RESUMO
Trastuzumab, a humanized monoclonal antibody against the HER-2 receptor, was the first targeted therapy for HER-2 positive breast cancer. The treatment of HER-2 positive breast cancer in monotherapy, but mainly in combination with cytostatics trastuzumab, showed significant efficacy and increased the time to progression/relapse and overall survival. On the other hand, despite it being administered to only a selected patient population, the response rate varies in range and duration due to the primary or acquired tumor resistance to trastuzumab. Several mechanisms contributing to the drug resistance are presumed and overcoming strategies are in development. In connection with the drug resistance there are the mechanisms of trastuzumab's action on tumor cells and the search for feasible biomarkers in order to predict the response of trastuzumab-based targeted therapies. Furthermore, we present here the actual possibilities to overcome primary or acquired trastuzumab resistance.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Anticorpos Monoclonais Humanizados , Neoplasias da Mama/genética , Feminino , Genes erbB-2 , Humanos , TrastuzumabRESUMO
Currently, there are no effective biomarkers for ovarian cancer prognosis or prediction of therapeutic response. The objective of this study was to examine a panel of 10 serum biochemical parameters for their ability to predict response to chemotherapy, progression and survival of ovarian cancer patients. Sera from ovarian cancer patients were collected prior and during chemotherapy and were analysed by enzyme-linked immunosorbent assay for CA125, kallikreins 5, 6, 7, 8, 10 and 11, B7-H4, regenerating protein IV and Spondin-2. The odds ratio and hazard ratio and their 95% confidence interval (95% CI) were calculated. Time-dependent receiver-operating characteristic (ROC) curves were utilised to evaluate the prognostic performance of the biomarkers. The levels of several markers at baseline (c(0)), or after the first chemotherapy cycle (rc(1)), predicted chemotherapy response and overall or progression-free survival in univariate analysis. A multiparametric model (c(0) of CA125, KLK5, KLK7 and rc(1) of CA125) provided predictive accuracy with area under the ROC curve (AUC) of 0.82 (0.62 after correction for overfitting). Another marker combination (c(0) of KLK7, KLK10, B7-H4, Spondin-2) was useful in predicting short-term (1-year) survival with an AUC of 0.89 (0.74 after correction for overfitting). All markers examined, except KLK7 and regenerating protein IV, were powerful predictors of time to progression (TTP) among chemotherapy responders. Individual and panels of biomarkers from the kallikrein family (and other families) can predict response to chemotherapy, overall survival, short-term (1-year) survival, progression-free survival and TTP of ovarian cancer patients treated with chemotherapy.
Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/sangue , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/patologia , Prognóstico , Análise de SobrevidaRESUMO
The immunological dysfunction associated with human cancer is well known phenomenon. It comprises number of pathological changes within immune network including imbalance in cytokines of Th1/Th2 origin. The objectives of our study were (i) to evaluate the abnormalities in serum levels of selected cytokines in malignant melanoma patients with regional lymph node metastases as compared to normal values, (ii) to examine the relationship between postoperative cytokine levels and disease progression and (iii) to correlate cytokine profile changes during IFN-alpha therapy with the disease progression and potential therapeutical response. Nine Th1/Th2 related cytokines and sIL-2R were determined in 26 malignant melanoma patients at clinical stage III prior and during adjuvant immunotherapy. Control group consisted of 26 healthy persons. Patients were treated with rIFN-alpha according to EORTC Melanoma group protocol 18952. Cytokines were quantified in patients sera using commercial ELISA kits. Majority of melanoma patients showed significantly lower values of IL-2 and IFN-gamma and pathologically elevated levels of IL-4, IL-6, IL-10 as compared to healthy subjects what indicates disease associated Th1/Th2 imbalance. In addition increased IL-12 and IL-15 values were noted in some patients (54% and 27%, respectively). All patients who manifested early relapse during immunotherapy had significantly lower pretreatment levels of IL-2 and IL-12 than those remaining without progression and probably benefiting from the treatment. Cytokine changes during immunotherapy disclosed that decreases in IL-2 and IL-12 and raises in IL-6 and IL-10 values occurred at least one month prior to relapse. Moreover, the continuous elevation of TNF-alpha and sIL-2R could be observed in patients who remained without progression during 10 months lasting immunotherapy. Our data illustrate that malignant melanoma associates with Th1/Th2 perturbances which are directed towards extended Th2 responses and that measurement of selected cytokines of Th1/Th2 category may be used as an early signal of disease deterioration and for evaluation of immunotherapy response.
