RESUMO
The work discusses the two biomedical problems: family diabetes (bearing in mind the presence of cases of type 2 diabetes mellitus in the family, including its different generations) and the features of relationship of family diabetes with major non-communicable human diseases (NCDs). The paper is timed to the anniversary of the famous - in our country and abroad - expert in the field of gerontology and endocrinology, Professor V.M.Dilman. The widely recognized works of V.M.Dilman, based on original ideas and giving rise to important practical consequences (including the use of antidiabetic biguanides in areas not studied before him, the need to eliminate metabolic immunodepression, to take into account the changes with age at the level of the hypothalamic threshold in various homeostatic systems and a whole number of other essential proposals), which for a long time, as it seems, will stimulate the further scientific search of his followers and specialists, who have yet to get acquainted with the area that attracted Prof. Dilman and interested him for many years.
Assuntos
Diabetes Mellitus Tipo 2 , Geriatria , Metformina , Doenças não Transmissíveis , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , Hipoglicemiantes , Masculino , Doenças não Transmissíveis/tratamento farmacológico , Doenças não Transmissíveis/epidemiologiaRESUMO
Processes important for hormone-mediated carcinogenesis are present on different, even very early, ontogenesis stages. Early shifts in hormone-metabolic status often display opposite correlations with the risk of most common age-associated non-communicable pathologies (namely, hormone-dependent cancers and cardiovascular diseases). Additional known contradiction is the raise of reproductive system tumors incidence in the age associated with lower production of mitogenic hormones. Consequently, one should take into account production of steroids in target tissues themselves, recognize the importance of progenotoxic effect, which, apart from mitogenic function, is characteristic for estrogens and their derivatives, as well as the role of endocrine-genotoxic switchings forming so called basic triad, which is born under the influence of age-associated endocrine shifts and environmental factors. Aside from steroids-related system of increased cancer risk, attention should be paid to non-steroid ones (in particular insulin resistance- and inflammatory cytokines-associated), with their close connection to immune system functional state, low-grade chronic inflammation, obesity phenotype, and pro-/anti-inflammatory lipid factors ratio. In total, it confirms and importance of timely preventive interventions on both ontogenesis stages, early and late ones, which are often separated by several decades.
Assuntos
Fatores Etários , Carcinogênese , Neoplasias Hormônio-Dependentes/etiologia , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/metabolismo , Citocinas/metabolismo , Dano ao DNA , Estrogênios/metabolismo , Humanos , Inflamação/complicações , Inflamação/metabolismo , Resistência à Insulina , Neoplasias Hormônio-Dependentes/metabolismo , Obesidade/complicações , Obesidade/metabolismo , Esteroides/metabolismo , Neoplasias Urogenitais/etiologia , Neoplasias Urogenitais/metabolismoRESUMO
Blood levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) were measured by enzyme immunoassay after overnight fasting in untreated breast cancer and endometrial cancer patients (N=170) of mainly postmenopausal age with and without type 2 diabetes mellitus. The concentrations of 8-OHdG in patients with breast cancer were higher than in patients with endometrial cancer and in patients with breast cancer and diabetes in comparison with patients with breast cancer without diabetes. No correlations of blood 8-OHdG levels with glycemia, age, and clinical stage of disease were detected. In cancer patients with diabetes, the concentration of 8-OHdG increases proportionally to the increase in body mass index, though this does not lead to disappearance of the above differences between patients with breast cancer and endometrial cancer by the level of 8-OHdG. The causes of the trend to a less favorable course of tumor process in patients with breast cancer and diabetes in comparison with endometrial cancer and diabetes deserve further studies.
