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Dietary and serum carotenoids and cervical
intraepithelial neoplasia.
VanEenwyk J; Davis FG; Bowen PE
Department of Epidemiology and Biostatistics, School of
Public Health, University of Illinois, Chicago.
Int J Cancer (United States) Apr 22 1991, 48 (1)
p34-8
A case-control study examined the association between
cervical intra-epithelial neoplasia (CIN) and serum and
dietary alpha-carotene, beta-carotene, cryptoxanthin, lutein,
and lycopene. Cases (n = 102) had biopsy confirmed CIN I, II
or III. Controls matched for age, ethnic origin and clinic (n
= 102) had normal Pap smears. Participants completed health
history and food frequency questionnaires. Fasting venous
blood samples were assayed for serum carotenoids.
Multivariable conditional logistic regression analyses yielded
odds ratios and 95% confidence intervals (CIs) for those in
quartiles 3, 2, and 1 (lowest) compared to quartile 4
(highest) of serum lycopene of 3.5 (1.1-11.5), 4.7 (1.2-17.7)
and 3.8 (1.1-12.4), respectively. Similar analyses yielded
adjusted odds ratios (ORaS) and 95% CIs of 4.6 (1.1-19.7), 5.8
(1.6-21.3) and 5.4 (1.3-23.3) for dietary intake of lycopene.
The findings for lycopene-rich foods (tomatoes) were
consistent with this result. CIN was not associated with the
lutein. Findings for alpha-carotene, beta-carotene and
cryptoxanthin were ambiguous. Quartile of vitamin C intake was
also inversely associated with CIN with ORaS and 95% CIs of
3.7 (0.9-14.6), 4.1 (1.0-17.2), and 6.4 (1.4-30.0) for those
in quartiles 3, 2, and 1 compared to quartile 4.
Plasma vitamin C and uterine cervical
dysplasia.
Romney SL; Duttagupta C; Basu J; Palan PR; Karp S; Slagle NS;
Dwyer A; Wassertheil-Smoller S; Wylie-Rosett J
Am J Obstet Gynecol (United States) Apr 1 1985, 151 (7)
p976-80
Plasma concentrations of vitamin C were determined in a
case-control study of women (n = 80) who had sought a
Papanicolaou test in the Bronx Municipal Hospital Center.
Controls (n = 34) were women having negative cytologic tests,
negative colposcopic findings, and no known gynecologic
dysfunction. Cases (n = 46) were defined as women who had
either one positive or two consecutive suspicious Papanicolaou
smears in a 12-month period. The mean concentration of vitamin
C in the plasma was significantly lower in the cases than in
the controls (0.36 versus 0.75 mg/dl, p less than 0.0001).
Cases were further stratified according to the histopathologic
diagnosis. The data direct attention to a possible etiologic
association of vitamin C in human cervical epithelial
abnormalities. A clinical trial with vitamin C intervention is
suggested.
Dietary intake and blood levels of lycopene:
association with cervical dysplasia among non-Hispanic, black
women.
Kantesky PA; Gammon MD; Mandelblatt J; Zhang ZF; Ramsey E;
Dnistrian A; Norkus EP; Wright TC Jr
Department of Biostatistics and Epidemiology, University of
Pennsylvania School of Medicine, Philadelphia 19104, USA
pkanetsk@cceb.med.upenn.edu
Nutr Cancer (United States) 1998, 31 (1) p31-40
We examined whether elevated levels of retinoids,
carotenoids, folate , and vitamin E protected against cervical
dysplasia among non-Hispanic, black women. We enrolled 32
women with incident cervical dysplasia , including cervical
intraepithelial neoplasia (CIN) I, CIN II, and CIN
III/carcinoma in situ, and 113 control women with normal
cervical cytology in case-control study. Micronutrient levels
were estimated from a food-frequency questionnaire (FFQ) and
measured from blood samples. Information on risk factors for
cervical neoplasia was elicited by interview. Hybrid capture
was used to determine infection with human papillomavirus.
After adjustment for potential confounders, analysis of
micronutrient levels estimated from the FFQ suggested that
women in the upper tertile of lycopene and vitamin A intake
were one-third (odds ratio = 0.32, 95% confidence interval =
0.8-1.3) and one-fourth (odds ratio = 0.24, 95% confidence
interval = 0.05-1.2) as likely, respectively, to have
dysplasia as women in the lower tertile. Borderline protective
trends (p < or = 0.10) were apparent. Elevated levels of
serum lycopene also suggested some protection against
dysplasia. Results were not significant at alpha = 0.05
because of the small number of case women enrolled. Overall,
correlations between estimates from the FFQ and serum levels
were poor. This study indicates that, among black women,
lycopene and perhaps vitamin A may play a protective role in
the early stages of cervical carcinogenesis.
Serum micronutrients and the subsequent risk of
cervical cancer in apopulation-based nested case-control
study.
Batieha AM; Armenian HK; Norkus EP; Morris JS; Spate VE;
Comstock GW
Department of Epidemiology, School of Hygiene and Public
Health, Johns Hopkins University, Baltimore, Maryland
21205.
Cancer Epidemiol Biomarkers Prev (United States) Jul-Aug
1993, 2 (4) p335-9
A nested case-control study was conducted in Washington
County, MD, to determine whether low serum micronutrients are
related to the subsequent risk of cervical cancer. Among the
15,161 women who donated blood for future cancer research
during a serum collection campaign in 1974, 18 developed
invasive cervical cancer and 32 developed carcinoma in situ
during the period January 1975 through May 1990. For each of
these 50 cases, two matched controls were selected from the
same cohort. The frozen sera of the cases and their matched
controls were analyzed for a number of nutrients. The mean
serum levels of total carotenoids, alpha-carotene,
beta-carotene, cryptoxanthin, and lycopene were lower among
cases than they were among controls. When examined by
tertiles, the risk of cervical cancer was significantly higher
among women in the lower tertiles of total carotenoids (odds
ratio 2.7; 95% confidence limit, 1.1-6.4), alpha-carotene
(odds ratio, 3.1; 95% confidence limit, 1.3-7.6), and
beta-carotene (odds ratio, 3.1; 95% confidence limit, 1.2-8.1)
as compared to women in the upper tertiles and the trends were
statistically significant. Cryptoxanthin was significantly
associated with a lower risk of cervical cancer when examined
as a continuous variable. Retinol, lutein, alpha- and
gamma-tocopherol, and selenium were not related to cervical
cancer risk. Smoking was also strongly associated with
cervical cancer. These findings are suggestive of a protective
role for total carotenoids, alpha-carotene and beta-carotene
in cervical carcinogenesis and possibly for cryptoxanthin and
lycopene as well.
Change of vitamin a status and its influence on
cervical dysplasia
Volz J.; Van Rissenbeck A.; Blanke M.; Melchert F.; Schneider
A.; Biesalski H.K.
OA Universitats-Frauenklinik, Theodor-Kutzer-Ufer 10,68135
Mannheim Germany
Zentralblatt fur Gynakologie (Germany) 1995, 117/9
(472-475)
In 34 patients with HVP-infection of the cervix and in 40
patients with CIN III standardised biopsies were taken from
the involved area and normal cervical epithelium for
determination of the local concentration of retinylester. In
all cases diagnosis was confirmed colposcopically,
cytologically and by histology. HPV infection was confirmed by
in situ hybridisation. Determination of retinylester was
performed by HPLC. No significant difference of local
retinyl-palmitate concentration was detectable in HPV infected
versus normal tissue. Retinyl-palmitate concentration was
extremely lower in CIN III compared with normal cervical
epithelium and HPV-infected tissue. The determination of
plasma level of retinol showed no significant difference
between the two groups. So it can be presumed that the
reduction of retinyl-palmitate in CIN III is a local process
and a local supplementation of Vitamin A might contribute to
the prevention of cervical neoplasia.
Folates: supplemental forms and therapeutic
applications.
Kelly GS
gregnd@worldnet.att.net
Altern Med Rev (United States) Jun 1998, 3 (3)
p208-20
Folates function as a single carbon donor in the synthesis
of serine from glycine, in the synthesis of nucleotides form
purine precursors, indirectly in the synthesis of transfer
RNA, and as a methyl donor to create methylcobalamin, which is
used in the re-methylation of homocysteine to methionine. Oral
folates are generally available in two supplemental forms,
folic and folinic acid. Administration of folinic acid
bypasses the deconjugation and reduction steps required for
folic acid . Folinic acid also appears to be a more
metabolically active form of folate , capable of boosting
levels of the coenzyme forms of the vitamin in circumstances
where folic acid has little to no effect. Therapeutically,
folic acid can reduce homocysteine levels and the occurrence
of neural tube defects, might play a role in preventing
cervical dysplasia and protecting against neoplasia in
ulcerative colitis, appears to be a rational aspect of a
nutritional protocol to treat vitiligo, and can increase the
resistance of the gingiva to local irritants, leading to a
reduction in inflammation. Reports also indicate that
neuropsychiatric diseases secondary to folate deficiency might
include dementia, schizophrenia-like syndromes, insomnia,
irritability, forgetfulness, endogenous depression, organic
psychosis, peripheral neuropathy, myelopathy, and restless
legs syndrome. (103 Refs.)
Folic acid and cervical dysplasia
Zarcone R.; Bellini P.; Carfora E.; Vicinaza G.; Raucci
F.
Via Cappuccini, 16,Montesarchio (BN) Italy
Minerva Ginecologica (Italy) 1996, 48/10
(397-400)
The localized folate deficiency, which is sometimes
misdiagnosed as cervical dysplasia, because of morphologic
similarities between the cytologic features of megaloblastosis
seen with folate deficiency and the changes associated with
dysplasia, could be a component of the dysplastic process. In
this study we attempted the effect of oral folic in women with
cervical dysplasia . A total of 154 subjects with grade 1 or 2
CIN were randomly assigned either 10 mg of folic acid or a
placebo daily for 6 months. Clinical status, human
papillomavirus type 16 infection and blood folate levels were
monitored at 2 month intervals. After 6-months no significant
differences were observed between supplemented and
unsupplemented subjects regarding dysplasia status, biopsy
results, or prevalence of human papillomavirus type 16
infection. Folate deficiency may be involved as a cocarginogen
during the initiation of cervical dysplasia , but folic acid
supplements do not alter the course of estabilished
disease.
Folate status, women's health, pregnancy outcome,
and cancer
Butterworth Jr. C.E.
Dept. of Nutrition Sciences, University of
Alabama,Birmingham, AL 35294 United States
Journal of the American College of Nutrition (United States)
1993, 12/4 (438-441)
Key observations by Dr. Lucy Wills 65 years ago have led to
the identification of folate as a nutrient essential for the
prevention of megaloblastic anemia of pregnancy. The more
recently discovered relationships of folate status to cervical
dysplasia , neural tube defects, and atherosclerosis are
reviewed here.