Assuntos
Interferon-alfa/uso terapêutico , Melanoma/imunologia , Células Th1/imunologia , Células Th2/imunologia , Adulto , Citocinas/sangue , Feminino , Humanos , Masculino , Melanoma/terapia , Pessoa de Meia-IdadeRESUMO
The past decade has witnessed an explosion of knowledge concerning the structure and function of chromosome terminal structures-telomeres. Today's telomere research has advanced from a pure descriptive approach of DNA and protein components to an elementary understanding of telomere metabolism, and now to promising applications in medicine. These applications include 'passive' ones, among which the use of analysis of telomeres and telomerase (a cellular reverse transcriptase that synthesizes telomeres) for cancer diagnostics is the best known. The 'active' applications involve targeted downregulation or upregulation of telomere synthesis, either to mortalize immortal cancer cells, or to rejuvenate mortal somatic cells and tissues for cellular transplantations, respectively. This article reviews the basic data on structure and function of human telomeres and telomerase, as well as both passive and active applications of human telomere biology.
Assuntos
Telômero/fisiologia , Envelhecimento/genética , Antineoplásicos/farmacologia , Diferenciação Celular , Divisão Celular , Regulação Enzimológica da Expressão Gênica , Humanos , Neoplasias/enzimologia , Neoplasias/genética , Neoplasias/patologia , Telomerase/análise , Telomerase/antagonistas & inibidores , Telomerase/genética , Telomerase/metabolismo , Telômero/química , Telômero/enzimologia , Engenharia TecidualRESUMO
Telomerase plays an important role in maintaining the stability of chromosomes. This ribonucleoprotein prevents chromosome ends (telomeres) from gradual loss with each cell division. It enables tumor cells to maintain telomere length, allowing indefinite replicative capacity. Telomerase activity has been detected in the majority of tumor and germ cells and in immortalized cell lines. Quantitative telomerase PCR-ELISA (TeloTAGGG Telomerase PCR ELISA(PLUS)) was evaluated for distinguishing benign and malignant breast tissue. Activity of telomerase was determined in 27 samples of fibrocystic and dysplastic tissues, 28 fibroadenomas and phylloid tumors, and 154 breast cancer tissues; 59 specimens were analyzed retrospectively. Analytical precision and linearity of the assay was tested using breast carcinoma cell line ZR-75-1 and breast tumor tissue extracts. About 4% of tumor samples were excluded from analysis due to interferences in the PCR reaction. Relative telomerase activity differed significantly in the groups of dysplastic tissues, fibroadenomas and carcinomas. The highest activity was found in breast cancer tissue. This method can identify breast cancer tissue with 73% clinical sensitivity and 93% specificity as compared to benign breast tumors. We did not find a correlation between telomerase activity and the tissue levels of estrogen and progesterone receptors, HER-2/neu oncoprotein concentration, tumor size, and lymph node positivity. Probability of disease-free survival was significantly lower for patients with telomerase activity higher than median value. As the assay for telomerase activity has very high analytical sensitivity and high specificity for cancer cells, this routinely used method may prove useful for distinguishing malignant phenotype of breast tissues.
Assuntos
Neoplasias da Mama/diagnóstico , Ensaios Enzimáticos Clínicos/métodos , Telomerase/análise , Doenças Mamárias/diagnóstico , Doenças Mamárias/enzimologia , Doenças Mamárias/patologia , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Carcinoma/diagnóstico , Carcinoma/enzimologia , Carcinoma/patologia , Diagnóstico Diferencial , Intervalo Livre de Doença , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Fibroadenoma/diagnóstico , Fibroadenoma/enzimologia , Fibroadenoma/patologia , Humanos , Reação em Cadeia da Polimerase/métodos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Células Tumorais CultivadasRESUMO
BACKGROUND: Elevated plasma homocysteine concentrations have been reported in a variety of carcinoma, including those of the breast. The risk of breast cancer is higher in patients suffering from gross cystic disease. The breast cyst fluid contains unusual amounts of low- and high- molecular substances, including steroid hormones and their conjugates. The present study was undertaken to find out the presence of homocysteine in the fluid filling the cysts and have its concentration compared with other thiols, levels of Na+/K+ ratio and steroid hormones. Materials and methods Fourteen women suffering from gross cystic disease were enrolled in this study. Cystic concentrations of homocysteine (Hcy), cysteine (Cys), cysteinylglycine (Cys-Gly) and glutathione (GSH) were determined by high performance liquid chromatography, with fluorescence detection; estradiol (E2), progesterone, allopregnanolone and pregnenolone sulfate (PregS) by RIA methods. RESULTS: Mean levels of Hcy, Cys, Cys-Gly, Na+/K+, E2 and PregS in the fluid filling the breast cysts were significantly higher than the corresponding plasma concentrations. In addition, a negative correlation was found between cystic Hcy and the Na+/K+ ratio (Rs = -0.72, P = 0.003) and positive correlations between cyst Hcy and estradiol (Rs = 0.64, P = 0.018) and Hcy and PregS (Rs = 0.60, P = 0.025). Conclusion The study provides the first evidence of thiol concentrations in the breast cyst fluid. The finding of a negative correlation between homocysteine and the Na+/K+ ratio support the idea that the homocysteine concentration in breast cysts might be used clinically as a marker for the development of breast cancer disease.
Assuntos
Doença da Mama Fibrocística/química , Homocisteína/análise , Adulto , Biomarcadores Tumorais , Neoplasias da Mama/etiologia , Cátions Monovalentes/análise , Exsudatos e Transudatos/química , Feminino , Doença da Mama Fibrocística/complicações , Humanos , Pessoa de Meia-Idade , Potássio/análise , Sódio/análise , Esteroides/análiseRESUMO
Immune parameters, including cytokine levels and CD profiles were determined in 78 renal cell carcinoma patients (RCC) prior to nephrectomy. The values were correlated with the outcome of disease and response to cytokine-based treatment during a 3-year follow-up. Significantly lower frequency of progressions and higher proportion of survivors were recorded in 24 treated patients compared to 43 untreated ones (22.9% vs. 53.5% and 82.9% vs. 55.8%) illustrating the beneficial effect of immunotherapy on the course of RCC at localized stage. RCC-related immune changes are demonstrated by reduced proportion of CD19+, CD28+, HLA-DR+, CD19+/80+ and CD8+/28+ subsets, by increased serum levels of IL-6, sIL-2R, CRP and by impaired production of IL-2 and TNF-alpha released by in vitro stimulated PBMC. Only increased CRP, IL-6 serum values, decreased CD8+ and increased CD122+ were significantly related to patients' prognosis. Comparisons of preoperative CD profiles and cytokine values with the response to IL-2/IFN-alpha based therapy disclosed significant correlation in only CD80+ and CD19+/80+ subsets. Treated patients who relapsed during the 3-year follow-up exhibited at the diagnosis significantly reduced proportion of CD80+ and CD19+/80+ cells (CD80+ means - 0.79 vs. 1.69 and CD19+/80+ means - 0.32 vs. 0.61) comparing to those surviving disease-free. In addition initial proportion of CD3+, CD8+ and CD19+ cells was reduced in treated patients who manifested progression but statistical difference from those remaining disease-free was not proved.
