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1.
Carcinogenesis ; 22(10): 1653-9, 2001 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-11577005

RESUMEN

High intake of red meat is associated with increased colon cancer risk. We have shown earlier that this may be due to the high haem content of red meat, because dietary haem increased cytolytic activity of faecal water and colonic epithelial proliferation. Dietary calcium inhibits diet-induced epithelial hyperproliferation. Furthermore, it has been shown that supplemental calcium inhibited the recurrence of colorectal adenomas. Therefore, we studied whether dietary calcium phosphate can exert its protective effects by inhibiting the deleterious effects of haem. In vitro, calcium phosphate precipitated haem and inhibited the haem-induced cytotoxicity. Subsequently, rats were fed diets, differing in haem (0 or 1.3 micromol/g) and calcium phosphate content only (20 or 180 micromol/g). Faeces were collected for biochemical analyses. Cytolytic activity of faecal water was determined from the degree of lysis of erythrocytes by faecal water. Colonic epithelial proliferation was measured in vivo using [(3)H]thymidine incorporation. In rats fed low calcium diets, dietary haem increased cytolytic activity of faecal water (98 +/- 1 versus 1 +/- 1%, P < 0.001) and the concentration of cations in faeces (964 +/- 31 versus 254 +/- 20 micromol/g), when compared with controls. This indicates that dietary haem increased colonic mucosal exposure to luminal irritants. Colonic epithelial proliferation was increased compared with controls (70 +/- 4 versus 48 +/- 8 d.p.m./microg DNA, P < 0.001). This was accompanied by metabolism of the ingested haem and solubilization of haem compounds in the faecal water. A high calcium diet largely prevented this metabolism and solubilization. It also inhibited the haem-induced cytolytic activity of faecal water and increase in faecal cation concentration. In accordance, the haem-induced colonic epithelial hyperproliferation was prevented. We therefore suggest that dietary calcium phosphate acts as a chemopreventive agent in colon carcinogenesis by inhibiting the cytolytic and hyperproliferative effects of dietary haem.


Asunto(s)
Fosfatos de Calcio/farmacología , Colon/efectos de los fármacos , Neoplasias del Colon/prevención & control , Hemo/toxicidad , Carne/toxicidad , Animales , División Celular/efectos de los fármacos , Colon/patología , Neoplasias del Colon/inducido químicamente , Neoplasias del Colon/patología , Dieta , Heces/química , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/patología , Masculino , Ratas , Ratas Wistar , Agua/metabolismo
2.
J Pathol ; 194(4): 493-9, 2001 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-11523059

RESUMEN

Chronic sennoside use induces melanosis coli (MC) and possibly increases colorectal cancer risk. Sennosides alter colonic crypt length, proliferative activity, and bcl-2 expression 18 h after administration. To investigate possible mechanisms for carcinogenesis, the effects of acute sennoside use and the presence of MC on colorectal epithelium were studied. Colorectal biopsies from 15 subjects receiving sennosides 6 h before sigmoidoscopy (Sen), 15 controls (NSen), and 27 with MC [11 moderate (MMC) and 16 severe (SMC)]. were analysed for degree of apoptosis (H&E staining), immunohistochemical p53, p21/WAF and bcl-2 expression, and proliferative activity (labelling index, LI). Apoptosis (p=0.0004), intensity of p53 staining (p=0.01), and p21/WAF expression (p=0.008) were increased in Sen and SMC compared with NSen and MMC. p53 expression was increased in Sen (p=0.004). No difference in bcl-2 expression or LI was observed. Crypts were shorter in Sen (p=0.05) and longer in SMC (p=0.04) than in NSen. It is concluded that sennosides acutely induce apoptosis of colonic epithelial cells, presumably by a p53, p21/WAF-mediated pathway, resulting in shorter crypts. In severe melanosis coli, apoptosis seems to be delayed, causing longer crypts without a rise in proliferative activity or bcl-2 expression. This escape from a presumably protective mechanism may enhance the risk of carcinogenesis during chronic sennoside use.


