beta-carotene and Uterine-Cervical-Dysplasia

Cervix carcinoma is an important health problem world-wide, being the second most common cancer among women, ranking first in many developing countries. A number of important epidemiological risk factors have been identified as contributing to the development of CIN and invasive cervix carcinoma. Of key importance is infection with human papillomavirus (HPV), which is the primary risk factor. There are evolving primary and secondary preventive strategies that could further reduce the burden from cervical carcinoma. The possible primary preventive strategies include risk reduction, diet or dietary supplements, HPV vaccines, and other chemopreventive agents. The possible advances in secondary preventive strategies include new technologies for Pap smears, HPV typing triage, and other adjuvant screening procedures. The impact of these strategies will depend upon evidence to support their use along with the characteristics of the population and environment in which they are used.

Topics: Anticarcinogenic Agents; Antioxidants; Ascorbic Acid; beta Carotene; Carcinoma, Squamous Cell; Clinical Trials as Topic; Colposcopy; Diet; Female; Folic Acid; Humans; Image Processing, Computer-Assisted; Mass Screening; Nutritional Requirements; Papanicolaou Test; Papillomaviridae; Papillomavirus Infections; Photochemotherapy; Risk Factors; Tumor Virus Infections; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms; Vaginal Smears; Viral Vaccines; Vitamin E; Vitamins

Invasive cervical cancer accounts for 11.6% of all cancers worldwide and is the second most common cancer among women. It is the most common cancer among women living in less developed countries. Although infection with oncogenic-type human papillomaviruses (HPV) is associated with most cases of cervical cancer, HPV infection alone is an insufficient cause of cervical cancer. Research from the last two decades suggests a role for nutrients in the prevention of cervical cancer. However, results from phase III folic acid and beta-carotene chemoprevention trials have been negative. Potential reasons for the lack of treatment effect are discussed within the context of cervical carcinogenesis.

Topics: beta Carotene; Dietary Supplements; Female; Folic Acid; Humans; Treatment Outcome; Tretinoin; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms

We review the current status of prevention trials in the management of cervical intraepithelial neoplasia (CIN) and cervical cancer. Two large, randomized controlled trials have shown that folic acid is inactive in reversing low to moderate grade CIN. A large randomized trial of locally applied beta-trans retinoic acid showed that the agent was effective in reversing moderate but not severe CIN. Results from a pilot trial involving 30 patients with CIN I (mild dysplasia) and CIN II (moderate dysplasia) indicate that beta-carotene can suppress CIN; a large ongoing randomized trial will answer the question more definitively.

Topics: Antioxidants; beta Carotene; Carotenoids; Female; Humans; Randomized Controlled Trials as Topic; Tretinoin; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms

The aim of this paper was to evaluate the factors that predict regression of untreated CIN 2 and 3. A total of 93 patients with colposcopic persistent CIN 2 and 3 lesions after biopsy were followed for 6 months. Human papillomavirus (HPV) types were determined by polymerase chain reaction at enrolment. We analysed the biologic and demographic predictors of natural regression using univariate and multivariate methods. The overall regression rate was 52% (48 out of 93), including 58% (22 out of 38) of CIN 2 and 47% (26 out of 55) of CIN 3 lesions (P=0.31 for difference). Human papillomavirus was detected in 84% (78 out of 93) of patients. In univariate analysis, 80% (12 out of 15) of lesions without HPV regressed compared to 46% (36 out of 78) of lesions with HPV infection (P=0.016). Women without HPV and those who had a resolution of HPV had a four-fold higher chance of regression than those with persistent HPV (relative odds=3.5, 95% CI=1.4-8.6). Women with five or fewer lifetime sexual partners had higher rates of regression than women with more than five partners (P=0.003). In multivariate analysis, HPV status and number of sexual partners remained as significant independent predictors of regression. In conclusion, HPV status and number of lifetime sexual partners were strongly predictive of regression of untreated CIN 2 and 3.

Topics: Adolescent; Adult; beta Carotene; Colposcopy; DNA, Viral; Double-Blind Method; Female; Humans; Incidence; Marital Status; Middle Aged; Papillomaviridae; Papillomavirus Infections; Polymerase Chain Reaction; Prospective Studies; Risk Factors; Sexual Partners; Sexually Transmitted Diseases, Viral; Tumor Virus Infections; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms

To evaluate the effect of daily beta-carotene (30 mg) versus placebo over a 2-year period on cervical intraepithelial neoplasia (CIN) 2 and 3 lesions. Human papillomavirus (HPV) typing was done to determine whether lesion regression was related to HPV. Micronutrient levels were measured to determine whether levels were predictive of regression. Variables that influence the risk of HPV infection and CIN, such as cigarette smoking and sexual behavior, were evaluated. Women were randomized to beta-carotene or placebo, with cytology and colposcopy every 3 months. Cervical biopsies were performed before treatment and after 6 and 24 months to evaluate response. Persistence of or progression to CIN 3 resulted in removal from the study, whereas treatment continued for 2 years on all others. The presence and type of HPV was determined by PCR. Response was defined as an improvement in CIN by 2 grades. Mantel-Haenszel chi(2) test was used to analyze response to treatment. Fisher's exact test was used to determine the effect of HPV and CIN grade on response Wilcoxon's rank-sum tests were used to compare micronutrient levels between groups. Twenty-one of 124 enrolled women were not randomized because they either moved, became pregnant, voluntarily withdrew, or the pathological review of their initial cervical biopsies did not confirm CIN 2 or 3. Of the remaining 103 women, 33 experienced lesion regression, 45 had persistent or progressive disease, and 25 women did not complete the study and were considered nonresponders in the final analysis. The overall regression rate (32%) was similar between treatment arms and when stratified for CIN grade. Data on 99 women with HPV typing showed that 77% were HPV-positive and 23% HPV-negative at enrollment. HPV-positive lesions were subdivided into indeterminate-, low-, and high-risk categories; the response rate was highest for women with no HPV detected (61%), lower for indeterminate/low-risk (30%), and lowest for high-risk (18%; P =.001). CIN regression was negatively correlated with retinol levels. In conclusion, beta-carotene does not enhance the regression of high-grade CIN, especially in HPV-positive subjects.

Topics: Administration, Oral; Adolescent; Adult; Antioxidants; beta Carotene; Biopsy, Needle; Dietary Supplements; Double-Blind Method; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Logistic Models; Long-Term Care; Middle Aged; Probability; Reference Values; Severity of Illness Index; Treatment Outcome; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms; Vaginal Smears

A double-blind, placebo-controlled, randomized, factorial study using a daily oral administration of 30 mg beta-carotene and/or 500 mg vitamin C was conducted in 141 women with colposcopically and histologically confirmed minor squamous atypia or cervical intra-epithelial neoplasia (CIN) I. Over approximately 2 years of follow-up, 43 lesions regressed to normal and 13 progressed to CIN II. The regression rate was slightly higher, but not significantly so, in those randomized to beta-carotene compared to no beta-carotene (hazard ratio = 1.58, 95% CI: 0.86-2.93, P = 0.14) and slightly lower, but not statistically significant, for those randomized to vitamin C compared to no vitamin C (hazard ratio = 0.65, 95% CI: 0.35-1.21, P = 0.17). In a model with no interaction, the progression rate was slightly higher in those randomized to beta-carotene (hazard ratio = 1.75, 95% CI: 0.57-5.36, P = 0.32) and also in those randomized to vitamin C (hazard ratio = 2.40, 95% CI: 0.74-7.80, P = 0.13). Neither of these were statistically significant. However, there was some evidence of an interaction effect of the two compounds on the progression rate (P = 0.052), with seven of the progressed lesions occurring in those randomized to both vitamins compared to a total of six in the three other groups. The currently available evidence from this and other trials suggests that high doses of these compounds are unlikely to increase the regression or decrease the progression of minor atypia and CIN I.