Assuntos
Antígenos CD/sangue , Carcinoma de Células Renais/sangue , Citocinas/sangue , Interferon-alfa/uso terapêutico , Interleucina-2/uso terapêutico , Neoplasias Renais/sangue , Linfócitos/imunologia , Adulto , Idoso , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/cirurgia , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/cirurgia , Masculino , Pessoa de Meia-Idade , Nefrectomia/métodos , Estudos Prospectivos , Receptores de Interleucina-2/sangue , Resultado do TratamentoRESUMO
This prospective study was carried out to explore cytokine-related immune alterations in 69 renal cell carcinoma patients (RCC) and to look for changes which might potentially serve as a reliable predictors of response to cytokine-based therapy. Interleukin-2 (IL-2), its soluble receptor (sIL-2R) and tumor necrosis factor (TNF-alpha) levels produced in vitro by PHA activated and intact mononuclear cells (PBMC) were determined. Concentrations of IL-2, IL-4, IL-6, sIL-2R, TNF-alpha and CRP were measured in sera. Cytokine level was evaluated by enzyme-linked immunoadsorbent assay (ELISA) and CRP was determined by means of turbidimetric method. All measurements were performed in patients without any prior treatment. PHA activated PBMC of RCC patients were significantly defective in producing IL-2 and TNF-alpha comparing to controls (p < 0.03 and p < 0.001). The difference of sIL-2R was noted in metastatic stage only (p < 0.03). Unstimulated PBMC manifested decrease in IL-2 (p < 0.03) and increased level of TNF-alpha in advanced disease (p < 0.02). This impairment reflected tumor size and differentiation stage. Serum concentrations of IL-2, sIL-2R and TNF-alpha were within normal range. However, in relation to the clinical stage, significantly increased serum IL-2 was noted in combined Stage I and II as compared to controls (p = 0.012). IL-6 and CRP showed markedly elevated levels with a significancy which allowed to distinguish samples from metastatic patients. In conclusion careful comparisons of these data with clinical course of cytokine treated patients will disclose which of those tests may possess predictive power in the individual patients who are likely to respond to cytokine-based treatment.
Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/imunologia , Citocinas/sangue , Citocinas/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/imunologia , Linfócitos/imunologia , Adulto , Idoso , Proteína C-Reativa/análise , Carcinoma de Células Renais/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Interleucinas/sangue , Neoplasias Renais/sangue , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Receptores de Interleucina-2/sangue , Fator de Necrose Tumoral alfa/análiseRESUMO
BACKGROUND/AIMS: In this study, we have compared the profiles of peripheral blood lymphocyte (PBL) subsets and serum cytokine levels of healthy individuals with those of patients with unresectable liver metastases from colorectal carcinoma before starting regional chemoimmunotherapy. Since the therapeutic responses are limited only to a subset of patients, we hypothesize that the initial status of immunity and individual immune response to a tumor might be significant to the therapeutic outcome. METHODOLOGY: Cellular and humoral immunological parameters were compared between 10 patients with colorectal cancer metastases to the liver responding and non-responding to regional intra-arterial chemo-immunotherapy, and 5 healty individuals. Analyses included a flow cytometric immunophenotyping of peripheral blood mononuclear cells (CD3, CD4, CD8, CD19, CD25, CD28, CD56, CD57, CD80 and HLA.DR), estimation of serum cytokine levels of interleukin-2 (IL-2), interleukin-4 (IL-4), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), and other immunological parameters are soluble IL-2 receptor (sIL-2), carcinoembryonic antigen (CEA), gastrointestinal cancer-associated antigen (CA 19-9), and C-reactive acute phase protein (CRP). A significantly lower proportion of CD8 lymphocytes and a trend for decreased CD19, CD28 and CD80 was detected among colorectal cancer patients before liver-directed chemotherapy compared to healthy controls. RESULTS: The cancer patients showed a significantly increased population of peripheral NK cells as detected by both CD56+ and CD57+ phenotypes. Elevated serum levels of CRP, IL-4 and TNF-alpha, sIL-2R, but not IL-2, were also demonstrated in cancer patients as compared to controls. Activated CD25+ lymphocytes correlated negatively with CD28+ lymphocytes (r = -0.68, p < 0.01) and less significantly with CD4+ lymphocytes (r = -0.56, p < 0.05). The CD8+ cytotoxic cell subset might be negatively influenced by serum IL-4 (r = -0.57, p < 0.05). Positive correlation was found between sIL-2R and CRP (r = -0.78, p < 0.01), and between sIL-2R and TNF-alpha (r = 0.64, p < 0.05) serum levels in patients with progressive disease during the course of therapy, the initial proportions of CD4+, CD19+ and CD28+ lymphocytes were significantly lower than those among responders. Among humoral parameters, only sIL-2R showed a marginal correlation with therapeutic response, being more elevated among non-responding patients. Pre-treatment serum levels of CEA and CA 19-9 showed correlation with neither therapeutic response nor with any of the cellular or humoral immunological parameters analyzed. CONCLUSIONS: The results may serve as an initial guideline to open a discussion on the rationale of such a panel of tests, hopefully leading to standardized laboratory pre-selection and monitoring of patients treated with regional chemoimmunotherapy.
