RESUMO
BACKGROUND: The phenomenon of hormesis is characterized by a biphasic dose-response, exhibiting opposite effects in the low- and high-dose zones. In this study, we explored the possibility that the hormesis concept may describe the interactions between two tumors implanted in a single mouse, such that the resulting tumors are of different sizes. MATERIALS AND METHODS: We used two murine tumors of spontaneous origin and undetectable immunogenicity growing in BALB/c mice. A measure of cell proliferation was obtained by immunostaining for Ki-67 protein and by using the [(3)H] thymidine uptake assay. For serum fractionation, we utilized dialysis and chromatography on Sephadex G-15. RESULTS: The larger primary tumor induced inhibitory or stimulatory effects on the growth of the smaller secondary one, depending on the ratio between the mass of the larger tumor relative to that of the smaller one, with high ratios rendering inhibition and low ratios inducing stimulation of the secondary tumor. CONCLUSION: Since metastases can be considered as natural secondary tumor implants in a tumor-bearing host and that they constitute the main problem in cancer pathology, the use of the concept of hormesis to describe those biphasic effects might have significant clinical implications. In effect, if the tumor-bearing host were placed in the inhibitory window, tumor extirpation could enhance the growth of distant metastases and, reciprocally, if placed in the stimulatory window, tumor extirpation would result not only in a reduction or elimination of primary tumor load but also in a slower growth or inhibition of metastases.
Assuntos
Neoplasias Experimentais/patologia , Segunda Neoplasia Primária/patologia , Animais , Proliferação de Células , Antígeno Ki-67/análise , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Metástase Neoplásica , Transplante de Neoplasias , Neoplasias Experimentais/sangueRESUMO
Insulin-like growth factor-I (IGF-I) provides a physiologic feedback effect within the somatotropic axis. Gene therapy was implemented in young female Sprague-Dawley rats which received 2 pituitary stereotaxic injections of a control recombinant adenoviral vector expressing green fluorescent protein (RAd-GFP) or IGF-I (RAd-IGF-I). The animals were sacrificed 7 days after injection. Previously, on day -23, the experimental groups received subcutaneous implants of 17-beta estradiol. Morphometric analysis revealed that the somatotrope cells in estrogen-treated rats without stereotaxic injections showed a significant (p < 0.01) increase in the cell size compared with intact controls (59.9 +/- 1.1 vs. 42.9 +/- 1.2 microm(2)) and had a significant (p < 0.05) decrease in cell density with respect to intact animals (10.5 +/- 0.1 vs. 19.7 +/- 1.7). The treatment of pituitary adenomas with RAd-IGF-I induced a significant (p < 0.05) decrease in cell size with respect to E(2) + RAd-GFP (51.3 +/- 0.3 vs. 58.9 +/- 0.3 microm(2)) and no changes in cell density compared with RAd-GFP-injected animals (12.8 +/- 1.7 vs. 10.5 +/- 0.1). Serum growth hormone was higher (p < 0.01) in estrogen-treated animals versus controls (146.7 +/- 6 vs. 73.9 +/- 9 ng/ml). In rats carrying estrogen-induced adenomas, RAd-IGF-I injection induced a significant (p < 0.05) decrease in serum growth hormone compared to RAd-GFP-injected animals (107.5 +/- 7 vs. 142.4 +/- 9 ng/ml). IGF-I gene therapy appears to be an effective approach for the treatment of experimental somatomammotropic pituitary tumors and could be potentially useful as an adjuvant of conventional therapies.
