I-kappa B/metabolismo , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/prevención & control , Fosforilación/efectos de los fármacos , Proctitis/diagnóstico , Proctitis/inmunología , Proctitis/patología , Recto/efectos de los fármacos , Recto/metabolismo , Recto/patología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Receptores Toll-Like/inmunología , Receptores Toll-Like/metabolismo , Resultado del Tratamiento
7.
Mol Carcinog ; 56(2): 412-424, 2017 02.
Artículo en Inglés | MEDLINE | ID: mdl-27254743

RESUMEN

APC/ß-catenin pathway malfunction is a common and early event in colorectal carcinogenesis. To assess calcium and vitamin D effects on the APC/ß-catenin pathway in the normal-appearing colorectal mucosa of sporadic colorectal adenoma patients, nested within a larger randomized, double-blind, placebo-controlled, partial 2 × 2 factorial chemoprevention clinical trial of supplemental calcium (1200 mg daily) and vitamin D (1000 IU daily), alone and in combination versus placebo, we assessed APC, ß-catenin, and E-cadherin expression in colon crypts in normal-appearing rectal mucosa biopsies from 104 participants at baseline and 1-yr follow up using standardized, automated immunohistochemistry and quantitative image analysis. For vitamin D versus no vitamin D, the ratio of APC expression to ß-catenin expression in the upper 40% (differentiation zone) of crypts (APC/ß-catenin score) increased by 28% (P = 0.02), for calcium versus no calcium it increased by 1% (P = 0.88), and for vitamin D + calcium versus calcium by 35% (P = 0.01). Total E-cadherin expression increased by 7% (P = 0.35) for vitamin D versus no vitamin D, 8% (P = 0.31) for calcium versus no calcium, and 12% (P = 0.21) for vitamin D + calcium versus calcium. These results support (i) that vitamin D, alone or in combination with calcium, may modify APC, ß-catenin, and E-cadherin expression in humans in directions hypothesized to reduce risk for colorectal neoplasms; (ii) vitamin D as a potential chemopreventive agent against colorectal neoplasms; and (iii) the potential of APC, ß-catenin, and E-cadherin expression as treatable, pre-neoplastic risk biomarkers for colorectal neoplasms. © 2016 Wiley Periodicals, Inc.


Asunto(s)
Adenoma/prevención & control , Proteína de la Poliposis Adenomatosa del Colon/análisis , Calcio de la Dieta/uso terapéutico , Colon/patología , Neoplasias Colorrectales/prevención & control , Recto/patología , Vitamina D/uso terapéutico , beta Catenina/análisis , Adenoma/patología , Anciano , Biomarcadores de Tumor/análisis , Cadherinas/análisis , Neoplasias Colorrectales/patología , Femenino , Humanos , Mucosa Intestinal/patología , Masculino , Persona de Mediana Edad , Transducción de Señal , Vitaminas/uso terapéutico
8.
N Engl J Med ; 373(16): 1519-30, 2015 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-26465985

RESUMEN

BACKGROUND: Epidemiologic and preclinical data suggest that higher intake and serum levels of vitamin D and higher intake of calcium reduce the risk of colorectal neoplasia. To further study the chemopreventive potential of these nutrients, we conducted a randomized, double-blind, placebo-controlled trial of supplementation with vitamin D, calcium, or both for the prevention of colorectal adenomas. METHODS: We recruited patients with recently diagnosed adenomas and no known colorectal polyps remaining after complete colonoscopy. We randomly assigned 2259 participants to receive daily vitamin D3 (1000 IU), calcium as carbonate (1200 mg), both, or neither in a partial 2×2 factorial design. Women could elect to receive calcium plus random assignment to vitamin D or placebo. Follow-up colonoscopy was anticipated to be performed 3 or 5 years after the baseline examinations, according to the endoscopist's recommendation. The primary end point was adenomas diagnosed in the interval from randomization through the anticipated surveillance colonoscopy. RESULTS: Participants who were randomly assigned to receive vitamin D had a mean net increase in serum 25-hydroxyvitamin D levels of 7.83 ng per milliliter, relative to participants given placebo. Overall, 43% of participants had one or more adenomas diagnosed during follow-up. The adjusted risk ratios for recurrent adenomas were 0.99 (95% confidence interval [CI], 0.89 to 1.09) with vitamin D versus no vitamin D, 0.95 (95% CI, 0.85 to 1.06) with calcium versus no calcium, and 0.93 (95% CI, 0.80 to 1.08) with both agents versus neither agent. The findings for advanced adenomas were similar. There were few serious adverse events. CONCLUSIONS: Daily supplementation with vitamin D3 (1000 IU), calcium (1200 mg), or both after removal of colorectal adenomas did not significantly reduce the risk of recurrent colorectal adenomas over a period of 3 to 5 years. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00153816.).


Asunto(s)
Adenoma/prevención & control , Calcio/uso terapéutico , Neoplasias Colorrectales/prevención & control , Suplementos Dietéticos , Vitamina D/uso terapéutico , Vitaminas/uso terapéutico , Adenoma/epidemiología , Anciano , Calcio/efectos adversos , Neoplasias Colorrectales/epidemiología , Suplementos Dietéticos/efectos adversos , Método Doble Ciego , Quimioterapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Riesgo , Insuficiencia del Tratamiento , Vitamina D/análogos & derivados , Vitamina D/sangre
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA