RESUMEN
Selective estrogen receptor modulators and a combination of mechanistically distinct chemotherapeutic agents represent conventional therapeutic interventions for estrogen receptor-positive (ER+) clinical breast cancer. Long-term treatment with these agents is associated with acquired tumor resistance and other adverse side effects that impact on patient compliance. Herbal medicines are being widely used in complementary and alternative medicine. However, long-term safety and efficacy of the use of herbal medicines, as well as their interaction with conventional endocrine and chemotherapeutic drug regimens remain largely unknown. The present study utilized a human cell culture model for ER+ clinical breast cancer to examine the potential therapeutic efficacy of an aqueous extract prepared from the fruit of popular Chinese herb Cornus officinalis (CO), also known as Fructus cornii. The human mammary carcinoma-derived MCF-7 cell line represented the model. Status of anchorage-independent growth and cellular metabolism of 17ß-estradiol (E2) represented the quantitative end-point biomarkers for efficacy. MCF-7 cells adapted for growth in serum-depleted medium (0.7% serum, <1 nM E2) retained their endocrine responsiveness as evidenced by growth promotion by physiological levels of E2, and growth inhibition by the selective ER modulator tamoxifen at the clinically achievable concentrations. Treatment of MCF-7 cells with CO resulted in inhibition of E2-stimulated growth in a dose-dependent manner. Similarly, CO treatment also produced a dose-dependent progressive reduction in the number of anchorage-independent colonies, indicating effective reduction of the carcinogenic risk. Treatment of MCF-7 cells with CO at a maximally effective cytostatic concentration resulted in a 5.1-fold increase in the formation of the anti-prolifertive E2 metabolite 2-hydoxyestrone (2-OHE1), a 63.6% decrease in the formation of the pro-mitogenic metabolite 16α-hydroxestrone (16-αOHE1) and a 9.1% decrease in the formation of mitogenically inert metabolite estrone (E3). These alterations led to a 14.5-fold increase in the 2-OHE1:16α-OHE1, and a 3.3-fold increase in the E3:16α-OHE1 ratios. These data validate a rapid cell culture-based mechanistic approach to prioritize efficacious herbal medicinal products for long-term animal studies and future clinical trials on ER+ clinical breast cancer.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Cornus/química , Extractos Vegetales/farmacología , Receptores de Estrógenos/metabolismo , Neoplasias de la Mama , Agregación Celular/efectos de los fármacos , Técnicas de Cultivo de Célula , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Medicamentos Herbarios Chinos , Estradiol/metabolismo , Femenino , Frutas/química , Cromatografía de Gases y Espectrometría de Masas , Humanos , Hidroxiestronas/metabolismo , Modelos BiológicosRESUMEN
UNLABELLED: Indole-3-carbinol (I3C) when given orally is converted to diindolylmethane (DIM) and other oligomers catalyzed by stomach acid. This suggests that DIM is the predominant active agent and that I3C is a precursor, 'pro-drug' in vivo. However, in cell culture studies carried out in neutral solutions, I3C has been considered fully active. MATERIALS AND METHODS: The stability of I3C in cell culture media was studied. RESULTS: In the 8 different cell culture media tested, greater than 50% dimerization of I3C into DIM occurred in 24 hours. At 48 hour, greater than 60% conversion was found. When neutral synthetic cerebrospinal fluid (CSF) or peritoneal fluid (PF) was studied, a large peak, tentitively identified as I3C's linear trimer (LTR) conversion product by mass spectra, and two smaller peaks, were seen. When CSF or PF was diluted 1:1 with media, the formation of these additional peaks was diminished. CONCLUSION: Because of the greater biologic potency of DIM when studied in parallel with I3C in vitro, this extent of dimerization shows that DIM rather than I3C is the active agent in cell culture studies.
Asunto(s)
Indoles/metabolismo , Animales , Biotransformación , Neoplasias de la Mama/metabolismo , Calibración , Técnicas de Cultivo de Célula/métodos , Medios de Cultivo , Dimerización , Femenino , Ácido Gástrico/metabolismo , Humanos , Masculino , Profármacos/metabolismo , Neoplasias de la Próstata/metabolismo , Especificidad de la Especie , Neoplasias del Cuello Uterino/metabolismoRESUMEN
Whether postmenopausal hormone-replacement therapy (HRT) increases the risk of breast cancer remains controversial, despite numerous epidemiological studies. We approached the question from a biochemical rather than an epidemiological direction - we hypothesized that if estrogen administration increases the risk of breast cancer, it should also alter a known estrogen biomarker of risk towards what has been observed in patients who already have breast cancer. The specific biomarker we studied was the ratio of the urinary excretion of two principal estradiol metabolites, 2-hydroxyestrone and 16 alpha-hydroxyestrone, which is markedly decreased in women with breast cancer and women with familial risk for breast cancer. We studied 34 healthy postmenopausal women not on HRT and 19 women on HRT (Premarin 0.625 mg daily plus Provera, 2.5 mg daily, in women with a uterus and Premarin alone in women without a uterus); treatment duration ranged from 3 months to 15 years. We also studied four women with recently diagnosed, untreated breast cancer. The women with breast cancer showed a significantly lower 2-hydroxyestrone to 16 alpha-hydroxyestrone ratio than control women on HRT (1.35 +/- 0.13 vs. 2.71 +/- 0.84; p < 0.0001). There was no significant difference in the metabolite ratio between healthy women on HRT and women not on HRT (2.82 +/- 0.92 vs. 2.71 +/- 0.84). There was no significant difference between women receiving Premarin alone and women receiving Premarin plus Provera (2.46 +/- 0.84 vs. 3.13 +/- 0.90), and neither differed significantly from women not on HRT (2.71 +/- 0.84). The finding that the ratio of women on HRT was not decreased to or toward the ratio in women with breast cancer can be interpreted, we believe, as a suggestive item of biochemical evidence that HRT is not a risk for breast cancer.
Asunto(s)
Biomarcadores de Tumor/orina , Neoplasias de la Mama/orina , Terapia de Reemplazo de Estrógeno/efectos adversos , Hidroxiestronas/orina , Posmenopausia , Estudios Transversales , Estrógenos Conjugados (USP)/administración & dosificación , Femenino , Humanos , Acetato de Medroxiprogesterona/administración & dosificación , Factores de RiesgoRESUMEN
Studies of circulating estrogen levels in relation to pre-menopausal breast cancer risk have yielded inconsistent results. Various estrogen metabolites might affect the risk differently. Estradiol metabolism occurs primarily via two mutually exclusive pathways, yielding 2-hydroxyestrone (2-OHE) and 16alpha-hydroxyestrone (16alpha-OHE). Most, but not all, studies have found that a relatively high 2-OHE/16alpha-OHE ratio is associated with a low breast cancer risk. Our objective was to determine if the 2-OHE/16alpha-OHE ratio in plasma correlates with suspected breast cancer risk factors and other lifestyle factors, such as ethnicity, body size, age at menarche, oral contraceptive use, smoking, vegetarian diet, coffee and alcohol consumption in 513 nulliparous women, aged 17-35. Oral contraceptive users had significantly lower 2-OHE/16alpha-OHE ratios than pill non-users (P = 10(-21)). Among women who were not using oral contraceptives, the median 2-OHE/16alpha-OHE ratio in plasma was similar for white, black, Indian/Pakistani and Asian women, after adjustment for age and menstrual cycle phase. Among oral contraceptive users, Asian women had significantly lower 2-OHE/16alpha-OHE ratios than white women, and this result remained after adjustment for age and day of menstrual cycle. Daily coffee consumption was significantly positively correlated with 2-OHE/16alpha-OHE ratios (r(s) = 0.18, P = 0.002) only among pill non-users. Our findings suggest that the plasma 2-OHE/16alpha-OHE ratio is associated with constitutional factors and with modifiable lifestyle factors. The reported elevated risk of early onset breast cancer among young oral contraceptive users could be mediated in part through altered estrogen metabolism induced by synthetic estrogens and progestins.
Asunto(s)
Neoplasias de la Mama/sangre , Neoplasias de la Mama/etnología , Etnicidad , Hidroxiestronas/sangre , Premenopausia , Administración Oral , Adolescente , Adulto , Población Negra , Anticonceptivos/efectos adversos , Terapia de Reemplazo de Estrógeno , Femenino , Humanos , Ciclo Menstrual , Paridad , Factores de Riesgo , Población BlancaRESUMEN
The etiology of non-insulin-dependent diabetes mellitus (NIDDM) is complex and development is manifested by initial insulin resistance coupled with elevated insulin levels in the early diabetic state with concomitant increases in circulating levels of glucose and triglycerides. This is followed by a decline in insulin levels due to pancreatic exhaustion. Our results show that administration of DHEA-PC, a phosphocholine conjugate of dehydroepiandrosterone (DHEA), delayed the development of NIDDM symptoms and the onset of type 2 diabetes in the ZDF/Gmi-fa/fa rat model. The treatment consisted of weekly implantation of subdermal osmotic infusion pumps in the rats starting at 6 weeks of age (n = 5 animals per group). For the first three weeks the pumps delivered 6 mg/day/rat followed by 12 mg/day/rat for 1 week (control group pumps delivered only carrier vehicle) after which the pumps were removed. Plasma was collected weekly from day 0 through day 58, and glucose, triglycerides, cholesterol, insulin, IGF-1, and IGF-BP3 levels were measured. Data were analyzed by two-way ANOVA. Following 3 weeks of treatment with DHEA-PC, plasma glucose levels in the treated group remained low, 150+/-9 mg/dL, while the levels in the control animals steadily increased to 320+/-100 mg/dL (p < 0.05). After the DHEA-PC treatment ended, plasma glucose plateaued for 10 days and then took 25 days to reach the level in the control animals (p < 0.05). After 2 weeks of DHEA-PC treatment, plasma triglyceride levels in the treated group remained low, 85+/-24 mg/dL, while the level in the control rats increased to 180+/-35 mg/dL (p < 0.05). After the treatment was terminated triglyceride levels in the treated group increased to control levels within 2 days. Insulin, IGF-1, IGF-BP3, cholesterol, body weight, and food consumption were not changed by DHEA-PC treatment (p < 0.05). Therefore, the delay of increases in plasma glucose and triglycerides, caused by DHEA-PC, was not the result of differences in caloric intake, increased insulin, or increased IGF-1 levels. The data suggest that DHEA-PC delayed the onset of the two most important parameters of NIDDM, namely hyperglycemia and hypertriglyceridemia. (ZDF/Gmi-fa/fa rats and their care was supplied by contract with Genetic Models Inc., Indianapolis, IN.).
Asunto(s)
Deshidroepiandrosterona/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Fosforilcolina/uso terapéutico , Animales , Glucemia/análisis , Diabetes Mellitus/genética , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/fisiopatología , Combinación de Medicamentos , Prueba de Tolerancia a la Glucosa , Masculino , Obesidad , Ratas , Ratas Zucker/genética , Triglicéridos/sangreRESUMEN
It has been hypothesized that women who metabolize their endogenous estrogens predominantly via 16(alpha)-hydroxylation rather than via 2-hydroxylation and, as a result, have a low ratio of 2-hydroxyestrone (2-OHE1):16(alpha)-hydroxyestrone (16(alpha)-OHE1) are at an increased risk of breast cancer. Epidemiological evidence in support of this hypothesis is scarce and mostly based on measurements made after the onset of the disease. To gain insight into the role of these metabolites in the etiology of breast cancer, we assessed their relationship with high-density Wolfe mammographic parenchymal patterns (P2/DY), a recognized indicator of risk of this tumor. The study was nested within a large cross-sectional survey on determinants of mammographic patterns carried out in a population-based breast screening program in Northern Greece. Urinary levels of 2-OHE1 and 16(alpha)-OHE1 were measured in a random sample of 70 postmenopausal women with P2/DY mammographic patterns and in a random sample of 70 women with N1 mammographic patterns, individually matched to the P2/DY women on year of birth, years since menopause and date of urine collection. Women with a P2/DY pattern had, on average, 58% higher levels of 2-OHE1 (P = 0.002) and 15% higher levels of 16(alpha)-OHE1 (P = 0.37) than those with an N1 pattern. The ratio of 2-OHE1:16(alpha)-OHE1 was 35% higher (P = 0.005) in women with a P2/DY pattern. Women in the highest one-third of this ratio were six times more likely to have a P2/DY pattern than those in the lowest one-third after adjusting for potential confounders (prevalence odds ratio, 6.2; 95% CI, 1.7-22.9; test for linear trend, P = 0.002). These findings seem to suggest that a high, rather than a low, 2-OHE1:16(alpha)-OHE1 ratio may be associated with an increase in breast cancer risk at postmenopausal ages, unless the pathway through which estrogen metabolites may affect breast cancer risk is unrelated to mammographic parenchymal patterns.
Asunto(s)
Neoplasias de la Mama/fisiopatología , Estrógenos/metabolismo , Hidroxiestronas/orina , Adulto , Anciano , Neoplasias de la Mama/diagnóstico por imagen , Estudios de Casos y Controles , Estudios Epidemiológicos , Femenino , Humanos , Mamografía , Persona de Mediana Edad , Posmenopausia , Factores de Riesgo , Esteroide 16-alfa-HidroxilasaRESUMEN
Menopausal hormone replacement therapy has been widely used to alleviate the symptoms of menopause and to decrease the detrimental effects of ovarian hormone loss on bone density and cardiovascular health. Multiple studies of colorectal cancer epidemiology also support a role for hormone replacement therapy in prevention of colorectal cancer. We studied the effect of ovariectomy and estrogen replacement on tumor formation in C57BL/6J-Min/+ (Min/+) mice, animals that bear a germline mutation in murine Apc. These mice develop multiple intestinal tumors that show loss of wild-type Apc protein. After ovariectomy, intestinal adenomas in Min/+ mice increased by 77% (P = 0.0004). Ovariectomized Min/+ mice that were treated with a replacement dose of 17beta-estradiol had the same number of tumors as Min/+ mice that were neither castrated nor treated with estrogen replacement (P = 0.85). Examination of estrogen receptor (ER) levels in intestinal tissue by immunoblot showed changes in relative expression levels of ERalpha and ERbeta, with highest ERalpha and lowest ERbeta expression in the normal-appearing intestine of Min/+ mice, and lowest ERalpha and highest ERbeta expression in the enterocytes of animals that received 17beta-estradiol. These results suggest that endogenous estrogens protect against Apc-associated tumor formation and that tumor prevention by 17beta-estradiol is associated with an increase in ERbeta and a decrease in ERalpha expression in the target tissue.
Asunto(s)
Estrógenos/fisiología , Neoplasias Intestinales/metabolismo , Receptores de Estrógenos/biosíntesis , Proteína de la Poliposis Adenomatosa del Colon , Animales , Proteínas del Citoesqueleto/genética , Enterocitos/metabolismo , Estradiol/farmacología , Receptor alfa de Estrógeno , Receptor beta de Estrógeno , Terapia de Reemplazo de Estrógeno , Femenino , Genes APC/genética , Mutación de Línea Germinal , Mucosa Intestinal/metabolismo , Neoplasias Intestinales/etiología , Neoplasias Intestinales/genética , Ratones , Ratones Endogámicos C57BL , OvariectomíaAsunto(s)
Neoplasias de la Mama/enzimología , Neoplasias de la Mama/genética , Polimorfismo Genético , Esteroide 17-alfa-Hidroxilasa/genética , Adolescente , Adulto , Pueblo Asiatico/genética , Australia , Población Negra/genética , Neoplasias de la Mama/orina , Femenino , Genotipo , Humanos , Hidroxiestronas/orina , Nativos de Hawái y Otras Islas del Pacífico/genética , Regiones Promotoras Genéticas/genética , Población Blanca/genéticaRESUMEN
OBJECTIVE: Estrogen metabolites have been associated in the pathogenesis of breast and cervical cancer; 16alpha-hydroxyestrone(16alpha-OHE1) demonstrated proliferative effects whereas 2-hydroxyestrone(2-OHE1) had antiproliferative effects. Our study's objective is to demonstrate that head and neck (H&N) cancer patients metabolize estrogen differently than healthy controls, which may constitute a risk factor for H&N cancer development. STUDY DESIGN: Urinary metabolite levels of 2-OHE1 and 16alpha-OHE1 from 50 H&N cancer patients and 50 age- and sex-matched controls were measured using enzyme-linked immunosorbent assay (ELISA). Absolute values and 2-/16alpha-OHE1 ratios were calculated. Conditional logistic regression for univariate and multivariate analysis with odds ratio (OR) and 95% confidence interval (CI) were used. RESULTS: Thirty percent (15 of 50) from the case group had a low 2-/16alpha-OHE1 ratio compared with only 4% (2 of 50) in the control group (OR = 11.1; 1.4-91.5, 95% CI) (P < 0.05). When adjusted for tobacco, OR remained significant at 15.6 (1.1-212.5, 95% CI) (P < 0.05). CONCLUSION: H&N cancer patients are more likely to express abnormal estrogen metabolism than healthy controls; 2-/16alpha-OHE1 may serve as a potential biological marker of individuals at increased risk of H&N cancer.
Asunto(s)
Carcinoma de Células Escamosas/metabolismo , Hidroxiestronas/metabolismo , Neoplasias Orofaríngeas/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/terapia , Creatinina/orina , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Hidroxiestronas/orina , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Oportunidad Relativa , Neoplasias Orofaríngeas/patología , Neoplasias Orofaríngeas/terapia , Factores de RiesgoRESUMEN
The use of naturally occurring phytoantiestrogens for prevention and therapy of breast cancer is an alternative to synthetic antiestrogens. We have been examining the mechanism of action of the antiestrogen indole-3-carbinol (I3C), a constituent of compounds present in cruciferous vegetables. I3C abrogates the cell-proliferative effect of 17 beta-estradiol (E2), as observed in several different estradiol-responsive breast cancer cell lines and isolated cell clones. Modulation of E2 activity by I3C, in part, was by the induction of the 2-hydroxylation pathway, one of the two competing hydroxylation pathways of estrone conversion that resulted in the formation of metabolites with antiestrogenic properties. I3C-mediated induction of the 2-hydroxylation pathway correlated with a selective induction of cytochrome P-450 1A1 by I3C in E2-responsive human breast cancer cells. Induction of neither the 2-hydroxylation pathway nor cytochrome P-450 1A1 was observed in estrogen-nonresponsive human breast cancer cells. This selective effect warranted a further search for biochemical targets of I3C related to E2 function. To this end, we observed that E2-mediated phosphorylation of the estrogen receptor is inhibited by I3C. Our results are consistent with the hypothesis that I3C exerts its antiestrogenic effect by intervention in the E2-estrogen receptor signal transduction pathways and by alterations in E2 metabolism that resulted in the formation of metabolites with antiestrogenic activity.
Asunto(s)
Neoplasias de la Mama/patología , Antagonistas de Estrógenos/farmacología , Estrógenos/fisiología , Indoles/farmacología , Brassicaceae/química , División Celular/efectos de los fármacos , Citocromo P-450 CYP1A1/análisis , Estradiol/metabolismo , Estradiol/farmacología , Estrona/metabolismo , Humanos , Hidroxilación , Fosforilación , Receptores de Estrógenos/fisiología , Transducción de Señal , Células Tumorales Cultivadas , Verduras/químicaRESUMEN
Indole-3-carbinol (I3C) or, more correctly, its acid condensation products act as chemoprotective agents via several mechanisms. It induces the expression of cytochrome P-450 1A1, which shifts the estrogen metabolic pathway in favor of C-2 hydroxylation and away from the formation of 16 alpha-hydroxyestrone, a suspected endogenous carcinogen. Increased 16 alpha-hydroxylation of estrogen is associated with greater risk of cancer of the cervix, breast, endometrium, and larynx. The production of 4-hydroxyestrone is also inhibited by I3C. I3C can induce a G1 cell cycle arrest in human MCF-7 breast cancer cells. It can suppress aberrant crypt foci. I3C significantly inhibits the cell adhesion, spreading, and invasion associated with an upregulation of PTEN (a tumor suppressor gene) and E-cadherin (a regulator of cell-cell adhesion) expression in T47-D human breast cancer cells. Thus I3C exhibits anticancer activities by suppressing breast tumor cell growth and metastatic spread. A gas chromatography-mass spectrometry method for the quantitation of diindolylmethane, the principal acid condensation product of I3C, has been developed for use in determining compliance in subjects who have been treated with I3C. The method utilizes a 1-ml urine sample. We have used this method to correlate I3C ingestion with regression of cervical intraepithelial neoplasia in a population of women at risk for cervical cancer. The assay provides an objective marker of consumption using a noninvasive biological fluid and illustrates that diindolylmethane may be used as a marker of compliance in I3C dietary intervention studies.
Asunto(s)
Anticarcinógenos/farmacocinética , Indoles/farmacocinética , Indoles/orina , Anticarcinógenos/administración & dosificación , Femenino , Cromatografía de Gases y Espectrometría de Masas , Semivida , Humanos , Indoles/administración & dosificación , Placebos , Sensibilidad y Especificidad , Displasia del Cuello del Útero/tratamiento farmacológico , Displasia del Cuello del Útero/orinaRESUMEN
Fibrocystic disease of the breast manifesting palpable cysts express breast cyst fluids frequently containing estrogen sulfates at concentrations far exceeding those found in sera of the patient. The study explored the potential of the breast cyst to synthesize some of these estrogen sulfates. Deuterated estrone and estradiol were synthesized and either (estradiol, 4 cases or estrone, 2 cases) was injected into a cyst. The cyst was aspirated at approximately 0, 4 and 8 h, the target being 1 ml, 50% and complete aspiration respectively. Metabolites were purified sequentially by ether extraction, enzymatic hydrolysis of estrogen conjugates, chromatography on Sephadex LH 20 and identified by gas chromatography linked to mass spectrometry. The unconjugated fraction isolated from the ether extract was subjected to the same purification and detection scheme. Among the conjugates, deuterated estrone sulfate was the major metabolite of either precursor in all studies, while estradiol sulfate was not detected in any of the 6 experiments. The sulfate fractions also yielded traces of 16alpha-hydroxyestrone (2 studies), 4-hydroxyestrone (4 studies) and 2-hydroxyestrone (1 study). In the unconjugated fraction, one study with deuterated estradiol, 4- hydroxyestrone was obtained. In one study with deuterated estrone, traces of 2-hydroxyestrone and 16alpha- hydroxyestrone were obtained. These novel data are significant because patients with fibrocystic disease are at slightly elevated risk for developing breast cancer and 16alpha-hydroxyestrone and 4- hydroxyestrone are reported carcinogens.