Epidemiologic studies of vitamins and cancer of the
lung, esophagus, and cervix.
Ziegler RG
Adv Exp Med Biol (United States) 1986, 206
p11-26
Epidemiologic studies of the relationships between vitamins
and 3 types of cancer are reviewed. First, the widely reported
association between vitamin A and beta -carotene and risk of
lung cancer is considered. In a large population-based
case-control study of lung cancer among white males in New
Jersey, increased intake of vegetables, dark green vegetables,
dark yellow-orange vegetables, and carotenoids were each
associated with reduced risk, but intake of retinol or total
vitamin A was not related. The protective effect of vegetables
was limited to current and recent cigarette smokers, which
suggests that vegetable intake prevents a late-stage event in
carcinogenesis. Consumption of dark yellow-orange vegetables
was consistently more predictive of reduced risk than either
the total carotenoid index or consumption of any other food
group, possible because of the high content of beta -carotene
in this food group. The results and limitations of other
epidemiologic studies of diet and lung cancer are reviewed.
Second, the evolving relationship between multiple
micronutrient deficiencies and esophageal cancer is discussed.
In a death certificate-based case-control study of esophageal
cancer in black males in Washington, D.C., several indicators
of general nutritional status, including consumption of fresh
or frozen meat and fish, dairy products and eggs, and fruit
and vegetables, and the number of meals eaten per day, were
inversely and independently correlated with the risk of
esophageal cancer. Estimates of intake of micronutrients, such
as carotenoids, vitamin C , thiamin, and riboflavin, were less
strongly associated with reduced risk than were the broad food
groups that provide most of each micronutrient. Thus no single
micronutrient deficiency was identified. Other studies suggest
that generally poor nutrition may partially explain the
susceptibility of urban black men to esophageal cancer.
Finally, the postulated association between low folacin levels
and risk of cervical cancer is examined. Among women who use
oral contraceptives, serum and red blood cell folacin levels
were reported to be lower among those with cervical dysplasia
. In a clinical trial involving oral contraceptive users,
cervical dysplasia gradually decreased in the group
supplemented with oral folate but remained unchanged in the
group given the placebo. Other epidemiologic studies of diet
and cervical cancer are discussed.
Folate deficiency and cervical dysplasia
Butterworth Jr. C.E.; Hatch K.D.; Macaluso M.; Cole P.;
Sauberlich H.E.; Soong S.-J.; Borst M.; Baker V.V.
Nutrition Sciences Department, University of Alabama, UAB
Station,Birmingham, AL 35294-3360 United States
Journal of the American Medical Association 1992, 267/4
(528-533)
Objective. - To test the hypothesis that nutritional
deficiency affects the incidence of cervical dysplasia in
young women.
Design and Setting. - Case-control study. Participants were
derived from community family-planning clinics and referrals
to a colposcopy center.
Participants. - A total of 726 subjects were screened,
yielding 294 cases of dysplasia and 170 controls defined by
coexistent cytologic and colposcopic evidence.
Main Outcome Measures. - Planned prior to data collection.
Odds ratios were computed using logistic regression models to
evaluate association between cervical dysplasia and
sociodemographic, sexual, and reproductive factors; smoking;
oral contraceptive use; human papillomavirus (HPV) infection;
and 12 nutritional indices determined by blind analysis of
nonfasting blood specimens.
Results. - The number of sexual partners, parity, oral
contraceptive use, and HPV-16 infection were significantly
associated with cervical dysplasia . Plasma nutrient levels
were generally not associated with risk. However, red blood
cell folate levels at or below 660 nmol/L interacted with
HPV-16 infection. The adjusted odds ratio for HPV-16 was 1.1
among women with folate levels above 660 nmol/L but 5.1 (95%
confidence interval, 2.3 to 11) among women with lower levels.
Interactions of red blood cell folate levels with cigarette
smoking and parity were also present but were not
statistically significant.
Conclusion. - Low red blood cell folate levels enhance the
effect of other risk factors for cervical dysplasia and, in
particular, that of HPV-16 infection.
Antineoblastic activity of antioxidant vitamins:
the role of folic acid in the prevention of cervical
dysplasia.
Grio R; Piacentino R; Marchino GL; Navone R
Department of Gynecology and Obstetrics, University of Turin,
Italy.
Panminerva Med (Italy) Dec 1993, 35 (4) p193-6
The authors made a study on 90 patients affected by various
degrees of uterine cervix dysplasia searching for folic acid
plasmatic concentrations. The team members affected by CIN
have been compared with a test team consisting of women with
normal pap-test and vaginoscopy. The study proved that the
average levels of folic acids have significantly decreased in
cases of dysplasia compared with the test team. These results
allow stating that low folic acid plasmatic concentrations may
be associated with cervix neoplasms development.
[Folic acid and cervix dysplasia]
Zarcone R; Bellini P; Carfora E; Vicinanza G; Raucci F
Istituto di Ginecologia ed Ostetricia, II Universita degli
Studi, Napoli.