Asunto(s)
Antraquinonas/farmacología , Apoptosis/efectos de los fármacos , Catárticos/farmacología , Colon/efectos de los fármacos , Adolescente , Adulto , Anciano , Biopsia , División Celular/efectos de los fármacos , Transformación Celular Neoplásica/efectos de los fármacos , Colon/metabolismo , Colon/patología , Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Ciclinas/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Extracto de Senna , Senósidos , Proteína p53 Supresora de Tumor/metabolismo
3.
Digestion ; 61(2): 113-20, 2000.
Artículo en Inglés | MEDLINE | ID: mdl-10705175

RESUMEN

BACKGROUND: Chronic use of sennoside laxatives often causes pseudomelanosis coli. A recent study suggested that pseudomelanosis coli is associated with an increased colorectal cancer risk. A single high dose of highly purified senna extract increased proliferation rate and reduced crypt length in the sigmoid colon compared to historical controls. AIMS: To evaluate in a controlled study the effects of highly purified senna extract on cell proliferation and crypt length in the entire colon and on p53 and bcl-2 expression. METHODS: Addition of a senna extract to colonic lavage was studied in 184 consecutive outpatients. From 32 randomised patients, 15 with sennosides (Sen), 17 without (NSen), biopsies were taken. Proliferative activity was studied in 4 areas of the colon, using 5-bromo-2'-deoxyuridine labelling and immunohistochemistry (labelling index, LI). Expression of p53 and bcl-2 in the sigmoid colon was determined immunohistochemically. RESULTS: Crypts were shorter in Sen than in NSen in the transverse and sigmoid colon. LI was higher in Sen than in NSen in the entire colon. No difference in p53 expression was seen. Bcl-2 expression was higher in both groups when crypts were shorter and/or proliferation was increased. CONCLUSION: Sennosides induce acute massive cell loss probably by apoptosis, causing shorter crypts, and increased cell proliferation and inhibition of apoptosis to restore cellularity. These effects may reflect the mechanism for the suggested cancer-promoting effect of chronic sennoside use.


Asunto(s)
Catárticos/efectos adversos , Colon/efectos de los fármacos , Colon/patología , Proteínas Proto-Oncogénicas c-bcl-2/análisis , Extracto de Senna/efectos adversos , Proteína p53 Supresora de Tumor/análisis , Adolescente , Adulto , Anciano , Apoptosis , Biopsia con Aguja , Catárticos/administración & dosificación , División Celular/efectos de los fármacos , División Celular/fisiología , Colonoscopía , Neoplasias Colorrectales/inducido químicamente , Neoplasias Colorrectales/patología , Intervalos de Confianza , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Persona de Mediana Edad , Probabilidad , Valores de Referencia , Medición de Riesgo , Extracto de Senna/administración & dosificación
4.
Cancer Res ; 59(22): 5704-9, 1999 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-10582688

RESUMEN

The intake of a Western diet with a high amount of red meat is associated with a high risk for colon cancer. We hypothesize that heme, the iron carrier of red meat, is involved in diet-induced colonic epithelial damage, resulting in increased epithelial proliferation. Rats were fed purified control diets, or purified diets supplemented with 1.3 micromol/g of hemin (ferriheme), protoporphyrin IX, ferric citrate, or bilirubin (n = 8/group) for 14 days. Feces were collected for biochemical analyses. Fecal cytotoxicity was determined from the degree of lysis of erythrocytes by fecal water. Colonic epithelial proliferation was measured in vivo using [3H]thymidine incorporation into colonic mucosa. The colonic epithelial proliferation in heme-fed rats was significantly increased compared to control rats [55.2 +/- 5.8 versus 32.6 +/- 6.3 dpm/microg DNA (mean +/- SE); P < 0.05]. The fecal water of the heme group was highly cytotoxic compared to the controls (90 +/- 2% versus 2 +/- 1%; P < 0.001), although the concentrations of cytotoxic bile acids and fatty acids were significantly lower. Organic iron was significantly increased compared to the controls (257 +/- 26 versus 80 +/- 21, microM; P < 0.001). Spectrophotometric analyses suggest that this organic iron is heme-associated. Thiobarbituric acid-reactive substances were greatly increased in the fecal water of heme-fed rats compared to the controls (177 +/- 12 versus 59 +/- 7 microM; P < 0.05). Heme itself could not account for the increased cytotoxicity because the addition of heme to the fecal water of the control group, which was equimolar to the organic iron content of the fecal water of the heme group, did not influence the cytotoxicity. Hence, an additional heme-induced cytotoxic factor is involved, which may be modulated by the generation of luminal-reactive oxygen species. Protoporphyrin IX, ferric citrate, and bilirubin did not increase proliferation and cytotoxicity. In conclusion, dietary heme leads to the formation of an unknown, highly cytotoxic factor in the colonic lumen. This suggests that, in heme-fed rats, colonic mucosa is damaged by the intestinal contents. This results in a compensatory hyperproliferation of the epithelium, which supposedly increases the risk for colon cancer.