Assuntos
Terapia Genética , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/uso terapêutico , Neoplasias Hipofisárias/terapia , Prolactinoma/genética , Prolactinoma/terapia , Somatotrofos/patologia , Animais , Contagem de Células , Tamanho Celular , Estrogênios/administração & dosagem , Estrogênios/farmacologia , Feminino , Proteínas de Fluorescência Verde/metabolismo , Hormônio do Crescimento/sangue , Implantes Experimentais , Neoplasias Experimentais/sangue , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Neoplasias Experimentais/terapia , Neoplasias Hipofisárias/sangue , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/patologia , Prolactina/sangue , Prolactinoma/sangue , Prolactinoma/patologia , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos , Somatotrofos/efeitos dos fármacosRESUMO
The effects of Tabebuia avellanedae (TACE), traditionally prescribed in the treatment of cancer, and the naphtoquinone beta-lapachone (beta-lap) on the growth and differentiation of granulocyte and macrophage progenitor cells (CFU-GM) were studied in Ehrlich ascites tumour-bearing mice. Myelosuppression concomitant with increases in spleen CFU-GM and in serum colony-stimulating activity (CSA) were observed in these animals. Treatment with TACE (30-500 mg/kg) and beta-lap (1-5mg/kg) reversed these effects in a dose-dependent manner. The optimal biologically active doses of 120 mg/kg TACE and 1mg/kg beta-lap prolonged life span of tumour-bearing mice, both producing the same rate of extension in the duration of survival. Toxic manifestations were produced by the higher doses of beta-lap in normal and tumour-bearing mice. In spite of similarities between treatments, TACE concentrations used to treat the animals presented no traces of beta-lap, as measured by TLC and HPLC analyses. Our findings suggest that the antitumour effect of TACE and beta-lap, acting synergistically with other factors, such as specific cytokines, may result from enhanced macrophage activation against tumour cells. In addition, it is clear from our results that hematopoietic disorders produced by tumours are an important pathological condition that must be considered in drug development.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Hematopoese/efeitos dos fármacos , Naftoquinonas/farmacologia , Neoplasias Experimentais/sangue , Tabebuia/química , Animais , Células da Medula Óssea/efeitos dos fármacos , Carcinoma de Ehrlich/sangue , Cromatografia Líquida de Alta Pressão , Cromatografia em Camada Fina , Fatores Estimuladores de Colônias/sangue , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Mielopoese/efeitos dos fármacos , Casca de Planta/química , Extratos Vegetais/farmacologia , Baço/citologia , Baço/metabolismo , Células-Tronco/efeitos dos fármacos , Análise de SobrevidaRESUMO
Liver extract, plasma from intact mice, ES2 tumour extract and plasma from tumour bearing mice has an inhibiting effect on the mitotic activity of hepatocytes and duodenal enterocytes. In the present experiments, the effect of these treatments on the mitotic activity of renal tubular cells was studied. C3HS 28 day-old male mice, standardized for periodicity analysis were used. The determination of normal mitotic circadian curve of the renocytes was done. A second batch of mice were injected with 0.01 ml/gr of either liver extract, plasma from intact mice, ES2 tumour extract or plasma from tumour bearing mice, at 16:00 hours and controlled at 08:00, 12:00 and 16:00 hs during 2 consecutive days post treatment. Colchicine (2 micrograms/gr) was injected 4 hours before killing. Kidneys were processed for histology and mitotic index determinations. Results were expressed as colchicine metaphases per 1000 nuclei, and showed that mitotic activity values of treated animals were significantly lower than those of controls. In conclusion, mitotic activity inhibition of renocytes may be due to some non specific plasmatic and/or tissue factors.
Assuntos
Túbulos Renais/citologia , Plasma , Extratos de Tecidos/farmacologia , Animais , Divisão Celular/efeitos dos fármacos , Fator de Crescimento de Hepatócito/farmacologia , Túbulos Renais/efeitos dos fármacos , Extratos Hepáticos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C3H , Mitose/fisiologia , Neoplasias Experimentais/sangue , Extratos de Tecidos/químicaRESUMO
Liver extract, plasma from intact mice, ES2 tumour extract and plasma from tumour bearing mice has an inhibiting effect on the mitotic activity of hepatocytes and duodenal enterocytes. In the present experiments, the effect of these treatments on the mitotic activity of renal tubular cells was studied. C3HS 28 day-old male mice, standardized for periodicity analysis were used. The determination of normal mitotic circadian curve of the renocytes was done. A second batch of mice were injected with 0.01 ml/gr of either liver extract, plasma from intact mice, ES2 tumour extract or plasma from tumour bearing mice, at 16:00 hours and controlled at 08:00, 12:00 and 16:00 hs during 2 consecutive days post treatment. Colchicine (2 micrograms/gr) was injected 4 hours before killing. Kidneys were processed for histology and mitotic index determinations. Results were expressed as colchicine metaphases per 1000 nuclei, and showed that mitotic activity values of treated animals were significantly lower than those of controls. In conclusion, mitotic activity inhibition of renocytes may be due to some non specific plasmatic and/or tissue factors.(AU)
Assuntos
Animais , Masculino , Camundongos , Túbulos Renais/citologia , Plasma , Extratos de Tecidos/farmacologia , Divisão Celular/efeitos dos fármacos , Fator de Crescimento de Hepatócito/farmacologia , Túbulos Renais/efeitos dos fármacos , Extratos Hepáticos/farmacologia , Camundongos Endogâmicos C3H , Mitose/fisiologia , Neoplasias Experimentais/sangue , Extratos de Tecidos/químicaRESUMO
Resistance of tumour-bearing mice to a second tumour challenge, that is concomitant resistance, was evaluated in euthymic and nude mice using nine tumours with widely different degrees of immunogenicity. Two temporally separate peaks of concomitant resistance were detected during tumour development. The first one was exhibited only by small immunogenic tumours; it was tumour specific and mediated by classical immunological T-cell-dependent mechanisms. The second peak was shared by both immunogenic and non-immunogenic large tumours; it was non-specific, thymus independent and correlated with the activity of a serum factor (neither antibody nor complement) that inhibited the in vitro proliferation of tumour cells. This factor was eluted from a Sephadex G-15 column at fractions corresponding to a molecular weight of approximately 1000 Da and it was recovered from a high-performance liquid chromatography column in one peak presenting maximum absorption at 215 and 266 nm. The data presented in this paper suggest for the first time, to our knowledge, that in spite of the differences between immunogenic and non-immunogenic tumours, a common serum-mediated mechanism seems to underlie the concomitant resistance induced by both types of tumours at late stages of tumour development.