Minerva Ginecol (Italy) Oct 1996, 48 (10)
p397-400
The localized folate deficiency, which is sometimes
misdiagnosed as cervical dysplasia , because of morphological
similarities between the cytologic features of megaloblastosis
seen with folate deficiency and the changes associated with
dysplasia, could be a component of the dysplastic process. In
this study we attempted the effect of oral folic in women with
cervical dysplasia . A total of 154 subjects with grade 1 or 2
CIN were randomly assigned either 10 mg of folic acid or a
placebo daily for 6 months. Clinical status, human
papillomavirus type 16 infection and blood folate levels were
monitored at 2 month intervals. After 6-months no significant
differences were observed between supplemented and
unsupplemented subjects regarding dysplasia status, biopsy
results, or prevalence of human papillomavirus type 16
infection. Folate deficiency the initiation of cervical
dysplasia , but folic acid supplements do not alter the course
of established disease.
Folate deficiency, cancer and congenital
abnormalities. Is there a connection?
Christensen B Seksjon for farmakologi Institutt for klinisk
biologi Universitetet i Bergen.
Tidsskr Nor Laegeforen (Norway) Jan 20 1996, 116 (2)
p250-4
The biochemical role of folate is in the interconversion of
one-carbon units in intermediary metabolism; a process in
which a methyl group is formed de novo. The methyl group is
subsequently transferred to adenosylmethionine, which is an
important methyl donor in the methylation of DNA. A negative
correlation exists between the intake of folate in pregnancy
and the occurrence of neural tube defects and certain
malignant brain tumours in children. Numerous clinical studies
have pointed to an association between folate status in adults
and both the occurrence of cancer and the premalignant
changes, cervical dysplasia , bronchial metaplasia, and
colorectal adenomas. Folate deficiency may cause chromosomal
damage, due to impaired DNA synthesis or repair. Moreover,
decreased production of adenosylmethionine may influence the
expression of developmental genes and of oncogenes and/or
tumour suppressor genes through disturbed methylation of DNA.
(45 Refs.)
Oral folic acid supplementation for cervical
dysplasia: A clinical intervention trial
Butterworth Jr. C.E.; Hatch K.D.; Soong S.-J.; Cole P.;
Tamura T.; Sauberlich H.E.; Borst M.; Macaluso M.; Baker
V.
Department of Nutrition, Sciences, University of
Alabama,Birmingham, AL 35294-3360 United States
American Journal of Obstetrics and Gynecology 1992, 166/3
(803-809)
Objective: We attempted to evaluate the effect of oral
folic acid supplementation on the course of cervical dysplasia
.
Study design: A total of 235 subjects with grade 1 or 2
cervical intraepithelial neoplasia were randomly assigned to
receive either 10 mg of folic acid or a placebo daily for 6
months. Clinical status, human papillomavirus type 16
infection, and blood folate levels were monitored at 2-month
intervals. Outcome data were subjected to chisup 2
analysis.
Results: The prevalence of human papillomavirus type 16
infection initially was 16% among subjects in the upper
tertile of red blood cell folate versus 37% in the lower
tertile (trend p = 0.035). After 6 months no significant
differences were observed between supplemented and
unsupplemented subjects regarding dysplasia status, biopsy
results, or prevalence of human papillomavirus type 16
infection.
Conclusion: Folate deficiency may be involved as a
cocarcinogen during the initiation of cervical dysplasia , but
folic acid supplements do not alter the course of established
disease.
Hypomethylation in cervical tissue: is there a
correlation with folate status?
Fowler BM; Giuliano AR; Piyathilake C; Nour M; Hatch K
Arizona Cancer Center, University Medical Center, University
of Arizona, Tucson 85716, USA.
Cancer Epidemiol Biomarkers Prev Oct 1998, 7 (10)
p901-6
We have shown previously that DNA hypomethylation is
significantly associated with grade of cervical
intraepithelial neoplasia (CIN; Y.I. Kim et al., Cancer, 74:
893-899, 1994). The objective of this study was to further
describe this relationship and to investigate the role of
folate in the observed association of DNA hypomethylation and
CIN. Eighty-three patients with abnormal PAP smear results
were referred to the Cervical Dysplasia Clinic at the
University of Arizona for colposcopic examination and biopsy.
Patients completed a short questionnaire and provided a
nonfasting serum sample. DNA hypomethylation was assessed by
incubating DNA extracted from biopsy samples with
[3H]methyl-S-adenosylmethionine and Sss 1 methylase. Cervical
tissue and serum folate concentrations were assessed using a
microbiological assay. All folate levels were log transformed
prior to statistical analysis. The histological distribution
of the samples was: 7 adjacent normal, 30 CIN I, 18 CIN II, 13
CIN III, and 11 carcinoma in situ (CIS). The mean age of
participants was 29.8 +/- 9.6 years. DNA hypomethylation was
significantly different between select histological levels.
Both cervical tissue folate and serum folate levels were
significantly correlated to methylation level (P = 0.0211 and
P = 0.0569, respectively). Smoking, hormonal contraceptive
use, parity, and human papillomavirus infection were not
associated with DNA hypomethylation or folate status. The
current use of vitamins was significantly associated with
serum folate level but not with methylation or cervical folate
levels. These data extend our earlier findings that DNA
hypomethylation is an early event in cervical carcinogenesis.
To conclude that the folate level is significantly related to
DNA hypomethylation, further investigation of DNA
hypomethylation of specific genes is required.
Improvement in cervical dysplasia associated with
folic acid therapy in users of oral contraceptives.