Topics: Adult; Antioxidants; Ascorbic Acid; beta Carotene; Disease Progression; Double-Blind Method; Female; Follow-Up Studies; Humans; Precancerous Conditions; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms

Women with histopathologically confirmed cervical intraepithelial neoplasia (CIN) were followed at 3-month intervals in a randomized double-blinded trial to evaluate the efficacy of beta-carotene to cause regression of CIN. Questionnaire data, plasma levels of micronutrients, and a cervicovaginal lavage for human papillomavirus (HPV) detection were obtained at each visit, and an endpoint biopsy was performed at 9 months. Sixty-nine subjects had a biopsy endpoint evaluation; 9 of 39 (23%) subjects in the beta-carotene group versus 14 of 30 (47%) in the placebo group had regression of CIN (P = 0.039). Independent risk factors for persistent CIN at 9 months included type-specific persistent HPV infection (OR = 11.38, P = 0.006) and continual HPV infection with a high viral load (OR = 14.25, P = 0.007) at baseline and 9 months, an initial diagnosis of > or =CIN II (OR = 6.74, P = 0.016), and older age (OR for > or =25 years = 4.10, P = 0.072). After controlling for these factors, the beta-carotene and placebo groups did not differ in risk for having CIN at 9 months (OR = 1.53, P = 0.550). Resolution of baseline HPV infection was significantly correlated with non-high-risk HPV types (RR = 2.94, P = 0.015), age <25 years (RR = 2.62, P = 0.014), and douching after sexual intercourse (RR = 3.02, P = 0.012), but not with randomization group. Our data indicate that a large proportion of mild CIN lesions regress; age and HPV infection play an important role in the natural course of CIN; and repeated HPV testing may have a value in distinguishing women who need aggressive treatment for CIN versus those who do not. Supplementation of beta-carotene does not appear to have a detectable benefit in treatment of CIN.

Topics: Adult; beta Carotene; Double-Blind Method; Female; Humans; Logistic Models; Longitudinal Studies; Multivariate Analysis; Odds Ratio; Papillomaviridae; Papillomavirus Infections; Treatment Outcome; Tumor Virus Infections; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms

Topics: beta Carotene; Biopsy; Cervix Uteri; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Neoplasm Staging; Treatment Outcome; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms

To evaluate the serial changes in colposcopic and cervicographic findings of women with cervical intraepithelial neoplasia (CIN) II and III enrolled in a phase III randomized comparison of oral beta carotene and placebo.. All subjects treated with beta carotene or placebo for at least 6 months were included if they met the criteria of persistent or progressive disease (no change or worsening of CIN grade) or disease regression (improvement of two grades or more). These two groups were compared for changes in colposcopic and cervicographic patterns. Colposcopically directed biopsies and cervicography were done at enrollment and after 6 months. Quarterly Papanicolaou smears and colposcopic assessments also were performed. Findings of mosaic pattern, punctation, and white epithelium were graded and diagrammed at colposcopic examinations. Cervicographic measurements of the centripetal movement of metaplastic epithelium were recorded. Data were analyzed by chi 2 analysis and Fisher exact tests.. Data were available for 23 subjects with regression and 16 with persistent lesions. Small lesions were significantly more likely to regress than large ones. Lesions without coarse punctation were significantly more likely to regress than lesions with coarse punctation, and lesions with mild acetowhite changes were more likely to regress than those with dense white epithelium. A pattern of centripetal movement of the metaplastic epithelium toward the cervical os was noted in lesions that regressed, but not in those that persisted or progressed.. This study describes the centripetal growth of metaplastic squamous epithelium associated with the regression of CIN II and III. This observation contributes to our understanding of the process of disease regression in CIN and may be useful in identifying individuals for conservative management. Failure to identify this pattern correlates with persistent or progressive disease.

Topics: Adult; Antioxidants; beta Carotene; Clinical Trials, Phase III as Topic; Colposcopy; Female; Humans; Middle Aged; Randomized Controlled Trials as Topic; Remission Induction; Retrospective Studies; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms

Transforming growth factor (TGF) beta1 is a potent growth inhibitor of epithelial cells. Loss of responsiveness to TGF-beta1 and/or loss of TGF-beta1 itself may be important in the progression of cervical intraepithelial neoplasia to invasive cervical cancer. Retinoids have antiproliferative effects on epithelial cells and have been used as chemopreventive and chemotherapeutic agents for several human cancers. There is evidence that retinoids exert their effects by promoting the induction of TGF-beta. The aim of this study was to determine whether the expression of TGF-beta1 was altered in patients enrolled in a clinical trial designed to test the therapeutic efficacy of beta-carotene, a carotenoid metabolized to retinol, in cervical intraepithelial neoplasia. Using an immunohistochemical technique, tissues were stained with two types of antisera that react with the intracellular and extracellular forms of TGF-beta1. Matched cervical biopsies taken from 10 patients before and after treatment with beta-carotene were immunostained simultaneously to allow direct comparison of relative staining intensity. A significant increase in intracellular TGF-beta1 immunoreactivity was noted in cervical epithelial cells in patients with cervical intraepithelial neoplasia after treatment with beta-carotene (P = 0.003). These results demonstrate regulation of a TGF-beta isoform in vivo in humans in response to beta-carotene administered as a chemopreventive agent.

Topics: beta Carotene; Chemoprevention; Female; Humans; Immunohistochemistry; Transforming Growth Factor beta; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms

The use of Papanicolaou smears for cervical cancer screening has led to an increased detection of preinvasive conditions of the cervix, cervical intraepithelial neoplasia (CIN). Epidemiological studies have shown an association between low levels of dietary beta-carotene and CIN. In this Phase II study, we have explored the effect of p.o. beta-carotene administration on CIN I and II. Patients with documented CIN I or II were treated with 30 mg daily of beta-carotene for 6 months. Response rates were determined at 0, 3, 6, and 12 months with cytology, colposcopy, and/or biopsies. Levels of beta-carotene and vitamin E were determined at the same time intervals in vaginal mucosa cells and serum. Response rates were 18 of 30 (60%), 21 of 30 (70%), and 10 of 30 (33%) at 3, 6, and 12 months, respectively. Significant changes occurred in the serum beta-carotene levels over time. Median levels over 2200 mg/ml were found at 3 and 6 months versus a baseline median level of 111 (P < 0.0001). Significant increases were also noted in the beta-carotene levels of the vaginal mucosa compared to baseline (P = 0.01) and a significant correlation was noted between serum and vaginal beta-carotene levels as well (P < 0.0001). This study indicates that a large percentage of patients with CIN I and II will respond clinically to p.o. beta-carotene supplementation. There is a positive relationship between serum and tissue levels of beta-carotene which suggests that serum levels can be used for monitoring purposes. Because of these encouraging results, prospective randomized studies are ongoing comparing the efficacy of beta-carotene against an untreated control arm.

Topics: Antioxidants; beta Carotene; Female; Humans; Mucous Membrane; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms; Vagina

Topics: Ascorbic Acid; Australia; beta Carotene; Carotenoids; Colposcopy; Female; Humans; Regression Analysis; Uterine Cervical Dysplasia

The effect of sexual behavior on the risk for cervical dysplasia was evaluated in a case-control study. Cases (n = 257) had a histologically confirmed diagnosis of cervical dysplasia. Controls (n = 705) were sampled from the general population. A postal questionnaire was used to obtain information about, among other things, age at first sexual intercourse, number of sexual partners, current frequency of intercourse and contraceptive use. Information was also collected about other risk factors for cervical dysplasia, in order to adjust for possible confounding. We observed higher risks for cervical dysplasia (mild, moderate and severe) with increasing number of sexual partners. This effect appeared to be dependent on smoking behaviour. For women who reported more than six sexual partners, the adjusted odds ratio (aOR) was 9.1 (95% CI: 3.5-23.7) for non-smokers, and 26.4 (95% CI: 11.8-58.8) for women who smoked > or = 20 cigarettes per day. The effects of age at first sexual intercourse and current frequency of intercourse disappeared after adjustment for other risk factors. Use of oral contraceptives for > 10 years increased the risk (aOR = 2.3; 95% CI: 1.2-4.6). Thus, the number of sexual partners, especially in combination with smoking behaviour, appeared to be the most important risk factor for cervical dysplasia.