Assuntos
Imunoterapia Adotiva , Neoplasias Experimentais/sangue , Neoplasias Experimentais/imunologia , Adenocarcinoma/sangue , Adenocarcinoma/imunologia , Adenocarcinoma/terapia , Animais , Formação de Anticorpos/imunologia , Feminino , Fibrossarcoma/sangue , Fibrossarcoma/imunologia , Fibrossarcoma/terapia , Imunidade Celular/imunologia , Imunidade Inata , Leucemia Linfoide/sangue , Leucemia Linfoide/imunologia , Leucemia Linfoide/terapia , Masculino , Neoplasias Mamárias Experimentais/sangue , Neoplasias Mamárias Experimentais/imunologia , Neoplasias Mamárias Experimentais/terapia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias , Neoplasias Experimentais/terapia , Sensibilidade e EspecificidadeAssuntos
Animais , Humanos , Invasividade Neoplásica/fisiopatologia , Metástase Neoplásica/fisiopatologia , Proteínas de Neoplasias/fisiologia , Ativadores de Plasminogênio/fisiologia , Matriz Extracelular/fisiologia , Fibrinólise , Células Neoplásicas Circulantes , Proteínas de Neoplasias/sangue , Neoplasias Experimentais/sangue , Neoplasias Experimentais/patologia , Prognóstico , Ativadores de Plasminogênio/sangue , Biomarcadores Tumorais/sangue , Ativador de Plasminogênio Tipo Uroquinase/uso terapêuticoAssuntos
Animais , Humanos , RESEARCH SUPPORT, NON-U.S. GOVT , Invasividade Neoplásica/fisiopatologia , Metástase Neoplásica/fisiopatologia , Proteínas de Neoplasias/fisiologia , Ativadores de Plasminogênio/fisiologia , Matriz Extracelular/fisiologia , Fibrinólise , Células Neoplásicas Circulantes , Proteínas de Neoplasias/sangue , Neoplasias Experimentais/sangue , Neoplasias Experimentais/patologia , Ativadores de Plasminogênio/sangue , Prognóstico , Biomarcadores Tumorais/sangue , Ativador de Plasminogênio Tipo Uroquinase/uso terapêuticoAssuntos
Invasividade Neoplásica/fisiopatologia , Metástase Neoplásica/fisiopatologia , Proteínas de Neoplasias/fisiologia , Ativadores de Plasminogênio/fisiologia , Animais , Biomarcadores Tumorais/sangue , Matriz Extracelular/fisiologia , Fibrinólise , Humanos , Proteínas de Neoplasias/sangue , Neoplasias Experimentais/sangue , Neoplasias Experimentais/patologia , Células Neoplásicas Circulantes , Ativadores de Plasminogênio/sangue , Prognóstico , Ativador de Plasminogênio Tipo Uroquinase/uso terapêuticoRESUMO
Serum from mice bearing five weakly immunogenic or nonimmunogenic tumors inducing concomitant resistance exhibited a growth-inhibitory activity on in vitro proliferation of the tumor cells. This activity was proportional to the intensity of concomitant resistance and correlated with the capacity to restrain metastatic development. It was not attributable to cytotoxic antibodies, was relatively nonspecific, and operated through a cytostatic and reversible mechanism. All attempts to transfer antitumor resistance in vivo by serum inoculation have failed, but this could be attained by parabiosis. Physical and chemical serum treatments suggest that heat-, acid-, and alkali-resistant peptide(s) with molecular weights ranging from 1000 to 3000 could account for this inhibitory effect.