Butterworth CE Jr; Hatch KD; Gore H; Mueller H; Krumdieck
CL
Am J Clin Nutr (United States) Jan 1982, 35 (1)
p73-82
Forty-seven young women with mild or moderate dysplasia of
the uterine cervix (cervical intraepithelial neoplasia)
diagnosed by cervical smears, received oral supplements of
folic acid, 10 mg, or a placebo (ascorbic acid, 10 mg) daily
for 3 months under double-blind conditions. All had used a
combination-type oral contraceptive agent for at least 6
months and continued it while returning monthly for follow-up
examinations. All smears and a biopsy obtained at the end of
the trial period were classified by a single observer without
knowledge of treatment status using an arbitrary scoring
system (1 normal, 2 mild, 3 moderate, 4 severe, 5 carcinoma in
situe). Mean biopsy scores from folate supplemented subjects
were significantly better than in folate-unsupplemented
subjects (2.28 versus 2.92, respectively; p less than 0.05).
Final versus initial cytology scores were also significantly
better in supplemented subjects (1.95 versus 2.32,
respectively; p less than 0.05), unchanged in patients
receiving the placebo (2.27 versus 2.30, respectively). Before
treatment the mean red cell folate concentration was lower
among oral contraceptive agent users than nonusers (189 versus
269 ng/ml, respectively; p less than 0.01) and even lower
among users with dysplasia (161 versus 269 ng/ml,
respectively; p less than 0.001). Morphological features of
megaloblastosis were associated with dysplasia and also
improved in folate supplemented subjects. These studies
indicate that either a reversible, localized derangement in
folate metabolism may sometimes be misdiagnosed as cervical
dysplasia, or else such a derangement is an integral component
of the dysplastic process that may be arrested or in some
cases reversed by oral folic acid supplementation.
Megaloblastic changes in the cervical epithelium:
association with oral contraceptive therapy and reversal with
folic acid
Whitehead N; Reyner F; Lindenbaum J
Harlem Hospital, Lenox Avenue and 135th Street, New York, New
York 10037
J. Am. Med. Assoc.; Vol 226 Iss Dec 17 1973, P1421-1424, (Ref
20)
ASHP Megaloblastic abnormalities of cervicovaginal cells
similar to those seen in severe folate and vitamin B12
deficiency were found in 22 (19%) of 115 women taking oral
contraceptive agents (combined estrogen-progestogen or
progestogens only). Similar changes were not observed in any
of 51 controls not taking these medications. The cytologic
abnormalities could not be related to hematologic findings or
serum folate and vitamin B12 concentrations. The changes
reverted to normal or improved markedly in all 8 patients
treated with pharmacologic doses of folic acid for 3 weeks. It
is hypothesized that oral contraceptive agents induce a
localized interference with folate metabolism at the end organ
level.
Folic acid deficiency megaloblastic anemia and
peripheral polyneuropathy due to oral contraceptives
Kornberg A; Segal R; Theitler J; Yona R; Kaufman S
Dep Hematol., Assaf Harofeh Med. Cent., 70300 Zerifin.
Isr J Med Sci 25 (3). 1989. 142-145. Israel Journal of
Medical Sciences
A 34-year-old women developed megaloblastic anemia and
peripheral polyneuropathy following the use of oral
contraceptives for 4 years. Low levels of folic acid and
vitamin B12 were found. Both the complete recovery after
therapy with the vitamins, and the absence of other causes of
vitamin B12 and folate deficiency , suggest that the vitamin
deficiencies were caused by the oral contraceptives and
resulted in the rare combination of megaloblastic anemia and
polyneuropathy. The poor response to vitamin B12 alone, and
the development of anemia and polyneuropathy 4 months after
cessation of vitmain B12 therapy suggest that folate
deficiency was the primary problem.
Megaloblastic anemia in a vegetarian taking oral
contraceptives.
Green JD
South Med J; Vol 68, Iss 2, 1975, P249-50
A case is reported of megaloblastic anemia resulting from
folate deficiency in a vegetarian who had been taking oral
contraceptives for eight years. A brief report of the
pertinent literature is included.
Folate deficiency and oral contraceptives
Streiff RR
Veterans Administration Hospital and the College of Medicine,
University of Florida, Gainesville, Florida
reprints: AMA Department of Foods and Nutrition, 535 N.
Dearborn Street, Chicago, Illinois 60610
J. Am. Med. Assoc.; Vol 214 Iss Oct 5 1970, P105-108, (Ref
38)
ASHP The report concerns 7 cases of folate deficiency and
anemia apparently due to orally administered contraceptives
and studies on the effect of this type of medication on folate
absorption.
Influence of vitamin A on cervical dysplasia and
carcinoma in situ
Wylie-Rosett J.A.; Romney S.L.; Slagle N.S.; et al.
Department of Obstetrics and Gynecology, Albert Einstein
College of Medicine, Bronx, NY 10461 United States
Nutrition and Cancer (United States) 1984, 6/1
(49-57)
A case-control study was undertaken to determine the
dietary intake of vitamin A in women having abnormal
uterocervical cytology. The study groups (87 cases and 82
controls) were drawn from a population of women who received a
screening Pap test in the ambulatory health care section of a
large municipal hospital center. A subset of cases (with
abnormal cytology) were matched to controls for age,
ethnicity, socioeconomic status, and parity. Nutrient intake
and retinol binding protein concentrations were determinde;
epidemiological data were also obtained. It was found that the
subset of cases with severe dysplasia or carcinoma in situ
(CIS) were more likely to have a total dietary vitamin A
intake below the pooled median (3,450 IU) and/or a
beta-carotene intake below the pooled median (2,072 IU) than
were normal controls (p<0.05 and p<0.025, respectively).
