Improvement in cervical dysplasia associated with folic acid therapy in users of oral contraceptives

Butterworth, Charles E.; Hatch, Kenneth D.; Gore, Hazel; Mueller, Helmut; Krumdieck, Carlos L.

doi:10.1093/ajcn/35.1.73

Cited by 192 publications

(27 citation statements)

References 18 publications

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“…Premalignant dysplasia of cervical, bronchial and colonic epithelial cells could be reversed by folate supplementation implying that folate deficiency may have a causal role in the process (Lashner et al, 1989;Rosenberg and Mason, 1989;Butterworth et al, 1991). Elucidation of the molecular mechanisms underlying folate deficiency and predisposition to cancer is, therefore, of critical importance for cancer prevention.…”

Section: Discussionmentioning

confidence: 99%

Suppression of the protein tyrosine phosphatase receptor type O gene (PTPRO) by methylation in hepatocellular carcinomas

et al. 2003

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A diet lacking folic acid and choline and low in methionine (folate/methyl deficient diet, FMD diet) fed to rats is known to produce preneoplastic nodules (PNNs) after 36 weeks and hepatocellular carcinomas (tumors) after 54 weeks. FMD diet-induced tumors exhibit global hypomethylation and regional hypermethylation. Restriction landmark genome scanning analysis with methylationsensitive enzyme NotI (RLGS-M) of genomic DNA isolated from control livers, PNNs and tumor tissues was performed to identify the genes that are differentially methylated or amplified during multistage hepatocarcinogenesis. Out of the 1250 genes analysed, 2 to 5 genes were methylated in the PNNs, whereas 5 to 45 genes were partially or completely methylated in the tumors. This analysis also showed amplification of 3 to 12 genes in the primary tumors. As a first step towards identifying the genes methylated in the PNNs and primary hepatomas, we generated a rat NotI-EcoRV genomic library in the pBluescriptKS vector. Here, we describe identification of one methylated and downregulated gene as the rat protein tyrosine phosphatase receptor type O (PTPRO) and one amplified gene as rat C-MYC. Methylation of PTPRO at the NotI site located immediate upstream of the trancription start site in the PNNs and tumors, and amplification of C-MYC gene in the tumors were confirmed by Southern blot analyses. Bisulfite genomic sequencing of the CpG island encompassing exon 1 of the PTPRO gene revealed dense methylation in the PNNs and tumors, whereas it was methylation free in the livers of animals on normal diet. Reverse transcription-polymerase chain reaction (RT-PCR) analysis showed significant decrease in the expression of PTPRO in the tumors and in a transplanted rat hepatoma. The expression of PTPRO mRNA in the transplanted hepatoma after demethylation with 5-azacytidine, a potent inhibitor of DNA methyltransferases, further confirmed the role of methylation in PTPRO gene expression. These results demonstrate alteration in methylation profile and expression of specific genes during tumor progression in the livers of rats in response to folate/methyl deficiency, and further implicate the potential role of PTPRO as a novel growth regulatory gene at least in the hepatocellular carcinomas.

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Section: Discussionmentioning

confidence: 99%

Suppression of the protein tyrosine phosphatase receptor type O gene (PTPRO) by methylation in hepatocellular carcinomas

et al. 2003

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“…Consistent associations between low serum levels, low tissue concentrations, and/or low dietary intake of vitamin A (5), ß-carotene (6)(7)(8), folie acid (9)(10)(11), vitamin C (5,9,12), and vitamin E (13) and an increased prevalence of cervical intraepithelial neoplasia (CIN) and/or invasive cervical cancer have been observed.…”

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confidence: 92%

Undemutrition as a risk factor for cervical intraepithelial neoplasia: A case‐control analysis