Asunto(s)
Colon/efectos de los fármacos , Heces/química , Hemo/efectos adversos , Mucosa Intestinal/efectos de los fármacos , Hierro/análisis , Animales , Bilirrubina/efectos adversos , División Celular/efectos de los fármacos , Colon/metabolismo , Colon/patología , Neoplasias del Colon/inducido químicamente , Compuestos Férricos/efectos adversos , Hemina/efectos adversos , Absorción Intestinal , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Hierro/metabolismo , Masculino , Protoporfirinas/efectos adversos , Ratas , Ratas Wistar , Organismos Libres de Patógenos Específicos
5.
Aliment Pharmacol Ther ; 13(4): 443-52, 1999 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-10215727

RESUMEN

Anthranoid laxatives are widely used laxatives of natural origin. Because of their chemical structure they are carried unabsorbed to the large bowel, where metabolism to the active aglycones takes place. These aglycones exert their laxative effect by damaging epithelial cells, which leads directly and indirectly to changes in absorption, secretion and motility. Damaged epithelial cells can be found as apoptotic bodies in the pigmented colonic mucosa, characteristic for pseudomelanosis coli. Pseudomelanosis coli is a condition caused by chronic (ab)use of anthranoid laxatives and has recently been associated with an increased risk of colorectal carcinoma. In vitro and animal studies have shown a potential role of anthranoid laxatives in both the initiation and promotion of tumorigenesis. Studies in humans have also suggested tumour promoting activities for these laxatives. Although the short-term use of these substances is generally safe, long-term use cannot be recommended.


Asunto(s)
Antraquinonas/efectos adversos , Catárticos/efectos adversos , Animales , Antraquinonas/metabolismo , Antraquinonas/farmacología , Carcinógenos/efectos adversos , Carcinógenos/metabolismo , Carcinógenos/farmacología , Cassia/química , Catárticos/metabolismo , Catárticos/farmacología , Neoplasias del Colon/inducido químicamente , Humanos , Plantas Medicinales , Plantas Tóxicas , Rhamnus/química , Factores de Riesgo , Extracto de Senna , Senósidos
6.
Eur Respir J ; 11(5): 1070-4, 1998 May.
Artículo en Inglés | MEDLINE | ID: mdl-9648957

RESUMEN

Acid gastro-oesophageal reflux may aggravate respiratory symptoms in patients with asthma and chronic obstructive pulmonary disease (COPD) by increasing airway hyperresponsiveness through vagally-mediated pathways. We wanted to determine whether elimination of acid reflux could improve symptoms in such patients. In a randomized, double-blind, placebo-controlled study, 36 allergic and nonallergic subjects (17 males and 19 females, mean age 52 yrs), with airway obstruction and severe airway hyperresponsiveness despite maintenance treatment with an inhaled corticosteroid and with increased acid gastro-oesophageal reflux, were treated either with omeprazole, 40 mg b.i.d., or placebo for 3 months. Primary endpoints were: airway hyperresponsiveness, as determined by the provocative concentration of methacholine producing a 20% fall in forced expiratory volume in one second (PC20); and airway obstruction. Secondary endpoints were: peak expiratory flow variability; reversibility to inhaled ipratropium bromide as a parameter of vagal activity; asthma symptoms scores; and medication used. Reflux was measured by 24 h ambulatory intraoesophageal pH measurement. Omeprazole, 40 mg b.i.d., for 3 months had no beneficial effect on any of the pulmonary parameters, despite its profound effect on acid reflux and improvement of reflux symptoms scores, compared to placebo. The results of this study do not support a role for intensive antireflux therapy to improve pulmonary symptoms and function in patients with asthma and chronic obstructive pulmonary disease, who have severe airway hyperresponsiveness despite maintenance treatment with inhaled corticosteroids.


Asunto(s)
Antiulcerosos/uso terapéutico , Reflujo Gastroesofágico/complicaciones , Reflujo Gastroesofágico/tratamiento farmacológico , Omeprazol/administración & dosificación , Hipersensibilidad Respiratoria/complicaciones , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Broncoconstrictores , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Masculino , Cloruro de Metacolina , Persona de Mediana Edad , Omeprazol/uso terapéutico , Hipersensibilidad Respiratoria/fisiopatología , Espirometría
7.
Z Gastroenterol ; 36(1): 13-8, 1998 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-9531685