Odds ratios revealed approximately a 3-fold greater risk for
severe dysplasia or CIS in women with lowered vitamin A or
beta-carotene intake. In addition, retinol binding protein was
either absent or undetectable in 78.8% of the dysplastic
tissue samples, versus 23.5% of the normal tissue samples
(p<0.005).
Enhancement of regression of cervical
intraepithelial neoplasia II (moderate dysplasia) with
topically applied all-trans-retinoic acid: A randomized
trial
Meyskens Jr. F.L.; Surwit E.; Moon T.E.; Childers J.M.; Davis
J.R.; Dorr R.T.; Johnson C.S.; Alberts D.S.
Irvine Clinical Cancer Center, University of California, 101
The City Dr.,Orange, CA 92668 United States
Journal of the National Cancer Institute (United States)
1994, 86/7 (539-543)
Background: Retinoids enhance differentiation of most
epithelial tissues. Epidemiologic studies have shown an
inverse relationship between dietary intake or serum levels of
vitamin A and the development of cervical dysplasia and/or
cervical cancer. Pilot and phase I investigations demonstrated
the feasibility of the local delivery of all-trans-retinoic
acid (RA) to the cervix using a collagen sponge insert and
cervical cap. A phase II trial produced a clinical complete
response rate of 50%.
Purpose: This randomized phase III trial was designed to
determine whether topically applied RA reversed moderate
cervical intraepithelial neoplasia (CIN) II or severe CIN.
Methods: Analyses were based on 301 women with CIN
(moderate dysplasia, 151 women; severe dysplasia, 150 women),
evaluated by serial colposcopy, Papanicolaou cytology, and
cervical biopsy. Cervical caps with sponges containing either
1.0 mL of 0.372% beta-trans-RA or a placebo were inserted
daily for 4 days when women entered the trial, and for 2 days
at months 3 and 6. Patients receiving treatment and those
receiving placebo were similar with respect to age, ethnicity,
birth-control methods, histologic features of the endocervical
biopsy specimen and koilocytotic atypia, and percentage of
involvement of the cervix at study. Treatment effects were
compared using Fisher's exact test and logistic regression
methods. Side effects were recorded, and differences were
compared using Fisher's exact test.
Results: RA increased the complete histologic regression
rate of CIN II from 27% in the placebo group to 43% in the
retinoic acid treatment group (P = .041). No treatment
difference between the two arms was evident in the severe
dysplasia group. More vaginal and vulvar side effects were
seen in the patients receiving RA, but these effects were mild
and reversible.
Conclusions: A short course of locally applied RA can
reverse CIN II, but not more advanced dysplasia, with
acceptable local side effects. Implications: A derivative of
vitamin A can reverse or suppress an epithelial preneoplasia,
lending further support to the notion that chemoprevention of
human cancer is feasible.
Phase II trial of beta- all- trans- retinoic acid
for cervical intraepithelial neoplasia delivered via a
collagen sponge and cervical cap
Graham V.; Surwit E.S.; Weiner S.; Meyskens Jr. F.L.
Departments of Medicine, Obstetrics and Gynecology,
University of Arizona Health Sciences Center, Tucson, AZ 85724
United States
Western Journal of Medicine (United States) 1986, 145/2
(192-195)
Retinoids are effective suppressors of the phenotypic
development of cancer in many animal systems, whether the
process is initiated by chemical, physical or viral
carcinogens. Cases of cervical intraepithelial neoplasia are
excellent for studying the effectiveness of retinoids as
chemopreventive agents because the process can be closely
followed by serial colposcopic and pathologic (cytology or
biopsy) means and changes in the condition safely monitored.
We have previously conducted a phase I study of trans-retinoic
acid (Tretinoin) given topically by a collagen sponge and
cervical cap. A dose of 0.372% was selected for phase II trial
. We have treated 20 patients with topical retinoic acid, and
a complete response with total regression of disease was
obtained in 50%. Systemic and cervical side effects were mild
and vaginal side effects moderate but tolerable. These results
provide a clinical basis for a randomized, double-blind phase
III study to definitely answer the question of whether
retinoic acid is an effective chemopreventive agent for
cervical cancer.
A phase I trial of topically applied trans-retinoic
acid in cervical dysplasia-clinical efficacy.
Weiner SA; Surwit EA; Graham VE; Meyskens FL Jr
Invest New Drugs 1986, 4 (3) p241-4
Forty-two patients were entered into a phase I trial to
evaluate the vitamin A derivative, trans-retinoic acid, in
cervical intraepithelial neoplasia. Treatment consisted of
four consecutive 24-h applications of retinoids via an inert
collagen sponge in a cervical cap. Patients were followed for
response at 3-month intervals using cytology, colposcopy, and
selected biopsies. Thirty-six patients were evaluable (mild
dysplasia, 13; moderate dysplasia, 17; severe dysplasia, 6)
with follow-up from 5 to 18 months. Complete regression was
seen in 2/14 (14%) patients treated with concentrations of
0.05%----0.1167% and in 10/22 (45%) patients treated with
concentrations of 0.1583%----0.484% (p less than 0.05). One
patient with negative biopsies at 12 months has subsequently
recurred at 18 months.
Retinoids and the prevention of cervical
dysplasias.