Assuntos
Neoplasias da Mama/sangue , Desoxiguanosina/análogos & derivados , Diabetes Mellitus Tipo 2/sangue , Neoplasias do Endométrio/sangue , 8-Hidroxi-2'-Desoxiguanosina , Adulto , Índice de Massa Corporal , Desoxiguanosina/sangue , Feminino , Humanos , Pessoa de Meia-IdadeRESUMO
An inflammation expressed in a moderate degree and hav- ing a chronic character is associated with the local changes in the tumor and adipose tissue (manifested, in particular, by lym- phocytic and macrophage infiltration) as well as with systemic shifts involving hormone and hormone-like elements for their implementation. The unfavorable consequences of these shifts may be restrained due to the endogenous anti-inflammatory re- serves (systems) and intentionally used exogenous agents with the same action. These issues are considered on the example of endometrial cancer, for the occurrence and course of which a considerable significance is attributed to the excess of body fat, especially in its <
Assuntos
Tecido Adiposo , Biomarcadores Tumorais , Neoplasias do Endométrio , Mediadores da Inflamação , Tecido Adiposo/imunologia , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Biomarcadores Tumorais/imunologia , Biomarcadores Tumorais/metabolismo , Neoplasias do Endométrio/imunologia , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Feminino , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismoRESUMO
Over the few past years there have been passed many significant and positive changes in various fields of oncology due to both the use of achievements, stimulated by previous generations, and the progress of modern technology. This largely concerns endocrinology of malignant tumors, which is reflected in this article on the basis of the experience of the N.N.Petrov Research Institute of Oncology gained during recent times. Above all it is about the features of tumors of hormone-dependent tissues, hormonal and metabolic shifts, associated with them, and the ways of their correction based on the principles of personalized medicine.
Assuntos
Sistema Endócrino , Hormônios/metabolismo , Neoplasias , Animais , Sistema Endócrino/metabolismo , Sistema Endócrino/patologia , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/terapiaRESUMO
The authors aimed to compare expression of UCP1, aromatase (CYP19), markers of macrophage infiltration (CD68, CD163), omentin and PTEN in omental fat of endometrioid or non-endometrioid endometrial cancer (EC) patients with signs of standard (SO) or metabolically healthy obesity (MHO) by immunohistochemical (IHC) or real-time PCR methods. Totally 57 omental fat samples collected during surgery in EC pts (average age 60.1) were studied. According to IHC data, statistically significant decrease in expression of aromatase and CD68 was revealed in omental fat of MHO patients. Expression of UCP1 demonstrated an inclination to decrease in the same group, simultaneously showing correlation with clinical stage of EC. According to real time PCR data, omentin expression displayed tendency to an increase with increase in body mass index (whole group), clinical stage of EC (in SO subgroup) and serum omentin level (MHO subgroup). No any difference in studied omental fat parameters was discovered between patients with endometrioid and non-endometrioid EC. Thus, omental fat properties in EC patients are associated with obesity phenotype and not with histologic subtype of this cancer. Apparently, the features of omental fat depot characteristic for visceral adipose tissue at least are equal to its attributes as a brown fat compartment. Decrease, according to IHC info, of the estrogen biosynthesis and macrophagal infiltration in omental fat of EC patients with MHO phenotype may indicate additional mechanisms for more favorable in this case clinical course of uterine body cancer. Supported by RFBR grant 15-04-00384.
RESUMO
73 randomly selected from the entire array menopausal endometrial cancer patients (34 of whom were subjected to further surgery by laparotomy and 39 - by laparoscopic ap- proach) were examined 48-72 hours before surgery. Patients passed anthropometry, their medical history was collected, and in the blood serum, taken on an empty stomach, glucose, gly- cated hemoglobin, lipid fractions, insulin, thyrotropin, estradiol and testosterone levels were measured while insulin resistance index was calculated. Although patients who later went through laparoscopic surgery were characterized by somewhat higher body mass and waist circumference, other investigated pa- rameters did not differ between laparoscopy and laparotomy groups. Moreover a frequency of so called "metabolically healthy" obesity appeared to be even higher in laparoscopic group. Taken together this confirms the fact that the overweight should not be considered as contraindication for videosurgery in patients with endometrial cancer. At the same time it is desirable to compare distant oncological results with individual characteristics of pre-surgical hormonal-metabolic status of pa- tients depending on the surgery type and obesity phenotype.