Asunto(s)
Estradiol/metabolismo , Estrona/análogos & derivados , Estrona/metabolismo , Enfermedad Fibroquística de la Mama/metabolismo , Arilsulfotransferasa/metabolismo , Biopsia con Aguja , Sistema Enzimático del Citocromo P-450/metabolismo , Deuterio , Estradiol/farmacocinética , Estrona/análisis , Estrona/farmacocinética , Exudados y Transudados/química , Exudados y Transudados/enzimología , Femenino , Enfermedad Fibroquística de la Mama/enzimología , Cromatografía de Gases y Espectrometría de Masas , Humanos , Hidroxiesteroide Deshidrogenasas/metabolismo , Factores de TiempoRESUMEN
Experimental and clinical evidence suggests that 16alpha-hydroxylated estrogen metabolites, biologically strong estrogens, are associated with breast cancer risk, while 2-hydroxylated metabolites, with lower estrogenic activity, are weakly related to this disease. This study analyzes the association of breast cancer risk with estrogen metabolism, expressed as the ratio of 2-hydroxyestrone to 16alpha-hydroxyestrone, in a prospective nested case-control study. Between 1987 and 1992, 10,786 women (ages 35-69 years) were recruited to a prospective study on breast cancer in Italy, the "Hormones and Diet in the Etiology of Breast Cancer" (ORDET) study. Women with a history of cancer and women on hormone therapy were excluded at baseline. At recruitment, overnight urine was collected from all participants and stored at -80 degrees C. After an average of 5.5 years of follow-up, 144 breast cancer cases and four matched controls for each case were identified among the participants of the cohort. Among premenopausal women, a higher ratio of 2-hydroxyestrone to 16alpha-hydroxyestrone at baseline was associated with a reduced risk of breast cancer: women in the highest quintile of the ratio had an adjusted odds ratio (OR) for breast cancer of 0.58 [95% confidence interval (CI) = 0.25-1.34]. The corresponding adjusted OR in postmenopausal women was 1.29 (95% CI = 0.53-3.10). Results of this prospective study support the hypothesis that the estrogen metabolism pathway favoring 2-hydroxylation over 16alpha-hydroxylation is associated with a reduced risk of invasive breast cancer risk in premenopausal women.
Asunto(s)
Neoplasias de la Mama/etiología , Estrógenos/metabolismo , Hidroxiestronas/metabolismo , Posmenopausia/metabolismo , Premenopausia/metabolismo , Adulto , Anciano , Constitución Corporal , Índice de Masa Corporal , Estudios de Casos y Controles , Femenino , Humanos , Modelos Logísticos , Persona de Mediana Edad , Paridad , Estudios Prospectivos , Sistema de Registros , Factores de Riesgo , Esteroide 16-alfa-HidroxilasaRESUMEN
OBJECTIVE: Most precancerous lesions of the cervix are treated with surgery or ablative therapy. Chemoprevention, using natural and synthetic compounds, may intervene in the early precancerous stages of carcinogenesis and prevent the development of invasive disease. Our trial used indole-3-carbinol (I-3-C) administered orally to treat women with CIN as a therapeutic for cervical CIN. METHODS: Thirty patients with biopsy proven CIN II-III were randomized to receive placebo or 200, or 400 mg/day I-3-C administered orally for 12 weeks. If persistent CIN was diagnosed by cervical biopsy at the end of the trial, loop electrocautery excision procedure of the transformation zone was performed. HPV status was assessed in all patients. RESULTS: None (0 of 10) of the patients in the placebo group had complete regression of CIN. In contrast 4 of 8 patients in the 200 mg/day arm and 4 of 9 patients in the 400 mg/day arm had complete regression based on their 12-week biopsy. This protective effect of I-3-C is shown by a relative risk (RR) of 0.50 ((95% CI, 0. 25 to 0.99) P = 0.023) for the 200 mg/day group and a RR of 0.55 ((95% CI, 0.31 to 0.99) P = 0.032) for the 400 mg/day group. HPV was detected in 7 of 10 placebo patients, in 7 of 8 in the 200 mg/day group, and in 8 of 9 in the 400 mg/day group. CONCLUSIONS: There was a statistically significant regression of CIN in patients treated with I-3-C orally compared with placebo. The 2/16 alpha-hydroxyestrone ratio changed in a dose-dependent fashion.