Romney SL; Palan PR; Duttagupta C; Wassertheil-Smoller S;
Wylie J; Miller G; Slagle NS; Lucido D
Am J Obstet Gynecol (United States) Dec 15 1981, 141 (8)
p890-4
Women with abnormal cytology were matched with normal
control subjects for age, parity, ethnicity, and socioeconomic
class and participated in a blind case-control study focused
on the role of nutrition in cervical dysplasia . Sucrose
gradient ultracentrifugation studies for determination of the
presence and concentration of the binding proteins for retinol
and retinoic acid were performed on colposcopic biopsy tissue
specimens. The nutritional survey revealed statistically
significant differences for vitamins A and C and beta carotene
. Retinol binding protein was absent or minimally detectable
and inversely related to the severity of the dysplasia. It is
proposed that a double-blind clinical trial be conducted to
evaluate whether retinoids may pharmacologically inhibit,
arrest, or reverse cervical dysplasia .
Use of vitamins A and D in chemoprevention and
therapy of cancer: control of nuclear receptor expression and
function. Vitamins, cancer and receptors.
Niles RM
Department of Biochemistry and Molecular Biology, Marshall
University School of Medicine, Huntington, WV 25755,
USA.
Adv Exp Med Biol 1995, 375 p1-15
Vitamin A is metabolized to several biologically active
compounds, the best known of which is retinoic acid. This
compound has been shown to inhibit the growth of a variety of
tumor cells and to induce a more differentiated phenotype in
several tumor types. Vitamin D is metabolized to the active
compound 1,25-dihydroxyvitamin D3. This vitamin is well-known
for its role in maintaining calcium homeostasis in the body.
Recently it has been shown that vitamin D3 can also inhibit
tumor cell replication and stimulate differentiation of
selected tumor types. Retinoic acid is being used clinically
to treat promyelocytic leukemia, head and neck tumors as well
as cervical dysplasia . Use of vitamin D3 clinically has been
restricted by its affect on calcium metabolism. Recently,
however, new analogs of vitamin D3 have been developed which
have much less calcium mobilizing activity, yet still retain
their tumor inhibitory properties. The action of both of these
vitamins is mediated by nuclear receptors which have the same
structure as steroid receptors. There are three nuclear
retinoic acid receptors (RAR alpha, beta, and gamma), but only
one vitamin D3 nuclear receptor. These receptors are expressed
in very small amounts. Since the ligand should be in vast
excess of receptor (ie not limiting), we explored the
possibility that response to vitamin A might be mediated by
control of RAR expression. Using B16 mouse melanoma cells as a
model system, we found that RAR alpha and gamma mRNAs were
constitutively expressed. RAR beta mRNA was induced by
treatment of the cells with RA. Induction of RAR beta mRNA
occurred within 1h and was not inhibited by cycloheximide. The
mRNA for all three RARs was dramatically decreased with
8-bromo-cyclic AMP treatment and could not be rescued by
addition of RA. Analysis of RAR gamma revealed that this
decrease occurred within 1h of exposure to 8-bromo-cyclic AMP
and was not blocked by simultaneous treatment with
cycloheximide. Nuclear extracts from cyclic AMP-treated cells
showed a large decrease in protein binding to a retinoic acid
response element (RARE) oligonucleotide compared to control
cells. This correlated with a marked reduction of
RA-stimulated RARE-reporter gene activity in transfected cells
which were treated with cyclic AMP. Pre-treatment of B16 cells
with cyclic AMP prior to RA addition dramatically reduced
induction of PKC alpha, an early marker of RA-induced cell
differentiation. Thus, cyclic AMP can antagonize the
physiological actions of RA via its ability to inhibit RAR
expression.
Specificity of retinoid receptor gene expression in
mouse cervical epithelia.
Darwiche N; Celli G; De Luca LM
Differentiation Control Section, National Cancer Institute,
National Institutes of Health, Bethesda, Maryland 20892.
Endocrinology May 1994, 134 (5) p2018-25
Retinoids are powerful regulators of epithelial
differentiation and are essential for its maintenance. Because
retinoids are necessary for cervical epithelial
differentiation, they have been used as chemopreventive agents
of cervical dysplasia and neoplasia. We were interested in
determining whether different cervical epithelial phenotypes
express specific retinoid receptors. The cervical epithelium
contains the two phenotypes, stratified squamous and simple
columnar, which join at the squamocolumnar junction. In
addition, the simple columnar epithelium undergoes squamous
metaplasia in response to vitamin A deficiency. Therefore, the
cervical epithelium is suitable to study the expression
pattern of the retinoid receptors in the three phenotypes,
simple columnar, stratified squamous, and squamous
metaplastic, simultaneously. The distribution pattern of the
major retinoic acid receptor (RAR) isoforms (alpha 1, alpha 2,
beta 2, beta 3, gamma 1, and gamma 2) and retinoid-X receptors
(RXR alpha, -beta, and -gamma) was studied by in situ
hybridization. At the tissue level, RAR alpha (1 and 2) and
RXR (alpha and beta) transcripts and, to a lesser extent, RAR
gamma (1 and 2) transcripts were associated with the cervical
stratified squamous subjunctional epithelium. The simple
columnar epithelium, which is highly responsive to vitamin A
status, expressed high levels of RAR alpha (1 and 2), RAR beta
(2 and 3), and RXR (alpha and beta) transcripts. Only RAR beta
(2 and 3) and RXR (alpha and beta) transcripts were
down-modulated by the condition of vitamin A deficiency and
expressed less in squamous metaplastic foci than the simple
columnar epithelium. RXR gamma was undetectable in all three
cervical epithelia. At the cellular level, basal and
suprabasal expression was found for RARs, and preferential
localization of RXRs was seen in basal cells. RXRs are
auxiliary proteins for a variety of other nuclear receptors
with which they form heterodimers, including RARs. The fact
that RXRs are mainly localized in basal and columnar cells of
the cervix suggests the need for the regulation and diversity
generated by potential heterodimeric interactions in these
rapidly proliferating cells in vivo. The unique pattern of
expression and localization of the RARs and RXRs in different
cervical epithelial tissues and cell types supports the
hypothesis that they perform specific functions in cervical
epithelial differentiation. This is in contrast to the major
isoforms of each RAR, which have similar patterns of
expression in the different cervical epithelial phenotypes and
cell types, suggesting a redundancy in function.