Assuntos
Glicemia/metabolismo , Neoplasias do Endométrio , Hormônios/sangue , Laparoscopia , Lipídeos/sangue , Período Pré-Operatório , Neoplasias do Endométrio/sangue , Neoplasias do Endométrio/cirurgia , Feminino , Humanos , Pessoa de Meia-Idade , Cuidados Pré-OperatóriosRESUMO
The aim of the study was to assess efficacy and safety of combined therapy with dacarbazine and melatonin or metformin in comparison with dacarbazine alone in the 1st line of therapy of cutaneous melanoma. Thirty-six patients with disseminated melanoma, therapy naïve, were included between March 2014 and December 2015. Patients received DTIC 1000 mg/m2 in day 1 of 28-day cycle either as monotherapy (group 1) or in combination with melatonin 3 mg PO daily (group 2) or metformin 850 mg 2 times a day PO daily (group 3). Thirty-four patients were randomized (15-in group 1, 8 - in group 2, 13 - in group 3) and received 119 cycles of therapy. Response rate was 11% in groups 1 and 2, and 8,3% - in group 3 (p=0,57). Median time to progression was 52, 79 and 63 days, respectively in the 1st, 2nd and 3rd group (Ñ=0,468). Two patients from the 2nd and 3rd group showed delayed response to therapy. No adverse events of grade 3-4 were seen. Thus, DTIC with melatonin or metformin was well tolerated. No meaningful increase of adverse event incidence was seen. No benefit of either combination was shown in this interim analysis. Delayed responses in melatonin and metformin combination groups were registered. This suggests immunologic effect of both drugs and warrants further study.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dacarbazina/administração & dosagem , Dacarbazina/efeitos adversos , Feminino , Humanos , Masculino , Melanoma/imunologia , Melanoma/mortalidade , Melanoma/patologia , Melatonina/administração & dosagem , Melatonina/efeitos adversos , Metformina/administração & dosagem , Metformina/efeitos adversos , Pessoa de Meia-Idade , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologiaRESUMO
The functions of hypothalamic-pituitary-thyroid axis are attenuated in type 1 diabetes mellitus due to insulin deficiency. The use of intranasally administered insulin is of considerable interest for treatment of diabetes and cognitive disorders, but its effect on the thyroid system has not been investigated yet. We studied the influence of long-term treatment with intranasal insulin on the hypothalamic-pituitary-thyroid axis of nondiabetic rats and diabetic animals with streptozotocin models of acute and mild type 1 diabetes mellitus. This treatment was carried out for 28 days in acute (daily does of 0.3, 0.6, and 1.5 IU of insulin per rat) and for 135 days in mild diabetes (daily dose of 0.45 IU/rat). Nondiabetic rats were treated in a similar manner. Intranasal insulin in both models of diabetes resulted in the improvement of thyroid status; manifested as increase of thyroid hormones levels and restoration of response to thyroliberin. In acute diabetes, a daily dose of 0.6 IU/rat was the most effective. Twenty eight days treatment of nondiabetic rats with intranasal insulin at a dose of 0.3 IU/rat resulted in a significant increase of free and total thyroxine levels. Longer treatment of rats with mild diabetes and nondiabetic animals significantly increased thyrotropin level. Thus, long-term intranasal insulin treatment restored the hypothalamic-pituitary-thyroid axis function in type 1 diabetes, but led to a significant increase in the thyrotropin level, which must be considered when designing a strategy for the use of intranasal insulin in clinical applications.
Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Sistema Hipotálamo-Hipofisário/fisiopatologia , Insulina/administração & dosagem , Glândula Tireoide/fisiopatologia , Administração Intranasal , Animais , Diabetes Mellitus Experimental/fisiopatologia , Masculino , Ratos , Ratos Wistar , Estreptozocina , Hormônios Tireóideos/sangue , Tireotropina/sangueRESUMO
AIM: to elucidate relationship between parameters of negative ischemic stress test and subclinical atherosclerosis of carotid arteries. MATERIAL AND METHODS: Electrocardiographic stress test on treadmill and ultrasound study of carotid arteries (CA) were carried out in 204 patients (100women and 104 men, mean age 54.16+/-8.07 years without verified ischemic heart disease and with more or equal 1 traditional factors of cardiovascular risk). Measurements of intima media thickness (IMT) in three extracranial CA segments and identification of atherosclerotic plaques (AP) were used for detection of subclinical atherosclerosis. CA total atherosclerotic plaque area (TAPA) was calculated when appropriate. RESULTS: Multifactorial regression analysis revealed the following predictors of increased IMT and TAPA: physical working capacity, increment and reserve of heart rate (HR), HR restoration, and increment of systolic arterial pressure (SAP). Presence of atherosclerotic plaque was associated with SAP rise >42% during exercise test and slow HR restoration ( less or equal 42 bpm at 2-nd minute of recovery period). CONCLUSION: Analysis of nonelectrocardiographic parameters of negative relative to ischemia induction exercise test allows predicting severity of atherosclerotic changes in CA. The information obtained can supplement assessment of traditional factors of cardiovascular risk.
RESUMO
It is shown that endometrial cancer features (including expression of the PTEN and HER-2/neu proteins) are connected dissimilarly with body mass index and with the belonging of the patients to the groups with standard, SO and metabolically healthy obesity, MHO. In the course of the last half-century an increases are discovered in the height and weight of the females with endometrial cancer that moves in the opposite direction with a reduction of the share of MHO cases among obese patients. This conclusion should be taken into account when one considers the means for contemporary prevention of both obesity and cancer of uterine body.
Assuntos
Biomarcadores Tumorais/análise , Índice de Massa Corporal , Neoplasias do Endométrio/patologia , Obesidade/patologia , Adulto , Idoso , Neoplasias do Endométrio/química , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Resistência à Insulina , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Obesidade/metabolismo , PTEN Fosfo-Hidrolase/análise , Receptor ErbB-2/análise , Fatores de TempoRESUMO
Two groups of breast cancer patients (53±2 years) in clinical remission receiving no specific therapy were examined: group 1, with BRCA1 gene mutations (N=11) and group 2, without mutations of this kind (N=11). The two groups did not differ by insulinemia and glycemia, insulin resistance index, blood levels of thyrotropic hormone, sex hormone-binding globulin, insulin-like growth factor-1, triglycerides, or lipoproteins. In group 1, blood estradiol level was higher. Intensive glucose-induced generation of reactive oxygen species in these patients was associated with a decrease of cholesterolemia, of the C-peptide/insulin proportion, and a trend to higher urinary excretion of 4-hydroxyestrone, one of the most genotoxic catecholestrogens. BRCA1 gene mutations in breast cancer patients were associated with signs of estrogenization and a pro-genotoxic shift in the estrogen and glucose system, which could modulate the disease course and requires correction.