RESUMEN

INTRODUCTION: A single high dose of sennosides is often used to optimize bowel preparation for diagnostic procedures. From previous studies it is suspected that sennosides in such a dose cause acute damage to the colonic mucosa. This study was designed to determine any effects of sennosides on histology of colonic mucosa and on bowel preparation. RESULTS: In a prospective study 171 patients were randomized for bowel preparation. 84 patients received 1 ml/kg (maximal 75 ml) of a syrup containing 2.0 mg/ml sennoside A and B and 3-5 l of a lavage solution (Sen), 87 patients only received 3-5 l lavage solution (NSen). All patients completed a questionnaire on which patient tolerance was scored. Another questionnaire was completed by the endoscopist, recording quality of the preparation. From the 40 patients with a normal colon (19 Sen, 21 NSen) a biopsy was taken from the sigmoid colon and analyzed for morphological abnormalities. No difference could be demonstrated in tolerance or quality of bowel preparation between the two groups. A marked increase of mononuclear infiltrate in the lamina propria was observed in Sen compared to NSen: in 10/19 vs. 2/21 patients respectively, p < 0.0005. CONCLUSION: As these microscopic effects could hamper the interpretation of colonic biopsies, bowel preparation without sennosides is to be recommended.


Asunto(s)
Antraquinonas/farmacología , Catárticos/farmacología , Colonoscopía , Mucosa Intestinal/efectos de los fármacos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Colon/efectos de los fármacos , Colon/patología , Femenino , Humanos , Mucosa Intestinal/patología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Extracto de Senna , Senósidos , Irrigación Terapéutica
8.
Eur J Cancer ; 31A(7-8): 1081-4, 1995.
Artículo en Inglés | MEDLINE | ID: mdl-7576996

RESUMEN

Nutritional factors are important determinants of colorectal cancer risk. Diets high in fat and/or low in fibre are especially recognised to increase risk. Dietary calcium and vitamin D have been suggested to be protective against colorectal cancer. With respect to calcium, its possible effect is thought to be mediated at least in part through intraluminal precipitation of hydrophobic, cytotoxic substances, in particular fatty and bile acids, which can promote colorectal cancer development. Data from studies in vitro and in animals support a protective effect of calcium, but studies in humans, both epidemiological and interventional, have given inconclusive results. With respect to vitamin D, data from only a small number of studies are available. Results suggest a protective effect by inhibition of cell proliferation, mediated through specific receptors. It is concluded that there are currently insufficient reasons to supplement subjects at increased colon cancer risk with calcium or vitamin D, especially when dietary intake of these substances is in agreement with general guidelines.


Asunto(s)
Calcio de la Dieta/uso terapéutico , Neoplasias Colorrectales/prevención & control , Vitamina D/uso terapéutico , Animales , División Celular/efectos de los fármacos , Transformación Celular Neoplásica/efectos de los fármacos , Humanos , Ratas
9.
Eur J Cancer ; 31A(7-8): 1145-8, 1995.
Artículo en Inglés | MEDLINE | ID: mdl-7577010

RESUMEN

A surveillance programme comprising either colonoscopy of sigmoidoscopy plus barium enema every 2-3 years was instituted in 50 hereditary nonpolyposis colorectal cancer (HNPCC) families. The families included 238 patients with colorectal cancer (CRC) (mean age at diagnosis: 43.7 years; range: 16-86 years). These patients had 597 first-degree relatives of whom 493 could be traced and 388 (79%) accepted the invitation for screening. The control group were relatives (index patients) with symptomatic CRC. The average follow-up duration was 5 years (1-20 years). Screening led to the detection of adenomas in 33 patients and CRC in 11 patients. Pathological examination revealed 1 Dukes' A, 7 Dukes' B and 3 Dukes' C cancers. In contrast, among the control group 47% had advanced CRC (Dukes' C or distant metastases). The 5-year survival of the screen-detected cases was 87% versus 63% in the control group. Of the 11 CRC cases in the screening group, 4 were detected within 1-4 years after a negative colonic examination. A large proportion of the polyps found in the screening and control groups showed a villous growth pattern and/or a high degree of dysplasia. We conclude that periodic examination of HNPCC families allows the detection of cancer at an earlier stage than in patients not under surveillance. Because of the possibly more aggressive nature of polyps associated with HNPCC, we recommend a screening interval of 1-2 years.


Asunto(s)
Adenoma/diagnóstico , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Adenoma/genética , Adenoma/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Colonoscopía , Neoplasias Colorrectales Hereditarias sin Poliposis/mortalidad , Femenino , Estudios de Seguimiento , Humanos , Cuidados a Largo Plazo , Masculino , Persona de Mediana Edad , Sigmoidoscopía , Tasa de Supervivencia
10.
J Natl Cancer Inst ; 87(8): 598-603, 1995 Apr 19.
Artículo en Inglés | MEDLINE | ID: mdl-7752258