Assuntos
Formação de Anticorpos , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Citocinas/sangue , Neoplasias Hepáticas/secundário , Humanos , Imunidade Celular , Imunofenotipagem , Interleucinas/sangue , Leucócitos Mononucleares , Subpopulações de Linfócitos , Resultado do TratamentoRESUMO
The concentrations of three steroid hormones (estrogen, progesteron and 1,25-dihydroxycholecalciferol) receptors (ER, PgR, DR) in tissue cytosol were analyzed in a group of 17 breast phylloid tumors. Comparison with breast carcinoma tissue samples (n = 37) did not reveal significant differences in average values of ER, PgR, and DR. Comparison with another control set of 30 samples of dysplastic tissue of the mammary gland showed significant differences only in PgR values. Only 18% of phylloid tumor samples contained levels above cut-of-line of all three receptors (ER, PgR, DR-5,10,10 resp. fmol/ mg protein). The most frequent combination was ER+PgR+DR-(41%). As far as we know, DR in phylloid breast tumors have never been examined before. In approximately 60% of our samples we found the expression of DR, in 36% the estimated values were above 10 fmol/mg protein. Cells of the tissue not expressing DR seem to belong to a special phenotype. We found no ER+PgR- or ER-PgR-combinations in them. The group which expresses DR is characterized by a higher dispersion of PgR values.
Assuntos
Neoplasias da Mama/química , Tumor Filoide/química , Receptores de Calcitriol/análise , Receptores de Estrogênio/análise , Receptores de Progesterona/análise , Mama/química , Neoplasias da Mama/patologia , Carcinoma/química , Feminino , Humanos , Tumor Filoide/patologiaRESUMO
A mathematical model of prediction of progression was tested in patients with breast cancer employing long-term monitoring of tumor markers CEA, CA 15-3, MCA and TPA, erythrocyte sedimentation rate (FW), and the enzymes gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP) and lactate dehydrogenase (LD) in serum. At the same time, specificity, sensitivity, lead time and positive predictive value were evaluated along with false positivity for all these parameters and their combinations. A model was proposed for the follow-up of patients with breast cancer after the completion of basic therapy.
Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Mama/diagnóstico , Antígenos Glicosídicos Associados a Tumores/análise , Antígeno Carcinoembrionário/análise , Feminino , Seguimentos , Humanos , Matemática , Pessoa de Meia-Idade , Metástase Neoplásica/diagnóstico , Curva ROCRESUMO
The concentration of carcinoembryonic antigen and alpha-lactalbumin in tumor tissue cytosol were analyzed in a group of 19 tumors of cystosarcoma phyllodes type. Both antigens were also localized in the tissue of identical tumors by means of immunohistochemical procedure. The cytosol levels of both proteins were found to be higher in the histologically defined malignant type of phylloid tumors. This group was also characterized by the simultaneous occurrence of both antigens. We did not manage to prove any relationship between the presence of alpha-lactalbumin and the steroid hormone receptor positivity in tumor tissue.
Assuntos
Neoplasias da Mama/química , Antígeno Carcinoembrionário/análise , Lactalbumina/análise , Proteínas de Neoplasias/análise , Tumor Filoide/química , Neoplasias da Mama/patologia , Carcinoma Intraductal não Infiltrante/química , Citosol/química , Doença da Mama Fibrocística/química , Humanos , Técnicas Imunoenzimáticas , Tumor Filoide/patologiaRESUMO
The quantitative biochemical analysis of tissue specimens from 76 human breast carcinomas consisted of examination for cytosolic estrogen receptors (cER), nuclear estrogen receptors (nER), progesterone receptors (PgR), 1,25-dihydroxycholecalciferol receptors (DR), carcinoembryonic antigen (CEA), alpha-lactalbumin (aLA), and gamma-glutamyl transferase (gGT). The highest incidence was found in CEA (76%), DR (70%), and aLA (62%). There was a high percentage of tumors containing only DR, in contrast to the tumors containing only cER or PgR. The simultaneous occurrence of DR and CEA was considerably high (61%). No statistically significant differences were observed in these biochemical parameters in relation to the grade of differentiation of the tumors. The values of aLA in tumors that invaded lymphatic or blood vessels were lower as compared to those tumors that invaded adipose or connective tissues. The level of statistical significance of this difference was close to 5%, the differences in other parameters were statistically insignificant. For prognosis assessed at the time of surgery, after a 2-3-year follow-up of 36 patients the level of gGT in the tumor seems to be the most promising prognostic factor. The values of gGT were significantly lower in those patients whose tumors were in progression during this time. The significance of nER and aLA was also taken into consideration.