Topics: Adjuvants, Immunologic; Adult; Aged; beta Carotene; Carotenoids; Case-Control Studies; Coitus; Contraceptives, Oral; Female; Humans; Logistic Models; Middle Aged; Netherlands; Odds Ratio; Risk Factors; Sexual Partners; Smoking; Uterine Cervical Dysplasia

The perceived informativeness of a publication can be assessed by measuring the change in belief it induces among the scientific public, regarding a certain hypothesis. In a randomized trial, we studied the effect of empirical evidence from a clinical experiment and a case-control study on the hypothesis that beta-carotene protects against (cervical) cancer. The study population consisted of first authors of recently published patient-oriented research papers. They received an abstract of the clinical experiment, of the case-control study, or a "placebo" abstract. The latter was used to assess the specific effect of the empirical evidence in the two real studies. The change in belief in the hypotheses was expressed as a likelihood ratio (LR). All three abstracts led to a decrease in belief in the hypothesis. The median LRs of the abstracts of the experiment, case-control study and "placebo" were 0.33, 0.45, 0.75 respectively. This paper shows that the belief in a certain hypothesis is influenced by the quality of empirical evidence in a study. The magnitude of change induced by the experimental and case-control abstract had the anticipated order, but the change in belief induced by the "placebo" abstract was larger than we had expected. Reasons for this may be the concise information in the abstract and the variable methodological training of the study population.

Topics: Anticarcinogenic Agents; beta Carotene; Carotenoids; Case-Control Studies; Diffusion of Innovation; Female; Humans; Random Allocation; Statistics as Topic; Surveys and Questionnaires; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms

In order to gain insight into the causality of the relation between beta-carotene and cancer, we performed a randomized placebo-controlled trial in which the effect of beta-carotene on the regression and progression rates of cervical dysplasia were examined. The experimental group (n = 137) received a supplemental dose of 10 mg of beta-carotene daily for 3 months. The control group (n = 141) received placebo capsules. As the outcome parameter, two definitions of regression and progression were used, which were based on the degree of dysplasia before and after the medication period. The number of patients who showed progression was too small to allow conclusions. No effect of beta-carotene on the regression percentages was observed: OR = 0.68 (95% CI: 0.28-1.60) using the broad definition; and OR = 1.22 (95% CI: 0.43-3.41) with the strict definition. A secondary analysis, in which the effect of the total intake of beta-carotene (diet + medication) on the regression percentages of cervical dysplasia was studied, did not show a positive effect either. The paper discusses to what extent issues in the study design may have masked a potential effect and how our results affect the evidence for a causal relation between beta-carotene and cancer.

Topics: Adult; Aged; beta Carotene; Carotenoids; Female; Humans; Middle Aged; Patient Compliance; Prognosis; Research Design; Surveys and Questionnaires; Uterine Cervical Dysplasia

The studies were carried out in a group of 228 female patients with normal cytological smear and 324 patients with cervical intraepithelial neoplasia (CIN). The applied method of human papillomavirus (HPV) identification, i.e., the HPV digene hybrid capture system, made it possible to select a control group consisting of 168 HPV-negative patients with normal Papanicolaou smears, as well as a group of 228 HPV-positive female patients with CIN. By examining the diet of the patients, it was shown that women with cervical dysplasia associated with high oncogenic risk of HPV infections consumed a smaller quantity of foods containing vitamin C, beta-carotene, and folacin. Our studies indicate a relationship between nutritional habits and the development of CIN associated with HPV infection.

Topics: Animals; Antioxidants; Ascorbic Acid; beta Carotene; Dairy Products; Diet; Dietary Fats; Dietary Fiber; Edible Grain; Female; Folic Acid; Fruit; Humans; Milk; Papillomaviridae; Papillomavirus Infections; Tumor Virus Infections; Uterine Cervical Dysplasia; Vegetables

The aim of the present study was to determine to what extent 9-cis beta-carotene, one of the most abundant naturally-occurring cis-isomers of beta-carotene, can inhibit the growth of cervical dysplasia-derived cells in comparison with all-trans beta-carotene. We found that 9-cis beta-carotene was dose-dependently more effective than all-trans beta-carotene. Both carotenes induced the intracellular accumulation of heat-shock protein-70 (HSP70), and the treated cells showed morphological changes indicative of apoptosis. The results of the present study strongly suggest that the induction of HSP70 by beta-carotene might be involved in beta-carotene-mediated suppression of the cell growth through apoptosis.