RESUMEN

BACKGROUND: A high-fat diet has been recognized for some time as a major risk factor for colorectal cancer. It is thought that fat promotes this disease by increasing the levels of fatty and bile acids within the colon. These acids irritate and damage the epithelial cells of the colon. As a result of this cellular destruction, an increase in the rate of cellular proliferation occurs. Oral calcium supplementation has been proposed as a dietary intervention for individuals at high risk of colorectal cancer because of its ability to reduce rectal epithelial cell proliferation through the binding of fatty and bile acids. Placebo-controlled studies, however, have yielded varying results. PURPOSE: We conducted a randomized, double-blinded, placebo-controlled trial to test oral calcium supplementation in patients at high risk of developing hereditary nonpolyposis colorectal cancer. METHODS: Thirty subjects at risk for this cancer, with an increased epithelial cell proliferation along the colon and rectum, were randomly assigned to either a placebo group (n = 15) or a treatment group (n = 15). They received either oral calcium carbonate (CaCO3) supplements (1.5 g) or placebo (cellulose and starch) three times a day during a 12-week period. Colonic biopsy specimens (rectal, sigmoidal, and descending) were obtained prior to and after the intervention trial, during endoscopy, for determination of labeling index (LI) of whole crypts and crypt compartments by 5-bromo-2'-deoxyuridine incorporation and immunohistochemistry. Proportional bile acid compositions in duodenal bile and cytolytic activity of fecal water were also determined. All P values represent two-tailed tests of statistical significance. RESULTS: Statistically significant reductions, comparing before with after intervention, in rectal whole-crypt LI after receiving either calcium supplements (from 10.9% +/- 5.2% [mean +/- SD] to 6.2% +/- 1.5%; P < .02) or placebo (from 11.7% +/- 4.7% to 8.2% +/- 3.1%; P < .05) were observed. In the three bowel segments, no statistically significant differences were observed between the supplemental calcium and placebo groups. A statistically significant reduction in cytolytic activity was determined during calcium supplementation (from 57% +/- 41% to 32% +/- 30%; P < .05), whereas in the placebo group, it did not change (from 42% +/- 41% to 36% +/- 27%; P > .10). CONCLUSIONS: Oral calcium supplementation was shown to cause only a minor nonstatistically significant reduction of epithelial cell proliferation in the rectum, compared with placebo, and to have no effect on the same parameter in the sigmoid and descending colon in first-degree relatives of hereditary nonpolyposis colorectal cancer patients. IMPLICATION: These results cast doubt on the value of calcium supplementation in the prevention of colorectal cancer, especially in individuals already consuming an adequate amount of dietary calcium.


Asunto(s)
Calcio/uso terapéutico , Neoplasias Colorrectales Hereditarias sin Poliposis/tratamiento farmacológico , Adolescente , Adulto , Bilis/química , División Celular , Neoplasias Colorrectales Hereditarias sin Poliposis/patología , Método Doble Ciego , Células Epiteliales , Heces/química , Femenino , Humanos , Mucosa Intestinal/citología , Masculino , Persona de Mediana Edad , Placebos
11.
Dig Dis ; 12(2): 85-97, 1994.
Artículo en Inglés | MEDLINE | ID: mdl-8045031

RESUMEN

Dietary factors are major determinants of colorectal cancer risk. Especially a diet high in fat and low in fiber is recognized to be a risk factor. Dietary calcium has been suggested to be protective against colorectal cancer through the binding of intraluminal fatty acids and bile acids. Because of their cell-damaging properties these substances may stimulate colorectal epithelial cell proliferation and so promote colorectal cancer development. In this article data from in vitro, animal and human studies on the intraluminal effects of calcium, on its effects on colorectal epithelium and on the association between calcium intake and colorectal cancer are reviewed. It is concluded that at present it should be advised to bring dietary calcium intake into agreement with general dietary guidelines, but that high expectations of extra calcium as an effective mode of colon cancer prevention should not be encouraged.


Asunto(s)
Calcio/farmacología , Colon/efectos de los fármacos , Neoplasias Colorrectales/prevención & control , Animales , Calcio/metabolismo , Calcio de la Dieta/metabolismo , Calcio de la Dieta/farmacología , Colon/citología , Neoplasias del Colon/etiología , Neoplasias del Colon/prevención & control , Neoplasias Colorrectales/etiología , Grasas de la Dieta/metabolismo , Grasas de la Dieta/farmacología , Epitelio/efectos de los fármacos , Epitelio/metabolismo , Humanos , Técnicas In Vitro
12.
Eur J Cancer Prev ; 2(5): 409-15, 1993 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-8401176

