The progressive nutritional deterioration frequently found in cancer patients, is often referred to as cancer cachexia. In contrast to starvation, where it is possible to reverse the body composition ...changes by the provision of extra calories, in cancer cachexia this reversal is not observed, suggesting that anorexia alone is unlikely to be responsible for this wasting syndrome. Over the past decades a number of studies have focused on the possible mediators which may be responsible for metabolic abnormalities observed in cancer patients. Pro-inflammatory cytokines have been strongly implicated, but evidence supporting such a direct role is lacking. Recently, exciting work regarding molecules produced by tumour cells, and which may induce lipolysis and proteolysis, has been published. There is also evidence that increased metabolism of host resources may provide substrates which might promote tumour growth. A number of studies have demonstrated that polyunsaturated fatty acids, such as linoleic and arachidonic acid, are able to promote tumour cell growth either by directly stimulating mitosis or by inhibiting apoptosis. Even more interesting is the discovery of antagonists of these catabolic factors such as eicosapentanoic acid for the lipolytic factor, which may play a role in the treatment of these patients in the near future.
The objective of this review is to present and discuss the current perspectives of homocysteine and one carbon metabolism in chronic alcoholism. Chronic alcoholics frequently suffer from specific ...micronutrient deficiencies, including vitamins involved in one carbon metabolism, i.e., folate, vitamin B
6 and vitamin B
12. The possible link between homocysteine and alcoholism stems from the fact that homocysteine metabolism is closely linked to the metabolism of these three vitamins. In fact, homocysteine stands at the intersection of two pathways: methylation and transsulfuration. In methylation, homocysteine acquires a methyl group from N-5-methyltetrahydrofolate in a vitamin B
12 dependent reaction, whereas in the transsulfuration pathway, homocysteine condenses with serine to form cystathionine in an irreversible reaction catalyzed by the pyridoxal-5′-phosphate-containing enzyme, cystathionine-β-synthase. Due to these relationships, nutritional deficiency of one of these vitamins, as a consequence of chronic alcohol intake, could lead to metabolic disruption and potentially to hyperhomocysteinemia. Consistent with an interference of alcohol in these metabolic pathways, a previous study performed in chronic alcoholics in whom hyperhomocysteinemia was observed along with disturbed vitamin status, DNA hypomethylation in peripheral lymphocytes was demonstrated as well. Because all these alterations were observed in the absence of clinically overt disease, one might speculate whether these metabolic abnormalities could be involved in the pathogenesis of organic diseases associated to chronic alcoholism.
Serum homocysteine concentrations have been shown to be a sensitive functional indicator of intracellular folate, vitamin B-12, and vitamin B-6 status. Chronic alcoholism is known to interfere with ...one-carbon metabolism, for which the above vitamins serve as coenzymes. In the present study, these vitamins were assessed in 32 chronic alcoholics and 31 healthy volunteers by measuring blood vitamin concentrations as well as serum homocysteine concentrations. In chronic alcoholics, serum pyridoxal 5'-phosphate and red blood cell folate concentrations were significantly lower than in the control subjects (P < 0.001 and P = 0.008, respectively). Mean serum homocysteine was twice as high in chronic alcoholics than in nondrinkers (P < 0.001). Beer consumers had significantly lower concentrations of homocysteine compared with drinkers of wine or spirits (P = 0.05). These results suggest that by interfering with folate or vitamin B-6 metabolism, chronic alcohol intake may impair the disposal of homocysteine through the transmethylation or transsulfuration pathways.
In patients with ulcerative colitis, epidemiological work has suggested an association between low folate status and an increased risk of colonic neoplasia. The aim of the present study was to ...determine if experimental folate deficiency increases the likelihood of developing neoplasia in rats treated with the carcinogen dimethylhydrazine. Weanling male Sprague-Dawley rats were fed with an amino acid-defined diet containing either 8 or 0 mg/kg folic acid. After 5 weeks of defined diet, weekly s.c. injections of dimethylhydrazine (20 mg/kg) were administered to both groups. Serum, whole blood, liver, and colonic folate concentrations at the time of sacrifice were significantly lower in folate-depleted animals (P less than 0.001). There were significant differences in the incidence of colonic neoplasia between the two groups after 20 weeks of dimethylhydrazine exposure: folate-deficient rats had a greater incidence of dysplasia (6 of 7 versus 2 of 7 animals; P less than 0.05) and carcinoma (6 of 7 versus 1 of 7 animals; P less than 0.01). Furthermore, a significantly greater proportion of folate-replete rats than folate-deficient rats were free of neoplastic lesions (5 of 7 versus 0 of 7 animals; P less than 0.05). These results suggest that, in this animal model, folate deficiency increases the risk of malignancy when there is an underlying predisposition to colorectal cancer.
We have evaluated the effect of folate supplementation (5 mg/day) on global deoxyribonucleic acid (DNA) methylation status of the rectal mucosa of 20 patients with resected colonic adenomas in a ...prospective, controlled, cross-over study. Baseline values of DNA methylation were inversely correlated with caloric (P = 0.03) and fat intake (P = 0.05) and patients harbouring multiple polyps consumed significantly more calories (P = 0.0006), fat (P = 0.009) and carbohydrates (P = 0.009) as compared to patients having one single lesion. Folate supplementation resulted in a significant decrease of DNA hypomethylation in 7/20 patients (P = 0.05) which returned to previous values after placebo treatment. This effect was significantly correlated with number of polyps, with all the responders presenting one single lesion, whereas 8/13 of the non-responders had multiple ones (χ2 = 7.17, P = 0.007). In conclusion, folate supplementation may decrease degree of DNA hypomethylation, but only in patients with one single polyp. In those with multiple lesions, other nutritional factors such as caloric and fat intake, may be more determinant.