Asunto(s)
Anticarcinógenos/uso terapéutico , Indoles/uso terapéutico , Lesiones Precancerosas/tratamiento farmacológico , Displasia del Cuello del Útero/tratamiento farmacológico , Administración Oral , ADN Viral/análisis , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Hidroxiestronas/orina , Papillomaviridae , Infecciones por Papillomavirus/genética , Infecciones por Papillomavirus/virología , Placebos , Reacción en Cadena de la Polimerasa , Lesiones Precancerosas/patología , Lesiones Precancerosas/virología , Infecciones Tumorales por Virus/genética , Infecciones Tumorales por Virus/virología , Neoplasias del Cuello Uterino/prevención & control , Displasia del Cuello del Útero/patología , Displasia del Cuello del Útero/virologíaAsunto(s)
Deshidroepiandrosterona/farmacología , Ingestión de Alimentos/efectos de los fármacos , Ratones Endogámicos/metabolismo , Consumo de Bebidas Alcohólicas , Animales , Peso Corporal/efectos de los fármacos , Deshidroepiandrosterona/administración & dosificación , Preferencias Alimentarias/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos/genética , Ratas , Ratas Zucker , Reproducibilidad de los Resultados , Especificidad de la EspecieRESUMEN
There is considerable controversy regarding the role of estrogen metabolites in breast cancer risk, fueled in part by the development of a rapid ELISA that is suitable for large scale investigations. An earlier version of the ELISA could detect values of the 2-hydroxyestrone (2-OHE1) and 16alpha-hydroxyestrone (16alpha-OHE1) metabolites as low as 2 ng/ml and produce consistent results in premenopausal urines. However, reproducibility was problematic in postmenopausal urines where concentrations of these compounds are much lower. In response to our concern, a new ELISA was developed with a sensitivity of 0.625 ng/ml, which we evaluated using the same pre- and postmenopausal urine samples analyzed in the earlier ELISA. In this report, we present findings on the new kit with regard to reproducibility of the 2-OHE1 and 16alpha-OHE1 measurements, comparability of results with gas chromatography-mass spectroscopy values, and with regard to the stability of the metabolites after repeated freeze-thaw cycles and after preservation by boric acid. For the most part, we found the new ELISA to be reproducible, with assay coefficients of variation ranging from 10 to 20%, and intraclass correlation coefficients (ICCs) ranging from 80 to 95% in both the pre- and postmenopausal urines. ELISA results for 16alpha-OHE1 differed from 1 day (i.e., batch) to the next, and the absolute values of the metabolites obtained by the ELISA were consistently lower than but well correlated with those obtained by gas chromatography-mass spectroscopy. Values of the 2-OHE1:16alpha-OHE1 ratio also differed between the methods, but because the range of values was not large, the magnitude of these differences was not as great. For the ratio, the correlation between methods was excellent, and the ICCs were high for both groups of women. After preservation by boric acid, values of the ratio varied according to acid concentration but not in a linear fashion. Ratio values were similar in urine samples exposed to four different freeze-thaw cycle treatments, although values for all treatments were consistently lower in one batch. Because batch-to-batch variability was not negligible, it is advisable that matched cases and controls be analyzed in the same batch. Provided this is done, the relatively low assay coefficient of variation and high ICC demonstrate that the new ELISA kit can reliably measure the 2-OHE1:16alpha-OHE1 ratio and detect small case-control differences in large population-based studies, where rapid and relatively easy laboratory methods are critical.
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Ensayo de Inmunoadsorción Enzimática , Estrógenos de Catecol/orina , Hidroxiestronas/orina , Juego de Reactivos para Diagnóstico , Ácidos Bóricos , Estudios de Casos y Controles , Ensayo de Inmunoadsorción Enzimática/métodos , Femenino , Congelación , Cromatografía de Gases y Espectrometría de Masas , Humanos , Vigilancia de la Población , Posmenopausia/orina , Premenopausia/orina , Conservadores Farmacéuticos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Método Simple Ciego , Factores de TiempoRESUMEN
Although endogenous sex steroid hormones in premenopausal women may be associated with the risk of breast cancer and other illnesses, direct evidence to support this hypothesis is limited in large part by methodological issues in the conduct of relevant studies. One major unresolved issue is whether a single blood sample (such as is available in most epidemiological studies), collected in a specific phase of the menstrual cycle, reflects long-term levels in that phase. To address this issue, two sets of blood and urine samples were obtained from 87 premenopausal women over a 1-year period in both the follicular and luteal phases. Plasma estradiol, estrone, and estrone sulfate were measured in the blood samples obtained in both phases, whereas progesterone and urinary 2- and 16a-hydroxyestrone were measured in luteal-phase samples only. For all of the women combined, intraclass correlation coefficients (ICCs) ranged, with one exception, from 0.52 to 0.71 for the plasma estrogens and the urinary estrogen metabolites. The sole exception was for estradiol in the luteal phase (ICC = 0.19); inclusion of only women who were ovulatory in both cycles and who collected each sample 4-10 days before their next period resulted in a substantially higher ICC for estradiol in the luteal phase (ICC = 0.62; 95% confidence interval, 0.43-0.78). These data indicate that, for several plasma and urinary sex hormones, a single follicular- or luteal-phase measurement in premenopausal women is reasonably representative of hormone levels in that phase for at least a 1-year period.