RESUMEN

In an effort to reduce the risk of colorectal cancer development, oral calcium carbonate supplementation has been used in previous studies for the precipitation of cytotoxic bile acids and fatty acids. In human intervention trials its effect on mucosal hyperproliferation in the colorectum has not always been satisfactory. Because the complexation of calcium and bile acids requires the formation of calcium phosphate, we performed an intervention study in 14 healthy volunteers, giving them 1,500 mg calcium as Ca3(PO4)2 for 1 week. The effects of tricalcium phosphate on luminal and faecal parameters of cytolytic activity were evaluated before, during, and after calcium phosphate supplementation. The cytolytic activity of faecal water and intestinal alkaline phosphatase activity in faecal water were not affected by supplemental calcium phosphate. In duodenal bile, the proportion of cholic acid tended to increase, whereas that of chenodeoxycholic acid tended to decrease during calcium phosphate supplementation. Neither concentrations of total and individual faecal bile acids, nor that of faecal fat were affected during calcium phosphate supplementation. It is suggested that, although phosphate is involved in bile acid precipitation, phosphate competes for calcium in the binding of fatty acids. This might possibly explain the unchanged cytolytic potency of faecal water, and therefore does not make tricalcium phosphate a suitable calcium compound for dietary intervention.


Asunto(s)
Fosfatos de Calcio/farmacología , Calcio de la Dieta/farmacología , Colon/efectos de los fármacos , Neoplasias del Colon/prevención & control , Heces , Adulto , Fosfatasa Alcalina/análisis , Ácidos y Sales Biliares/análisis , Fosfatos de Calcio/administración & dosificación , Fosfatos de Calcio/uso terapéutico , Calcio de la Dieta/uso terapéutico , Colon/citología , Citotoxinas , Duodeno , Estudios de Factibilidad , Heces/química , Heces/enzimología , Femenino , Humanos , Concentración de Iones de Hidrógeno , Secreciones Intestinales/química , Lípidos/análisis , Masculino
13.
Dig Dis Sci ; 38(5): 923-6, 1993 May.
Artículo en Inglés | MEDLINE | ID: mdl-8482192

RESUMEN

Columnar-lined or Barrett's esophagus is a premalignant condition. It is almost unvariably due to chronic gastroesophageal reflux. Since there are some reports that Barrett's esophagus can be induced by chemotherapy, we investigated 20 male patients, treated with chemotherapy for testicular cancer, and 18 female patients, treated with high-dose chemotherapy for breast cancer. Only one patient in the testicular cancer group had Barrett's esophagus of the circumferential type, in addition to typical reflux esophagitis and a hiatal hernia four years after chemotherapy. In the breast cancer group one patient had an indeterminate junction. Our results do not support the hypothesis that chemotherapy poses a substantially increased risk for the development of Barrett's esophagus.


Asunto(s)
Antineoplásicos/efectos adversos , Esófago de Barrett/etiología , Adulto , Esófago de Barrett/inducido químicamente , Neoplasias de la Mama/tratamiento farmacológico , Cisplatino/efectos adversos , Quimioterapia Combinada , Femenino , Fluorouracilo/efectos adversos , Reflujo Gastroesofágico/complicaciones , Humanos , Masculino , Metotrexato/efectos adversos , Persona de Mediana Edad , Neoplasias Testiculares/tratamiento farmacológico
14.
Br J Cancer ; 67(3): 500-3, 1993 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-8439500

RESUMEN

To study the effect of oral supplemental calcium on colonic epithelial proliferation, 17 adenomatous polyp patients received 1.5 g Ca2+ as calcium carbonate daily during 12 weeks, while on a calcium constant diet, based on the patients' habitual diet. Seven subsequently continued calcium supplementation for 9 months without dietary restrictions. Epithelial proliferation rate in colonic biopsies, expressed as labelling index (%), was determined with 5-bromodeoxyuridine and immunohistochemistry. Biopsies were taken from the midsigmoid at time of polyp excision and at the end of the intervention period. Median labelling index increased from 6.1% before to 8.7% after 12 weeks calcium (n = 17, P < 0.02). This was due to increased labelling in the basal third of the crypts (11.9 vs 16%), whereas labelling in mid and luminal compartments was not affected. Labelling index remained increased after 1 year calcium supplementation at 8.8%. Crypt length was not affected by calcium. These results are in contrast to those of others, who have shown a decrease of rectal epithelial proliferation during similar doses of calcium. Therefore, the effect of nutritional intervention on colonic epithelial proliferation should be studied in biopsies taken not only from the rectum, but also from more proximal parts of the colon. Caution with respect to large scale intervention studies with calcium in high risk groups is mandatory.