Microsatellite instability (MSI) detected in non-neoplastic mucosa of patients with ulcerative colitis has been ascribed to an excess of DNA damage associated with chronic inflammation. Folate ...deficiency, commonly found in patients with long-standing disease, could further contribute to this defect because folate is essential for DNA replication and repair. We evaluated MSI in the colonic mucosa of 26 patients with ulcerative colitis for >10 yr and 10 patients with Crohn's colitis and correlated MSI with folate status.
DNA was amplified using primers directed at nine different loci. Folate concentrations in serum, whole blood, and colonic mucosa were determined using the Lactobacillus casei assay.
MSI was found in 3/23 patients (13%) with ulcerative colitis and in none of the patients with Crohn's colitis. All three patients with MSI had inactive histological disease, whereas all patients with active disease were negative for MSI (p = 0.08). Serum, whole blood, and colonic concentrations of folate were 30-50% lower in patients with MSI (p > 0.05), and folate supplements had been administered less frequently during the past 5-yr (p = 0.06). One of the patients with MSI was randomized to receive folate 5 mg/d for 6 months, and a clear change in MSI pattern was observed in three of six markers.
A defect in DNA repair associated with a low folate status may be one additional cause for patients with ulcerative colitis exhibiting MSI in non-neoplastic mucosa.
Global and gene-specific DNA hypomethylation is considered to be an important early epigenetic event in several human neoplasms. A growing body of evidence has suggested that DNA methylation can be ...altered by dietary manipulation of methyl group donors. This study investigated whether moderate depletion of folate, a dietary component needed for the synthesis of methyl groups, would cause decreased hepatic and colonic S-adenosylmethionine concentrations, and thereby lead to global and/or protooncogene-specific DNA hypomethylation. Weanling rats were fed an amino acid-defined diet containing either 0 or 8 mg folate/kg diet for 15 or 24 wk. Significantly lower systemic, hepatic and colonic folate concentrations were observed in the moderately folate-depleted rats than in controls at both 15 and 24 wk (P < 0.005). Although hepatic S-adenosylmethionine was significantly lower in the moderately folate-depleted rats than in controls at the two time points (P < 0.03), colonic S-adenosylmethionine concentrations were not significantly different between the two groups at either time point. No significant differences between the folate-depleted and control animals could be detected with regard to global DNA methylation in the liver or colonic mucosa. Furthermore, c-myc protooncogene-specific DNA methylation in the colonic mucosa was not significantly different between these two groups of animals. These results indicate that moderate folate depletion does not cause a significant reduction in global DNA methylation in liver or colonic mucosa or in c-myc-specific colonic mucosal DNA methylation in this rat model.
In this study the deoxyuridine suppression test (dUST) was performed on isolated rat colonocytes to establish its value as an indicator of folate status in the colonic epithelium. 3Hthymidine ...incorporation into DNA was suppressed < 90% by deoxyuridine (dU) concentrations < 2.5 µmol/L. Preincubation of cells with 5-fluorouracil (1–100 µmol/L) but not methotrexate (10–100 µmol) resulted in a significant decrease in the degree of suppression. The dUST performed on colonocytes from folate-deficient animals displayed less suppression than on colonocytes from folate-replete animals (P < 0.05). The abnormal degree of suppression was corrected by adding 100 µmol folinic acid/L. There was a negative correlation between the degree of suppression and the folate concentration of the colonic epithelium (P < 0.001). These data indicate that the dUST is useful for detecting folate deficiency in the colonic epithelium and may therefore be valuable in assessing a deficiency state localized to that epithelium.
Background. Studies using DNA technology have reported the presence of human papillomavirus (HPV) DNA in esophageal carcinomas, suggesting that it could play a role in the pathogenesis of this tumor. ...In the present study, in addition to DNA from neoplasms, normal mucosa was screened for viral DNA, assuming that this would increase HPV detection substantially.
Methods. Seventeen patients with esophageal carcinoma and 10 control subjects were studied. In 8 of the patients, normal mucosa was also available. Polymerase chain reaction (PCR) was performed using primers for the E6 region of HPV‐16 and HPV‐18. Koilocytosis, a commonly accepted histopathologic marker of viral infection, was studied, and results were correlated with PCR findings.
Results. DNA from neoplastic lesions was positive for HPV‐16 and HPV‐18 in 8 of 16 (50%) and in 3 of 16 (18.8%), respectively. When tumor tissue and normal mucosa were available, PCR results were 3 of 8 (37.5%), 5 of 8 (62.5%), and 8 of 8 (100%) for HPV‐16, in tumor, normal mucosa, and both. For HPV‐18, results were 0 of 8 (0%), 5 of 8 (62.5%), and 5 of 8 (62.5%), respectively. In comparison with tumor samples, positivity in normal mucosa was increased for HPV‐18 and for both viral genotypes (P = 0.01). No amplification was obtained in the control group. Koilocytosis was present in 33% of the cases.
Conclusions. These results suggested a high prevalence of HPV in esophageal carcinoma. The detection rate is significantly higher in normal mucosa specimens, suggesting that infection probably antedates tumor development. Koilocytosis was substantially less sensitive than PCR. Cancer 1995; 76:1522–8.
PDF