Amburgey

VanEenwyk

Davis

et al. 1993

Nutrition and Cancer

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To evaluate the relationship between cervical intraepithelial neoplasia (CIN) and undernutrition, a pair-matched case-control study was conducted in a low-income urban population. As a broad measure of nutritional status, serum albumin, serum ferritin, hematocrit, percent desirable weight, and percent calories consumed as protein were examined. Cases (n = 102) had biopsy-confirmed CIN I, II, or III, and clinic controls (n = 102), matched on age, race, and clinic, had normal Pap smears. Survey-collected data and frozen serum were utilized to study the hypothesized association. Crude and adjusted odds ratios and 95% confidence intervals were estimated using conditional logistic regressions. Results suggest a protective role for serum ferritin for those in the highest quartile relative to those in the lowest quartile. Controlling for smoking and monthly personal income, an adjusted odds ratio of 0.2 with a corresponding 95% confidence interval of 0.1-0.7 was observed. Similar findings were noted when all other available CIN risk factors were controlled. In addition, a dose gradient was present for dietary iron intake (p = 0.01). No associations were observed between each of the other undernutrition indexes and CIN. Although only high levels of serum ferritin were associated with a protective effect against CIN, when coupled with the results from other studies that suggest carotenoids, folates, and vitamin C to be protective, the overall hypothesis that poor nutriture is associated with CIN remains viable. Lack of an association with the other nutritional indexes may reflect the relatively sufficient nutritional status of low-income individuals residing in the United States, as opposed to the undernourished population of the Third World.

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“…In vivo and in vitro studies have reported that low-folate conditions increase chromosomal breakage, micronucleus formation, defects in chromosome condensation (15,17,18), metastatic potential of cultured murine melanoma cells (19), and expression of chromosomal fragile sites (20,21). Evidence indicates that certain in vivo human cell populations may be folate-deficient even when blood folate values are normal and that cellular dysplasia associated with low-folate status in cervix and lung can be reversed by folate administration (22)(23)(24).…”

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confidence: 99%

Cytogenetic damage induced by folate deficiency in mice is enhanced by caffeine.

MacGregor

Schlegel

Wehr

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

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Folate deficiency in Swiss mice increased the incidence of micronuclei in peripheral blood erythrocytes, indicating increased chromosomal damage in nucleated erythrocyte precursors. Caffeine enhanced the incidence of micronuclei in blood and bone marrow by up to 5-fold in folatedeficient mice at doses that did not significantly alter the micronucleus frequency in the presence of adequate dietary folate. The lower dose of caffeine used in this study (75 mg/kg) approaches doses received by humans who consume large amounts of caffeinated beverages. Since folate deficiency and caffeine consumption are highly prevalent in the human population, the potential for a similar interaction in man should be evaluated.The occurrence of micronuclei in peripheral blood and bone marrow erythrocytes has been used as an indicator of cytogenetic damage in laboratory animals and man (1-3). Two recent studies indicate that folate deficiency and caffeinatedbeverage consumption may elevate the frequency of micronucleated erythrocytes in man. Caffeinated-coffee consumption was associated with an elevated frequency of micronucleated erythrocytes in a cross-sectional study of genotoxic risk factors (4), and folate supplementation lowered micronucleus frequency to normal in an individual with a marginal folate deficiency and an abnormally high micronucleus frequency (5). These studies suggest that folate status and caffeinated-beverage consumption may be risk factors for cytogenetic damage in man.Mild-to-moderate folate deficiency (6-9) and caffeinatedbeverage consumption (10) are both highly prevalent in the general population. Folate deficiency affects up to 60% of low-income and elderly persons (8,11) and is also common in subpopulations, such as alcoholics (12) Folate deficiency in pregnant women has been reported to range from 2% to 50%, depending on the population studied (25). Folate deficiency during pregnancy is associated with an elevated incidence of birth defects (26).Severe folate deficiency induced by antifolate drugs has been shown to increase the frequency of micronuclei in mouse bone marrow erythrocytes (27, 28), but we are not aware of previous reports of increased micronucleus frequencies induced by dietary folate deficiency in laboratory animals.Fragile-site expression induced in vitro by conditions of limiting folate is known to be strongly enhanced by caffeine, leading to micronucleus formation and increased frequencies of chromosome breaks (18,29). Under these conditions, caffeine increases folate-related breakage events, often by more than an order of magnitude. There appear to be no data indicating whether a similar interaction occurs in mammals in vivo. Although earlier studies of caffeine effects in animals and man have failed to demonstrate significant genotoxic effects in vivo at doses near those that would result from the consumption of caffeinated beverages (30-33), the recent report by Chen et al. (34) that chromosomal fragility in human lymphocytes cultured under low-folate conditions is linearly ...

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Improvement in cervical dysplasia associated with folic acid therapy in users of oral contraceptives

Cited by 192 publications

References 18 publications

Suppression of the protein tyrosine phosphatase receptor type O gene (PTPRO) by methylation in hepatocellular carcinomas

Suppression of the protein tyrosine phosphatase receptor type O gene (PTPRO) by methylation in hepatocellular carcinomas

Undemutrition as a risk factor for cervical intraepithelial neoplasia: A case‐control analysis

Cytogenetic damage induced by folate deficiency in mice is enhanced by caffeine.

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