Topics: beta Carotene; Cell Division; Cell Line; Dose-Response Relationship, Drug; Female; HSP70 Heat-Shock Proteins; Humans; Uterine Cervical Dysplasia

The presence of HPV, using the Digene Hybrid Capture System, was identified in a group of 324 women with CIN and in 228 women with normal cytological smears. Risk of occurrence of CIN was 40 times higher for high risk HPV types. The serum folic acid level and the level of antioxidant compounds in plasma (retinol, alpha-tocopherol, vitamins C and E) in women of the studied and control group was determined by HPLC (high-performance liquid chromatography-reversed phase). Statistically lower levels of folic acid were found in the women with CIN-HPV (+) (OR: 7.5: 95% CI: 1.2-9.7). Studies have shown that lower levels of antioxidants coexisting with low levels of folic acid increases the risk of CIN development.

Topics: Antioxidants; beta Carotene; Cocarcinogenesis; Female; Folic Acid; Folic Acid Deficiency; Humans; Papillomaviridae; Papillomavirus Infections; Regression Analysis; Risk Factors; Tumor Virus Infections; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms; Vitamin E

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.

Topics: Adolescent; Adult; beta Carotene; Female; Humans; Life Style; Middle Aged; Papillomaviridae; Papillomavirus Infections; Poland; Risk Factors; Smoking; Tumor Virus Infections; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms

Epidemiological studies continue to identify an association of dietary antioxidant micronutrients in cancer prevention. A number of case-control and cohort studies have demonstrated a relationship between high intake of foods rich in carotenoids, tocopherols, and vitamin C with a reduced risk of certain human malignancies. The purpose of this study was to investigate the comparative plasma levels of a profile of known dietary antioxidants, namely, beta-carotene, lycopene, canthaxanthin, retinol, alpha-tocopherol, and tau-tocopherol. The target population was women with a histopathological diagnosis of cervical intraepithelial neoplasia (CIN) or cervical cancer and a control group. All women resided in the same catchment area (Bronx Borough, New York City) and were of similar inner-city socioeconomic backgrounds representing a fairly homogenous population group. A cross-sectional sample of 235 women was recruited with informed consent. Plasma nutrient levels were measured by reverse-phase high pressure liquid chromatography under study codes. The mean plasma levels of carotenoids (beta-carotene, lycopene, and canthaxanthin), as well as alpha-tocopherol, were significantly lower in women with CIN and cervical cancer. In contrast, the mean plasma level of tau-tocopherol was higher among patients with CIN, while the mean plasma level of retinol was comparable among the groups. There were significant linear trends for all three carotenoids and quadratic trends for alpha- and tau-tocopherol with the degree of cervical histopathology. Plasma beta-carotene concentrations in cigarette smokers were significantly lower regardless of cervical pathology, whereas plasma lycopene and canthaxanthin levels were significantly lower in smokers with CIN. The findings of a decrease in all plasma antioxidant nutrient levels except tau-tocopherol in women with CIN and cancer suggest a potential role for antioxidant deficiency in the pathogenesis of CIN and carcinoma of the cervix, which requires further investigation.

Topics: Adult; Aged; beta Carotene; Canthaxanthin; Carotenoids; Chromatography, High Pressure Liquid; Cross-Sectional Studies; Female; Humans; Lycopene; Middle Aged; Smoking; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms; Vitamin A; Vitamin E

We used newly established cervical dysplasia-derived cell lines to elucidate a molecular mechanism of the preventive action of beta-carotene in cervical multi-step carcinogenesis. Liposomal beta-carotene was added to the culture medium for human cervical dysplasia cell lines, CICCN-2 from cervical intraepithelial neoplasia grade I (CIN I), CICCN-3 from CIN II, and CICCN-4 from CIN III, and human cervical carcinoma-derived cell lines such as CICCN-6, CICCN-18, and HeLa cells. beta-Carotene (10 mumol/L) induced significant growth retardation in three cervical dysplasia cell lines but not in three cervical carcinoma-derived cell lines. Binding activities of epidermal growth factor (EGF) and cellular amounts of either messenger RNA for EGF receptor gene or EGF receptor protein were all highest in CICCN-4 cells. Cell surface binding, as well as internalization, of 125I-labeled EGF was rapidly reduced after beta-carotene treatment in dysplasia cell lines and 170-kD protein bands of EGF receptor disappeared from protein immunoblots at day 3 of the treatment. Cellular amounts of EGF receptor messenger RNA remained constant until day 3 of the treatment and were substantially reduced after day 7. Chromatin condensations, morphologic evidence for apoptotic cell death, were observed at day 1 by staining. From these results, we contend that prevention of cervical carcinogenesis by beta-carotene is due to induction of apoptosis in cervical dysplastic cells, which are premalignant cells in cervical multi-step carcinogenesis, via down-regulation of EGF receptor protein.