Asunto(s)
Calcio/administración & dosificación , Colon Sigmoide/patología , Pólipos del Colon/patología , Neoplasias del Colon Sigmoide/patología , Administración Oral , Adulto , Anciano , Biopsia , Calcio/metabolismo , División Celular/efectos de los fármacos , Colon Sigmoide/efectos de los fármacos , Células Epiteliales , Epitelio/efectos de los fármacos , Femenino , Humanos , Masculino , Persona de Mediana Edad
15.
Eur J Clin Invest ; 23(1): 63-8, 1993 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-8444275

RESUMEN

Calcium has been proposed to prevent colon cancer in subjects at risk for this tumour. This effect is supposed to be due at least in part to binding the bile acids to calcium, making them insoluble and harmless. To evaluate the effects of oral calcium supplementation on intestinal bile acids, 19 patients with adenomatous colonic polyps were supplemented with 35.5 mmol Ca2+ daily for 12 weeks. Duodenal bile, 24-h feces and 24-h urine were collected before and at the end of the 12-week period. In duodenal bile proportional concentration of cholic acid increased (38 +/- 4 vs. 51 +/- 3%, P < 0.001), whereas that of chenodeoxycholic acid decreased (35 +/- 3 vs. 25 +/- 2%, P < 0.01). Total fecal bile acid excretion increased (950 +/- 126 vs. 1218 +/- 137 mumol 24 h-1, P < 0.01), with proportional concentrations of the main primary and secondary bile acids remaining the same. Cytolytic activity of fecal water, measured by the degree of lysis of erythrocytes by the water, decreased (45 +/- 8 vs. 30 +/- 7%, P < 0.05). Total excretion of calcium increased as expected from the supplementary dose. It is concluded that calcium supplementation markedly affects intestinal bile acids and lytic activity of fecal water and that, in view of similar results during 1-week calcium supplementation in young healthy subjects, these effects remain constant over at least 3 months and occur both in healthy persons and in patients at increased risk for colon cancer.


Asunto(s)
Ácidos y Sales Biliares/metabolismo , Calcio de la Dieta/administración & dosificación , Pólipos del Colon/dietoterapia , Agua Corporal/metabolismo , Neoplasias del Colon/prevención & control , Pólipos del Colon/metabolismo , Duodeno/metabolismo , Heces/química , Femenino , Hemólisis , Humanos , Masculino , Persona de Mediana Edad
16.
Cancer Res ; 53(2): 248-53, 1993 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-8417817

RESUMEN

Dietary calcium supplementation inhibits hyperproliferation of rectal epithelium, possibly by precipitating luminal surfactants and thus preventing their cell-damaging effects. Therefore, we studied the effects of supplemental dietary calcium (35.5 mmol/day) on composition and cytolytic activity of fecal water and on the release of the epithelial marker alkaline phosphatase in 12 healthy volunteers. Fecal water was isolated by low-speed centrifugation. Cytolytic activity was determined as lysis of human erythrocytes by fecal water. Intestinal alkaline phosphatase activity in fecal water was measured with the use of the uncompetitive inhibitor L-phenylalanine. Supplemental calcium increased soluble calcium and decreased soluble P(i). The logarithm of the concentration product of calcium and phosphate was linearly dependent on pH. These observations indicate formation of insoluble calcium phosphate. Supplemental calcium did not alter the total bile acid concentration in fecal water but significantly decreased the ratio of more hydrophobic to more hydrophilic bile acids from 3.3 to 2.3. Calcium also significantly decreased the concentration of fatty acids (from 2.9 to 2.1 mM). Consistent with these decreases in hydrophobic surfactants, calcium decreased the cytolytic activity of fecal water from 47 +/- 9 to 27 +/- 8% (n = 12, P < 0.05). Analogous to the decrease in cytolytic activity, the release of the epithelial marker alkaline phosphatase was also lowered by supplemental calcium. We conclude that supplemental dietary calcium decreases luminal cytotoxic surfactant concentrations and thus inhibits luminal cytolytic activity and the release of the epithelial marker alkaline phosphatase as an indicator of intestinal epitheliolysis. This mechanism may explain how dietary calcium could decrease epithelial cell proliferation.