Assuntos
Neoplasias da Mama/análise , Neoplasias da Mama/patologia , Calcitriol/análise , Antígeno Carcinoembrionário/análise , Feminino , Seguimentos , Humanos , Lactalbumina/análise , Prognóstico , Receptores de Calcitriol , Receptores de Estrogênio/análise , Receptores de Progesterona/análise , Receptores de Esteroides/análise , gama-Glutamiltransferase/análiseRESUMO
One hundred and eleven formalin-fixed breast cancer tissue samples were examined for the presence of alpha-lactalbumin using our polyclonal antibodies to this specific milk protein. Alpha-lactalbumin was shown to be present in 67 tumor samples (60%), in 15% of cases the occurrence of alpha-lactalbumin was questionable. No relationship was found between alpha-lactalbumin positivity and the histological type of the tumor, differentiation grading, type of invasivity, or stromal reactivity. Disease progression occurred in an equal number of patients with tumors either alpha-lactalbumin positive or negative. However, negativity was often connected with a disease-free interval shorter than 24 months after primary operation.
Assuntos
Neoplasias da Mama/análise , Lactalbumina/análise , Neoplasias da Mama/patologia , Carcinoma Intraductal não Infiltrante/análise , Feminino , Humanos , Técnicas Imunoenzimáticas , Metástase Linfática , Menopausa , Invasividade NeoplásicaRESUMO
A sandwich non-competitive enzyme immunoassay for the measurement of human alpha-lactalbumin in serum, milk, and tumour tissue cytosol was developed using affinity-purified polyclonal antibody adsorbed to solid phase. The detection limits of this procedure in tubes (macromethod) and in wells of microtitre plates (micromethod) are 50 pg and 25 pg/sample, respectively, which means 2.5 micrograms/l of serum at appropriate dilution. The micromethod enables a reduction of the volumes used in the reaction with equal sensitivity, accuracy and reproducibility. A comparison of alpha-lactalbumin concentrations in serum of healthy, pregnant, and lactating women determined by our method with those measured formerly by radioimmunoassays proved the specificity of our procedure.
Assuntos
Neoplasias da Mama/análise , Lactalbumina/análise , Leite Humano/análise , Especificidade de Anticorpos , Citosol/análise , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Humanos , Lactalbumina/sangue , Lactação , Masculino , GravidezRESUMO
The long-term administration of 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB) to rats causes marked changes in concentrations and synthesis of nucleic acids in the liver. In the beginning, a decrease in total cellular RNA concentration can be seen. On the other hand, at the stage of tumor onset the concentration of nuclear RNAs in precancerous lesions and hepatomas is elevated. Incorporation of 3H-orotic acid into nuclear RNA after 45 min of in vivo labeling serving as a measure of biosynthesis of nuclear RNAs is markedly decreased when compared to control livers. This decrease takes place from the very beginning of the process and goes on until primary hepatomas arise in which its values are approximately at 10% of those observed in controls. In the present study the problem of the increase of proliferative activity at early stages of carcinogenesis is discussed which is not in correlation with the changes in nuclear RNA biosynthesis.