Topics: Anticarcinogenic Agents; Antioxidants; Apoptosis; beta Carotene; Carotenoids; Down-Regulation; Epidermal Growth Factor; ErbB Receptors; Female; Humans; RNA, Messenger; Tumor Cells, Cultured; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms

The baseline, intra-, and interindividual variability as well as storage stability of carotenoids, tocopherols, and retinoids in human buccal mucosal cells were determined because this information is lacking. All the buccal mucosal cell samples were collected after an overnight fast. In the variability study, 154 subjects (median age 57.5 y) provided three samples each at 7-10-d intervals over a 1-mo period. In the stability study, 13 young volunteers provided four samples each before and during the 11 d of oral administration of beta-carotene, alpha-tocopherol, and vegetable juice; the cells were pooled and stored as a pellet at -80 degrees C. Eleven micronutrients were analyzed simultaneously with HPLC. The results indicated that 1) lycopene and beta-carotene were the two major carotenoids, retinol was not detected in most cell samples; 2) the intra-individual variability was small, but the interindividual variability was very large; 3) two measurements of micronutrient concentration in fasting buccal mucosal cells should be adequate to establish a representative baseline for each micronutrient; and 4) the micronutrients under the storage conditions were stable for > or = 8 mo.

Topics: Administration, Oral; Adult; Aged; beta Carotene; Carotenoids; Female; Humans; Keratosis; Leukoplakia; Male; Middle Aged; Mouth Mucosa; Precancerous Conditions; Reference Values; Retinoids; Uterine Cervical Dysplasia; Vegetables; Vitamin E

The effects of beta-carotene and several other dietary factors on the risk of cervical dysplasia were evaluated in a case-control study. Cases (n = 257) were the participants of a randomized trial assessing the effect of beta-carotene on cervical dysplasia. Controls (n = 705) were sampled from the general population. A postal questionnaire was used to obtain information about the frequency of consumption of several food items containing beta-carotene, retinol, vitamin C and dietary fibre. Information was also collected about other risk factors for cervical dysplasia, in order to adjust for possible confounding. To our surprise, we observed an increased risk of cervical dysplasia for women with a high intake of beta-carotene (odds ratio (OR) = 2.31; 95% confidence interval (CI): 1.27-4.19). No relationship was found with the intake of retinol, while both vitamin C and dietary fibre showed a weak and not statistically significant inverse relationship with cervical dysplasia. These findings do not support the hypothesis that beta-carotene protects against cervical dysplasia.

Topics: Adult; Ascorbic Acid; beta Carotene; Carotenoids; Case-Control Studies; Dietary Fiber; Epidemiologic Methods; Female; Humans; Middle Aged; Netherlands; Risk Factors; Surveys and Questionnaires; Uterine Cervical Dysplasia; Vitamin A

Chronic human health problems, namely arteriosclerosis, myocardial ischemia, and cancer, may be caused by highly active oxygen species and may be preventable by antioxidant vitamins. In humans, the sources of two major antioxidants, beta-carotene and alpha-tocopherol, are dietary. In this study, we measured the plasma concentrations of beta-carotene and alpha-tocopherol by reverse-phase high-pressure liquid chromatography in a cross-sectional sampling of 116 women. Significantly reduced plasma levels of beta-carotene and alpha-tocopherol were observed in women with histopathologically diagnosed cervical dysplasias or cancer (p less than 0.0001 and p less than 0.005, respectively). There was an inverse association between the plasma levels of both beta-carotene and alpha-tocopherol and increasingly severe graded cervical histopathology. In groups with advanced dysplasias, the percentage of smokers was markedly increased and the women were comparatively older (p less than 0.0001). A strong association was noted between smoking status and plasma beta-carotene levels, independent of cervical pathology. However, this was not evident with respect to alpha-tocopherol. The findings suggest that the antioxidants beta-carotene and alpha-tocopherol have biologic functions that are interdependent in the pathogenesis of cervical intraepithelial lesions and cervical cancer.