Assuntos
Proteína BRCA1/metabolismo , Neoplasias da Mama/metabolismo , Sistema Endócrino/metabolismo , Estradiol/sangue , Proteína BRCA1/genética , Glicemia/análise , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Peptídeo C/sangue , Sistema Endócrino/patologia , Feminino , Humanos , Hidroxiestronas/urina , Insulina/sangue , Resistência à Insulina , Fator de Crescimento Insulin-Like I/metabolismo , Lipoproteínas/sangue , Pessoa de Meia-Idade , Mutação , Espécies Reativas de Oxigênio/sangue , Globulina de Ligação a Hormônio Sexual/metabolismo , Tireotropina/sangue , Triglicerídeos/sangueRESUMO
BRCA1 gene mutation is associated with a combination of excessive aromatase activity/expression, predominantly estrogen receptor-negative phenotypes of tumors, and only scarce information about estrogen contents in body fluids. In the present work, isotope dilution capillary gas chromatography/mass spectrometry was used to study urinary excretion of estrogens, their catechol metabolites, and phytoestrogens in 22 women (11 with BCRA1 gene mutations and 11 without these mutations) in average 5.1+/-0.4 years before surgery for breast cancer. BCRA1 mutation carriers (including 3 premenopausal females) compared with respective controls showed significantly higher urinary estradiol and estrone excretion and a trend to an increased 2-OH-E2 excretion. In the subgroup of untreated postmenopausal women, BCRA1 mutation carriers showed a trend to increased estradiol and estrone excretion and to a higher value of the mean levels of all estrogen metabolites tested. The treatment after the baseline laboratory investigation of 6 women from postmenopausal group with the antidiabetic biguanide metformin for 3 months was associated with decreases in the excretion rates of 4-hydroxyestradiol, 2-methoxyestradiol, and 16-epiestriol and did not influence phytoestrogen excretion. The decrease in 2-methoxyestrogen excretion was more consistent in women without BCRA1 mutations than in BCRA1 mutation carriers. The data suggest the possibility that aromatase complex activation in BCRA1 mutation carriers is combined with increases in both, estrogen metabolism into catecholestrogens and their inactivation by methoxylation, and that metformin may affect both of these pathways.
Assuntos
Neoplasias da Mama/urina , Estrogênios de Catecol/urina , Estrogênios/urina , Genes BRCA1 , Hipoglicemiantes/administração & dosagem , Metformina/administração & dosagem , Fitoestrógenos/urina , Neoplasias da Mama/genética , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Projetos Piloto , Pós-Menopausa/efeitos dos fármacos , PrognósticoRESUMO
he progenotoxic (G, generation of reactive oxygen forms in mononuclears) and hormonal (H, reactive insulinemia) effects of oral glucose, on the one hand, and the same effects of estradiol (10(-8)and 10(-5)M) in vitro on blood mononuclears (G: by comet tail length; H: by expression of AMP kinase and TNF and IL-6 secretion), on the other, were compared with consideration for the concepts on endocrine genotoxic switch-over in patients with breast cancer and endometrial cancer in remission. Coculturing of mononuclears with estradiol in general led to an increase in comet tail and was associated with a trend to more intense expression of AMP kinase and IL-6 secretion. The reaction to estradiol (primarily in a concentration of 10(-8)M) evaluated by the expression of AMP kinase and TNF secretion was more intensive than the reaction evaluated by comet tail lengths or by percentage of cells with comets in women with predominating progenotoxic effect of glucose vs. hormonal effect. This fact can be used as a landmark in search for means for optimization of the status and proportion of effects in the estrogen and glucose systems.
Assuntos
Neoplasias da Mama/metabolismo , Dano ao DNA , Neoplasias do Endométrio/metabolismo , Estradiol/farmacologia , Glucose/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Adenilato Quinase/metabolismo , Western Blotting , Ensaio Cometa , Feminino , Humanos , Interleucina-6/metabolismo , Leucócitos Mononucleares/metabolismo , Pessoa de Meia-Idade , Espécies Reativas de Oxigênio/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Deprivation of estrogen causes breast tumors in women to adapt and develop enhanced sensitivity to this steroid. Accordingly, women relapsing after treatment with oophorectomy, which substantially lowers estradiol for a prolonged period, respond secondarily to aromatase inhibitors with tumor regression. We have utilized in vitro and in vivo model systems to examine the biologic processes whereby long-term estradiol deprivation (LTED) causes cells to adapt and develop hypersensitivity to estradiol. Several mechanisms are associated with this response, including up-regulation of estrogen receptor-alpha (ERalpha) and the MAP kinase, phosphoinositol 3 kinase (PI3-K) and mammalian target of rapamycin (mTOR) growth factor pathways. ERalpha is four- to tenfold up-regulated and co-opts a classical growth factor pathway using Shc, Grb-2 and Sos. This induces rapid non-genomic effects which are enhanced in LTED cells. The molecules involved in the non-genomic signaling process have been identified. Estradiol binds to cell membrane-associated ERalpha, which physically associates with the adaptor protein Shc, and induces its phosphorylation. In turn, Shc binds Grb-2 and Sos, which result in the rapid activation of MAP kinase. These non-genomic effects of estradiol produce biologic effects as evidenced by Elk-1 activation and by morphologic changes in cell membranes. Additional effects include activation of the PI3-K and mTOR pathways through estradiol-induced binding of ERalpha to the IGF-I and epidermal growth factor receptors. A major question is how ERalpha locates in the plasma membrane since it does not contain an inherent membrane localization signal. We have provided evidence that the IGF-I receptor serves as an anchor for ERalpha in the plasma membrane. Estradiol causes phosphorylation of the adaptor protein, Shc and the IGF-I receptor itself. Shc, after binding to ERalpha, serves as the 'bus' which carries ERalpha to Shc-binding sites on the activated IGF-I receptors. Use of small inhibitor (si) RNA methodology to knockdown Shc allows the conclusion that Shc is needed for ERalpha to localize in the plasma membrane. In order to abrogate growth factor-induced hypersensitivity, we have utilized a drug, farnesylthiosalicylic acid, which blocks the binding of GTP-Ras to its membrane acceptor protein, galectin 1, and reduces the activation of MAP kinase. We have also shown that this drug is a potent inhibitor of mTOR as an additional mechanism of inhibition of cell proliferation. The concept of 'adaptive hypersensitivity' and the mechanisms responsible for this phenomenon have important clinical implications. The efficacy of aromatase inhibitors in patients relapsing on tamoxifen could be explained by this mechanism and inhibitors of growth factor pathways should reverse the hypersensitivity phenomenon and result in prolongation of the efficacy of hormonal therapy for breast cancer.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Estradiol/deficiência , Estradiol/farmacologia , Substâncias de Crescimento/metabolismo , Transdução de Sinais , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias da Mama/metabolismo , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos/fisiologia , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Quinases/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologia , Proteínas Adaptadoras da Sinalização Shc , Transdução de Sinais/efeitos dos fármacos , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src , Serina-Treonina Quinases TOR , Células Tumorais Cultivadas , Regulação para CimaRESUMO
Aromatase activity (AA) was evaluated totally in 80 tumors collected from primary endometrial cancer (EC) patients. All patients were divided into cases belonging to the types I or II of EC (respectively, 50 and 30 observations). Samples of malignant endometrium from type II demonstrated inclination to the higher AA in comparison with type I samples; the difference reached level of statistical significance in non-smoking patients (p=0.02). Although no positive correlation was revealed between AA in EC tissue and percentage of cells with DNA damage in normal endometrium from the same patients, the rate of DNA damage (percent of comets, comet's tail average length, etc.) was higher in intact endometrium collected from patients with type II of the disease. In 19 tumor samples, CYP19 gene expression was evaluated by RT-PCR and level of mRNA signal demonstrated positive correlation with AA (R(s)=+0.63, p=0.05) in the whole this material. Of note, though, CYP19 mRNA expression was not revealed in six cases, and all of them belonged to the type I of disease. Finally, in 23 EC patients (15 with type I and 8 with type II of the disease) effects of 2 weeks treatment with letrozole (10 pts) and exemestane (13 pts) were evaluated in neoadjuvant setting. Although diminishing of endometrial M-echo signal and the increases in FSH and LH concentration after treatment were more pronounced in type I patients, decrease in tumor PR content (p=0.04) was more revealing in patients with type II of EC; besides, the decreases in AA in tumor tissue by the end of treatment were noted predominantly in patients with lower body weight (BMI <27.5). Thus, although type II of EC is frequently considered as hormone-independent, increased ability of this type of the tumor to estrogen biosynthesis (at CYP19 gene and protein level) may lead to the reconsideration of such conclusion and warrants further investigation. The search of possible ethnic differences in AA and in the biologic response to aromatase inhibitors in EC can be of importance too.
