RESUMEN
PURPOSE: This study examined the effect of insulin on sex cord stromal tumors in the rat. METHODS: Sex cord stromal tumors were induced by transplantation of ovaries under the splenic capsule of ovariectomized rats (Lewis-inbred). These tumors were then transplanted into new inbred rats. Hyperglycemic conditions were induced by treatment with streptozotocin (STZ, which selectively destroyed pancreatic islet cells) and hypoglycemic conditions by treatment with a subcutaneously implanted insulin pump (Alzet). The animals were killed 28, 56, and 84 days later. Tumor growth, animal weight, food and water consumption, and serum concentrations of glucose, FSH, LH, and estradiol were measured. RESULTS: Treatment with STZ and insulin with osmotic Alzet pumps induced continuous hypoglycemic and hyperglycemic conditions, respectively. No significant influence of the hypoglycemic or hyperglycemic status on tumor growth was measured during the first 28 and 56 days. Eighty-four days after transplantation and substitution of 1 or 2 IU/100 g body weight/d insulin, there was a significant stimulation of tumor growth (2.2-fold and 2.7-fold, respectively). In hyperglycemic animals (treated with STZ), no influence on tumor growth was found in comparison with the controls. CONCLUSION: This study confirms that hyperinsulinemic conditions contribute to the progression of tumors.
Asunto(s)
Biomarcadores de Tumor/sangre , Hiperinsulinismo/complicaciones , Insulina/metabolismo , Tumores de los Cordones Sexuales y Estroma de las Gónadas/etiología , Tumores de los Cordones Sexuales y Estroma de las Gónadas/metabolismo , Animales , Glucemia/metabolismo , Peso Corporal , Progresión de la Enfermedad , Femenino , Hormona Folículo Estimulante/sangre , Hormona Luteinizante/sangre , Trasplante de Neoplasias , Ovariectomía , Ratas , Ratas Endogámicas Lew , Tumores de los Cordones Sexuales y Estroma de las Gónadas/sangre , Tumores de los Cordones Sexuales y Estroma de las Gónadas/patología , Estreptozocina , Factores de TiempoRESUMEN
OBJECTIVE: Ovarian cancer cell lines and tissues express gonadotropin receptors. Conjugation of cytostatics to ligands of these receptors may increase the specificity of cytotoxic drugs. STUDY DESIGN: Toxicity of doxorubicin-human chorionic gonadotropin conjugates was determined in 4 ovarian cancer cell lines. Expression and regulation of luteinizing hormone/human chorionic gonadotropin receptors were analyzed before and after treatment with human chorionic gonadotropin, epidermal growth factor, and 8-bromo-cyclic adenosine monophosphate with a nested reverse transcriptase-polymerase chain reaction approach. RESULTS: Toxicity of human chorionic gonadotropin-doxorubicin conjugates was increased compared with unconjugated doxorubicin in OVCAR-3 cells. However, drug conjugates failed to demonstrate increased toxicity in other cell lines, especially after preincubation with human chorionic gonadotropin. All cell lines expressed luteinizing hormone/human chorionic gonadotropin receptors. Receptor expression in OVCAR-3 cells was not effected by human chorionic gonadotropin, endothelial growth factor, or 8-bromo-cyclic adenosine monophosphate treatment. In other cell lines, receptor expression was down-regulated by these agents. CONCLUSION: Cytotoxic activity of doxorubicin was increased specifically by conjugation to human chorionic gonadotropin. However, the regulation of luteinizing hormone/human chorionic gonadotropin receptor expression and other compounds may reduce the drug-uptake of the conjugates.
Asunto(s)
Doxorrubicina/farmacología , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/metabolismo , Receptores de HL/metabolismo , Antibióticos Antineoplásicos/farmacología , Secuencia de Bases , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , ARN Mensajero/análisis , Receptores de HL/efectos de los fármacos , Receptores de HL/genética , Muestreo , Células Tumorales CultivadasRESUMEN
The long-term prognostic significance of immunohistochemically detectable occult tumor cells in bone marrow and axillary lymph nodes of breast cancer patients considered to be lymph node-negative in multilevel haematoxylineosin (H&E) lymph node sectioning was analyzed. A total of 212 patients with a median follow-up of 10.3 years were included in the study. Bone marrow was obtained during surgery and stained with anti-cytokeratin and anti-EMA antibodies. Additional consecutive sections of lymph nodes were stained either with H&E or with anti-cytokeratin antibodies. All histological sections were analyzed by the same pathologist. Micrometastases were detected in bone marrow of 67 (32%) patients. Immunohitochemical examination of negative axillary lymph nodes--based on multilevel H&E examination--revealed micrometastases in 14 (7%) cases. There was no difference in overall or disease-free survival between patients with or without epithelial cells in bone marrow. Immunohistological examination of axillary lymph nodes also did not add any prognostic information for overall or disease-free survival. However, patients with occult micrometastases in axillary lymph nodes had a slightly higher rate of local recurrences. Immunohistochemical analysis of bone marrow or axillary lymph nodes does not add prognostic information if multilevel H&E sectioning is performed. Therefore, decision about adjuvant therapy in breast cancer patients considered to be lymph node-negative in multilevel H&E microscopy should not be based on immunohistochemical detection of micrometastases in bone marrow or axillary lymph nodes.