Topics: Adolescent; Adult; Age Factors; Analysis of Variance; beta Carotene; Carotenoids; Female; Free Radicals; Humans; Middle Aged; Regression Analysis; Smoking; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms; Vitamin A; Vitamin E

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.

Topics: Adult; beta Carotene; Carotenoids; Case-Control Studies; Cryptoxanthins; Diet; Female; Humans; Lutein; Lycopene; Reference Values; Surveys and Questionnaires; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms; Xanthophylls

Topics: beta Carotene; Carotenoids; Female; Humans; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms

The concentrations of retinol and beta carotene were measured in serum samples taken from 113 women with cervical cancer, 32 with invasive and 81 with pre-invasive disease, and compared with those from 226 age-matched control women. There was little difference in serum retinol levels between women with cancer of the cervix, at any stage, and the control women, after adjusting for potential confounding factors. Serum beta carotene concentrations were likewise similar in women with invasive disease and the controls. However mean beta carotene levels were significantly reduced in women with pre-invasive disease compared to the controls (221.3 cf. 291.6 micrograms l-1, P less than 0.05). This reduction was more evident amongst women with a diagnosis of carcinoma-in-situ (mean 213.1 micrograms l-1 than amongst those with severe dysplasia (mean 228.7 micrograms l-1. There is a negative trend between beta carotene and risk of pre-invasive disease which is of borderline significance. These data have also been used to investigate the effects of smoking and oral contraceptive usage on the serum levels of retinol and beta carotene. Both habits tend to increase retinol and decrease beta carotene concentrations.. Women with invasive cancer of the cervix or with preinvasive disease and a control group of women with various benign gynecological problems were interviewed over the 1975-79 period at 2 hospitals and a health center in Oxfordshire, England, as part of a study designed to examine the hypothesis that the etiology of epithelial cancers might be related to a relative deficiency of dietary vitamin A. A sexual, obstetric, and contraceptive history was obtained from each woman. Blood samples were taken at the time of the interview from most of the study participants. Serum samples from 43 women with dysplasia, 38 women with carcinoma-in-situ, 32 women with invasive cancer, and 226 control women (matched for 5-year age group) were used. Serum samples were assayed for retinol and Beta-carotene. Analysis was carried out between 6-9 years after collection and initial freezing. Relative risks were computed for quintiles of serum levels of vitamin A and Beta-carotene as determined by the distributions among the controls, I being the lowest group and V the highest. The mean levels of serum retinol were similar in cases of all the disease categories and in cases and controls after full adjustment. This was the case for mean levels of serum Beta-carotene when comparing invasive cancer cases with controls. For both the preinvasive disease categories, the levels of Beta-carotene were lower among the cases than the controls at a significant level for the carcinoma-in-situ category and for both the preinvasive categories combined after full adjustment. No significant elevations, reductions, or trends in the odds ratios were found with retinol or Beta-carotene in any disease group. In the carcinoma-in-situ group, the odds ratio was greater than 4 in the 3 lowest Beta-carotene quintiles and of borderline significance. The comparison of the lowest 4 quintiles for the carcinoma-in-situ group with the highest gave an odds ratio of 4.0, a ratio of borderline significance. When the 2 preinvasive disease categories were combined, an elevated odds ratio of borderline significance was found for 2 of the 3 lower quintiles for the 4 low quintiles combined. Both smoking and OC use were independently associated with the serum measures; both habits tended to be linked with relatively high retinol and low Beta-carotene levels, respectively. The effect of smoking on Beta-carotene was quite strong. The results were similar in premenopausal and postmenopausal women. In sum, t

Topics: beta Carotene; Carcinoma in Situ; Carotenoids; Contraceptives, Oral; Female; Humans; Neoplasm Invasiveness; Smoking; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms; Vitamin A

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.

Topics: Ascorbic Acid; beta Carotene; Carcinoma in Situ; Carotenoids; Diet; Female; Humans; Retinol-Binding Proteins; Tretinoin; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms; Vitamin A