Asunto(s)
Calcio/farmacología , Heces/química , Mucosa Intestinal/metabolismo , Adulto , Fosfatasa Alcalina/metabolismo , Ácidos y Sales Biliares/metabolismo , Calcio/metabolismo , Ácidos Grasos/metabolismo , Hemólisis , Humanos , Concentración de Iones de Hidrógeno , Magnesio/metabolismo , Masculino , Fosfatos/metabolismo , Esteroles/metabolismo , Agua/metabolismo
17.
Eur J Cancer Prev ; 1 Suppl 2: 55-62, 1991 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-1842734

RESUMEN

The biochemical and nutritional studies discussed here are consistent with the model presented in Figure 1. As shown in vitro, bile acids are precipitated by insoluble calcium phosphate. This calcium phosphate dependent precipitation drastically inhibits their cytotoxicity. A diet-induced increase in luminal surfactant concentration stimulates lytic activity of faecal water and intestinal cell damage resulting in an increased proliferation. The increase in luminal surfactant concentration and lytic activity of faecal water can be counteracted by supplemental dietary calcium phosphate. Supplemental calcium in humans increases the formation of insoluble calcium-phosphate-bile acid complexes in faeces, decreases the soluble fatty acid concentration and decreases lytic activity of faecal water. This sequence of effects offers a molecular explanation of the protective effects of supplemental calcium on proliferation as frequently observed (see studies cited above). It should be realised that this chain of evidence still lacks final proof of a preventive effect of dietary calcium on colorectal cancer. Until now, only protective effects on the first stage of development of colorectal cancer (hyperproliferation) have been observed. More well-designed studies in patients and healthy volunteers are needed using a combined biochemical, nutritional and clinical approach to elucidate the complex mechanism of the protective effect of calcium on colon cancer.


Asunto(s)
Ácidos y Sales Biliares/fisiología , Fosfatos de Calcio/farmacología , Neoplasias Colorrectales/etiología , Animales , Ácidos y Sales Biliares/química , Fosfatos de Calcio/química , Humanos
18.
Artículo en Inglés | MEDLINE | ID: mdl-1775941

RESUMEN

Diet is a major determinant of colon cancer risk. Calcium may protect against colon cancer, presumably by binding cytotoxic bile acids and fatty acids. Numerous studies support this proposition. In subjects at risk for colon cancer oral calcium supplementation has been shown to reduce rectal epithelial proliferation rate, thereby supposedly decreasing cancer risk. In contrast to the original hypothesis that phosphate counteracts the effect of calcium, evidence has now been provided that phosphate is crucial for the intraluminal binding of bile acids in complexes of calcium, phosphate, and bile acids. Supplemental calcium has been shown to reduce the cytotoxic potential of fecal water, which is probably attributable to the profound effect of calcium on bile acid and fatty acid metabolism. However, some reservation with regard to the protective ability of calcium seems to be warranted as we found that oral calcium supplementation caused an increase in epithelial proliferation rate in the sigmoid of patients with adenomatous polyps. Further controlled studies evaluating the effects of calcium on the epithelium of different parts of the colon should now be performed.


Asunto(s)
Calcio/administración & dosificación , Neoplasias del Colon/prevención & control , Animales , Calcio/fisiología , Neoplasias del Colon/etiología , Neoplasias del Colon/fisiopatología , Grasas de la Dieta/efectos adversos , Humanos , Factores de Riesgo
19.
Gastroenterology ; 99(6): 1653-9, 1990 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-2121581

RESUMEN

It has been suggested that supplemental dietary calcium decreases hyperproliferation of colonic epithelial cells because calcium precipitates and thus inactivates luminal bile acids. Therefore, 12 healthy men were studied before and after dietary calcium supplementation (35.5 mmol/day) to quantify intestinal associations of calcium, phosphate, and bile acids. The supplemental dietary calcium was almost completely (95%) recovered, mainly in feces. Calcium increased the fecal excretion of both phosphate (31%) and bile acids (53%) and decreased the ratio of dihydroxy to trihydroxy bile acids in duodenal bile almost twofold. In vitro studies showed that precipitation of glycodeoxycholic acid was caused by the formation of insoluble calcium phosphate. Water-soluble and calcium-associated amounts of phosphate and bile acids in feces were measured by resolubilization studies, using the calcium chelator ethylenediaminetetraacetate. In both the control and calcium periods, significant amounts of phosphate (80% and 90%) and bile acids (33% and 50%) were calcium-associated. Moreover, the calcium-induced increments in fecal phosphate and bile acids were completely calcium-associated. Calcium decreased the amount of water-soluble phosphate but not of bile acids. These results indicate that supplemental calcium stimulates formation of insoluble calcium phosphate in the intestinal lumen and thus increases binding of luminal bile acids.


Asunto(s)
Ácidos y Sales Biliares/metabolismo , Calcio de la Dieta/farmacología , Calcio/metabolismo , Mucosa Intestinal/metabolismo , Fosfatos/metabolismo , Ácidos y Sales Biliares/orina , Calcio/orina , Ácido Edético , Heces , Humanos , Masculino , Fosfatos/orina
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