Studies of retinoids in the prevention and
treatment of cancer.
Meyskens FL
J Am Acad Dermatol Apr 1982, 6 (4 Pt 2 Suppl)
p824-7
Investigation of retinoids for anticancer activity in
humans, either in the chemopreventive or treatment mode, has
been little studied. We summarize here our ongoing
investigations in four different areas: (1) secondary
prevention of cervical dysplasia with topical application of
all-trans-retinoic acid; (2) adjuvant treatment of resected
high-risk stage I and II malignant melanoma with bacille
Calmette Guerin (BCG) plus or minus oral vitamin A ; (3)
topical vitamin A acid therapy for cutaneous metastatic
melanoma; an (4) oral isotretinoin as an anticancer agent.
Antioxidant nutrients: associations with persistent
human papillomavirus infection.
Giuliano AR; Papenfuss M; Nour M; Canfield LM; Schneider A;
Hatch K
Arizona Cancer Center, University of Arizona, Tucson 85724,
USA
minority@azcc.arizona.edu
Cancer Epidemiol Biomarkers Prev Nov 1997, 6 (11)
p917-23
Research from the past several years has definitively shown
intermediate and high risk-type human papillomavirus (HPV)
infection to play a significant role in cervical
carcinogenesis. Persistent compared with intermittent
infection appears to confer an elevated risk, and cofactors
may be necessary to allow the virus to progress to cervical
cancer. We explored the association between circulating
concentrations of the antioxidant nutrients (alpha- and
beta-carotene, lutein, lycopene, beta-cryptoxanthin,
alpha-tocopherol, gamma-tocopherol, and ascorbate) and
persistent HPV infection among 123 low-income Hispanic women
who were all nonsmokers and were not currently using vitamin
and mineral supplements. In addition, the association between
these nutrients and grade of cervical pathology, independent
of HPV status, was assessed. Intermediate and high risk-type
HPV infection was assessed by the Digene Hybrid Capture System
at two time points, 3 months apart. At the second interview,
cytology, colposcopy, and a fasting blood draw were conducted.
Mean concentrations of serum and plasma antioxidant nutrients
were calculated within categories of HPV status (two times HPV
negative, one time HPV positive, and two times HPV positive)
and colposcopy. Adjusted mean concentrations of serum
beta-carotene, beta-cryptoxanthin, lutein, and alpha- and
gamma-tocopherol were on average 24% (P < 0.05) lower among
women two times HPV positive compared with either two times
HPV negative or one time HPV positive. Independent of HPV
status, alpha-tocopherol was significantly inversely
associated with grade of cervical dysplasia (normal, 21.57
microM; cervical intraepithelial neoplasia III, 17.27 microM).
The results obtained in this study need to be confirmed in
larger cohort studies with a longer follow-up period.
Content of beta - carotene in blood serum of human
papillomavirus infected women with cervical dysplasias.
Kwasniewska A; Tukendorf A; Semczuk M
Department of Obstetrics and Gynecology, Medical Academy,
Lublin, Poland.
Arch Immunol Ther Exp (Warsz) (Poland) 1996, 44 (5-6)
p309-13
Studies were carried out in 528 women hospitalized in the
Department of Obstetrics and Gynecology Medical Academy in
Lublin. Besides the control group, patients were classified
according to the observed histopathological changes in the
cervix (CIN) and found infections with human papillomavirus
(HPV). In all cases beta -carotene content in blood serum was
examined. HPV infection was probably a cause of decrease of
beta -carotene content. It was found that with increased
advancement of cervical dysplasia the level of beta carotene
in serum decreased.
Premalignant lesions: role of antioxidant vitamins
and beta-carotene in risk reduction and prevention of
malignant transformation.
Singh VN; Gaby SK
Department of Clinical Nutrition, Hoffmann-La Roche, Inc.,
Nutley, NJ 07110-1199.
Am J Clin Nutr Jan 1991, 53 (1 Suppl) p386S-390S
Epidemiological studies have shown that diets rich in one
or more antioxidant nutrients may reduce the risk of cancers
of the lung, uterine cervix, mouth, and gastrointestinal
tract. Study of premalignant lesions offers a comparatively
expedient approach to identifying and evaluating the efficacy
of the cancer chemopreventive components of foods. Some recent
findings suggest roles for beta-carotene and/or vitamin C in
reversing or reducing the risk of cervical dysplasia and oral
leukoplakia. There are some indications that vitamin C and
beta-carotene may reduce the risk of atrophic gastritis and
gastric cancer. Additional epidemiological and molecular
biology studies and clinical intervention trials using
premalignant lesions as the marker of specific cancer risks
should become an important component of future research in the
area of cancer chemoprevention. (57 Refs.)
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