Assuntos
Antineoplásicos/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Aromatase/metabolismo , Carcinoma Endometrioide/tratamento farmacológico , Carcinoma Endometrioide/enzimologia , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/enzimologia , Adulto , Idoso , Aromatase/análise , Aromatase/genética , Carcinoma Endometrioide/genética , Ensaio Cometa , Dano ao DNA , DNA de Neoplasias/análise , Neoplasias do Endométrio/genética , Feminino , Humanos , Pessoa de Meia-Idade , RNA Mensageiro/análise , RNA Mensageiro/metabolismo , Resultado do TratamentoRESUMO
Breast tumors in women can adapt to endocrine deprivation therapy by developing hypersensitivity to estradiol. For this reason, aromatase inhibitors can be effective in women relapsing after treatment with tamoxifen or following oophorectomy. To understand the mechanisms responsible, we examined estrogenic stimulation of cell proliferation in a model system and provided in vitro and in vivo evidence that long-term estradiol deprivation (LTED) causes "adaptive hypersensitivity". The primary mechanisms responsible involve up-regulation of ER alpha as well as the MAP kinase, PI-3 kinase, and mTOR growth factor pathways. ER alpha is 4-10-fold up-regulated and co-opts a classical growth factor pathway using Shc, Grb2, and Sos. This induces rapid non-genomic effects which are enhanced in LTED cells. Estradiol binds to cell membrane associated ER alpha, physically associates with the adaptor protein Shc, and induces its phosphorylation. In turn, Shc binds Grb2 and Sos which result in the rapid activation of MAP kinase. These non-genomic effects of estradiol produce biologic effects as evidenced by Elk activation and by morphologic changes in cell membranes. Additional effects include activation of PI-3 kinase and mTOR pathways through estradiol induced binding of ER alpha to the IGF-1 and EGF receptors. Further proof of the non-genomic effects of estradiol involved use of "designer" cells which selectively express ER alpha in nucleus, cytosol, and cell membrane. We have used a new downstream inhibitor of these pathways, farnesyl-thio-salicylic acid (FTS), to block proliferation in hypersensitive cells as a model for a potentially effective strategy for treatment of patients.
Assuntos
Antineoplásicos Hormonais/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Estradiol/farmacologia , Receptor alfa de Estrogênio/metabolismo , Animais , Proliferação de Células , Receptor alfa de Estrogênio/genética , Estrogênios/metabolismo , Feminino , Humanos , Camundongos , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Transporte ProteicoRESUMO
Aromatase (CYP19) activity in malignant endometrium presents local mechanism with potential ability to support tumor growth. The data on interrelation between activity of this enzyme and its mRNA signal in endometrial cancer (EC) tissue are very scarce and inconclusive. To correct this gap we studied aromatase activity and gene expression totally in 19 samples of EC (17 of them -- from postmenopausal women) collected during surgery. Aromatase activity was evaluated by tritium water release assay and CYP19 gene expression -- with rt-PCR. Additionally, all studied EC cases were divided on the basis of case history and some characteristics of host and tumor and in accordance with existing classification into cases belonging to type I or II of the disease (correspondingly, 13 and 6 observations). Positive correlation between enzyme activity and CYP19 mRNA signal (R(s)=+0.63, p<0.05) was revealed in the whole group of studied samples. Aromatase activity varied in evaluated material between 1.45 fM/mg prot./hr and 11.49 fM/mg prot./hr, and in type II cases it was higher (7.27+/-0.96 fM/mg prot/hr) than in type I observations (4.96+/-0.66 fM/mg prot./hr, p=0.066). CYP19 mRNA expression was not revealed in 6 cases and all of them belonged to the type I of disease. Thus, although type II of EC is frequently considered as hormone non-dependent, increased ability of this tumor type to estrogen biosynthesis (on CYP19 gene and protein level) may lead to reconsideration of such conclusion and warrants further investigation.