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Hormonas Esteroides Gonadales/sangre , Hormonas Esteroides Gonadales/orina , Premenopausia/sangre , Premenopausia/orina , Adulto , Índice de Masa Corporal , Estradiol/sangre , Estrona/análogos & derivados , Estrona/sangre , Femenino , Fase Folicular/sangre , Fase Folicular/orina , Humanos , Hidroxiestronas/orina , Fase Luteínica/sangre , Fase Luteínica/orina , Menarquia , Persona de Mediana Edad , Paridad , Progesterona/sangre , Reproducibilidad de los Resultados , Factores de TiempoRESUMEN
BACKGROUND: Cervical cancer constitutes the second most common cancer in women. Estrogen promotes development of cervical cancer in cells infected with high risk human papillomaviruses (HPVs). We asked whether the phytochemical indole-3-carbinol (I3C) has anti-estrogenic activities in cervical cells with the goal of preventing cancer in HPV infected cells. MATERIALS AND METHODS: Using the cervical cancer cell line CaSki, we evaluated expression of HPV and cytochrome p450 (CYP) enzymes by Northern, RNase protection or quantitative RT-PCR. I3C binding to estrogen receptor was measured by competition with estradiol. Estrogen metabolites were measured by gas chromarography-mass spectrometry (GC-MS). RESULTS: Estradiol increased expression of HPV oncogenes whereas I3C and the estrogen metabolite 2-hydroxyestrone (2-OHE) abrogated the estrogen-increased expression of HPV oncogenes. Both I3C and 2-OHE competed with estradiol for estrogen receptor binding. I3C enhanced gene expression of CYP enzymes responsible for 2-hydroxylation of estrogen, and induced the formation of 2-OHE. CONCLUSION: I3C has anti-estrogenic activities which should prevent cancer in cervical cells.
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Anticarcinógenos/farmacología , Carcinoma de Células Escamosas/prevención & control , Cuello del Útero/efectos de los fármacos , Antagonistas de Estrógenos/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Regulación Viral de la Expresión Génica/efectos de los fármacos , Indoles/farmacología , Proteínas de Neoplasias/biosíntesis , Proteínas Represoras , Neoplasias del Cuello Uterino/prevención & control , Unión Competitiva , Carcinoma de Células Escamosas/enzimología , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/virología , Cuello del Útero/enzimología , Cuello del Útero/virología , Citocromo P-450 CYP1A1/biosíntesis , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A2/biosíntesis , Citocromo P-450 CYP1A2/genética , Sistema Enzimático del Citocromo P-450/biosíntesis , Inducción Enzimática/efectos de los fármacos , Estradiol/farmacología , Femenino , Humanos , Hidroxiestronas/farmacología , Proteínas Oncogénicas Virales/biosíntesis , Proteínas Oncogénicas Virales/genética , Oncogenes/efectos de los fármacos , Papillomaviridae/genética , Papillomaviridae/patogenicidad , Papillomaviridae/fisiología , Proteínas E7 de Papillomavirus , Infecciones por Papillomavirus/enzimología , Infecciones por Papillomavirus/patología , ARN Mensajero/biosíntesis , ARN Neoplásico/biosíntesis , ARN Viral/biosíntesis , Receptores de Estrógenos/efectos de los fármacos , Receptores de Estrógenos/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Tumorales Cultivadas , Infecciones Tumorales por Virus/enzimología , Infecciones Tumorales por Virus/patología , Infecciones Tumorales por Virus/virología , Neoplasias del Cuello Uterino/enzimología , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/virologíaAsunto(s)
Enfermedades Autoinmunes/inmunología , Autoinmunidad/fisiología , Sistema Hipotálamo-Hipofisario/fisiología , Enfermedades Reumáticas/inmunología , Andrógenos/fisiología , Animales , Enfermedades Autoinmunes/etiología , Enfermedades Autoinmunes/metabolismo , Citocinas/metabolismo , Hormonas Esteroides Gonadales/metabolismo , Hormonas/fisiología , Humanos , Hidrocortisona/metabolismo , Sistema Hipófiso-Suprarrenal/fisiología , Enfermedades Reumáticas/etiología , Enfermedades Reumáticas/metabolismo , Estrés Fisiológico/complicacionesRESUMEN
The immunological response to the administration of various C-19 steroids has been of increasing interest. Although the action of dehydroepiandrosterone has been studied, the responses to its metabolites have not been explored. In the present study the ability of dehydroepiandrosterone, its conjugates, and metabolites to oppose the anti-inflammatory action of glucocorticoids on the inflammatory response to 2,4-dinitrochlorobenzene in the sensitized mouse was examined. A clear difference was seen between the antiglucocorticoid activity of dehydroepiandrosterone, its conjugates, and its 5 beta-metabolites on the one hand and the planar 5 alpha- and delta 4-metabolites, which were devoid of antiglucocorticoid activity. The mechanism of this antiglucocorticoid activity remains to be established.