Assuntos
Núcleo Celular/metabolismo , Neoplasias Hepáticas Experimentais/metabolismo , Neoplasias Hepáticas/metabolismo , RNA Neoplásico/biossíntese , RNA/biossíntese , Animais , DCMP Desaminase/análise , Feminino , Fígado/metabolismo , Neoplasias Hepáticas/induzido quimicamente , Metildimetilaminoazobenzeno , Transplante de Neoplasias , Ratos , Ratos Endogâmicos Lew , Ratos EndogâmicosAssuntos
Carcinógenos/farmacologia , Fígado/análise , alfa-Fetoproteínas/análise , alfa-Macroglobulinas/análise , Proteínas de Fase Aguda , Animais , Proteínas Sanguíneas/análise , Dimetilnitrosamina , Fígado/efeitos dos fármacos , Neoplasias Hepáticas Experimentais/induzido quimicamente , Metildimetilaminoazobenzeno , Ratos , Distribuição TecidualRESUMO
Determination of activity of deoxycytidylate deaminase stabilized by etylene glycol was used to evaluate the rate of DNA synthesis in precancerous liver tissue and in transplantable rat hepatomas. Increased activity of the enzyme in macroscopically unchanged liver tissue occurred during hepatocarcinogenesis induced by 3'-Me-DAB in the period between weeks 1 and 10. The slow growing transplantable tumours derived from primary hepatomas induced by DAB and AF showed slightly increased activity, while the fast growing lines derived from primary tumours induced by 3'-Me-DAB were characterized by markedly increased activity. Thus the enzyme appeared to be a good marker of tumour growth rate. Correlation between increased DNA synthesis during carcinogenesis and the occurrence of alpha-fetoprotein is briefly discussed.
Assuntos
DCMP Desaminase/metabolismo , Neoplasias Hepáticas Experimentais/enzimologia , Nucleotídeo Desaminases/metabolismo , Aflatoxinas , Animais , Divisão Celular , Fígado/enzimologia , Neoplasias Hepáticas Experimentais/induzido quimicamente , Neoplasias Hepáticas Experimentais/patologia , Metildimetilaminoazobenzeno , Transplante de Neoplasias , Lesões Pré-Cancerosas/enzimologia , Ratos , p-DimetilaminoazobenzenoRESUMO
Recent findings concerning the significance of alpha 1-fetoprotein (AFP) as a tool for clinical diagnosis and monitoring of tumor diseases are reviewed briefly. The applicability of this protein marker to the early diagnosis of patients at carcinogenic risk is discussed. In addition, experimental data obtained with a model of chemical hepatocarcinogenesis are reported. The increase of proliferative activity in precancerous liver tissue preceded AFP production under experimental conditions with azodyes and aflatoxin B1 as carcinogens. Immunohistochemical analysis of the relation of AFP to changes of cell populations and to liver tissue rearrangement led to the conclusion that AFP-producing cells cannot be precursors of malignant hepatocytes; however, AFP appeared to be linked to dividing hepatocytes at a certain step of cell differentiation regardless of the stages of precancerous development. A decrease in the rate of nuclear RNA synthesis was observed in both precancerous and tumor tissues. A possible analogy between the early phase of AFP production in animal carcinogenesis and that in human carcinogenesis is considered.
Assuntos
Carcinoma Hepatocelular/diagnóstico , Neoplasias Hepáticas Experimentais/diagnóstico , Neoplasias Hepáticas/diagnóstico , alfa-Fetoproteínas/análise , Animais , Carcinógenos , Carcinoma Hepatocelular/análise , Núcleo Celular/metabolismo , Humanos , Neoplasias Hepáticas/análise , Neoplasias Hepáticas Experimentais/induzido quimicamente , Lesões Pré-Cancerosas/diagnóstico , RNA Neoplásico/biossíntese , Ratos , Risco , Fatores de Tempo , alfa-Fetoproteínas/biossínteseRESUMO
Localization of characteristic precancerous lesions was compared with that of alpha-fetoprotein (alpha-FP) positive cells during hepatocarcinogenesis in Wistar rats fed 0.06% 3'-methyl-4-dimethylaminoazobenzene in basal diet. Proliferative activity of liver cells was simultaneously followed by deoxycytidylate deaminase. The first alpha-FP positive hepatocytes were found after 3 weeks of carcinogenesis in certain parts of the capsule 0.1--0.2 mm thick. In the seventh week of carcinogenesis their number increased and they were present in groups also subcapsularly. At this stage, hyperplastic islets began to be formed in the liver parenchyma. After 14 weeks of carcinogenesis, alpha-FP positive cell clusters and islets were also found in the deeper layers of liver parenchyma in regions with proliferation of transitory cells. Hyperplastic basophilic foci and islets occurred regularly, however, these were not identical with alpha-FP positive sites and their incidence was more frequent.