RESUMEN
PURPOSE: The aim of this study was to increase the dose intensity of carboplatin in women with International Federation of Gynecology and Obstetrics (FIGO) Stage Ic-IV epithelial ovarian cancer with the use of granulocyte colony-stimulating factor (G-CSF; filgrastim; Amgen, Thousand Oaks, CA). PATIENTS AND METHODS: A phase I study of escalating target area under the curves (AUCs) of carboplatin with G-CSF (filgrastim) ws undertaken. The target AUCs were 5 mg/mL.min every 21 days for four cycles, 5 mg/mL.min every 14 days for four cycles, 7 mg/mL.min every 14 days for four cycles, 9 mg/mL.min every 14 days for four cycles, and 11 mg/mL.min every 14 days for four cycles. G-CSF was given at a dose of 5 microg/kg/d starting 24 hours after carboplatin administration and lasting until 24 hours before the next cycle and until day 14 after the last cycle. RESULTS: We were able to escalate to an AUC level of 9 mg/mL.min every 14 days for four cycles. At this dose, severe thrombocytopenia, that necessitated dosage delays, and failure to give subsequent cycles of carboplatin were observed. We then reduced the AUC level to 8 mg/mL.min every 14 days for four cycles. However, severe thrombocytopenia was also observed at this level. CONCLUSION: An AUC of 7 mg/mL.min every 14 days for four cycles is the maximum tolerated AUC level that can be achieved with G-CSF. Further escalations may be possible using either combinations of cytokines or peripheral stem-cell collections.
Asunto(s)
Antineoplásicos/administración & dosificación , Carboplatino/administración & dosificación , Carcinoma/tratamiento farmacológico , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Neoplasias Ováricas/tratamiento farmacológico , Adulto , Antineoplásicos/efectos adversos , Carboplatino/efectos adversos , Esquema de Medicación , Femenino , Filgrastim , Humanos , Neutropenia/inducido químicamente , Proteínas Recombinantes/administración & dosificación , Inducción de Remisión , Trombocitopenia/inducido químicamenteRESUMEN
A phase I study of frequently administered carboplatin with recombinant human granulocyte colony-stimulating factor (filgrastim) has been performed in patients with newly diagnosed epithelial ovarian cancer. Recombinant human granulocyte colony-stimulating factor was administered at a dose of 5 micrograms/kg/d for days 1 through 12 after carboplatin treatment. Carboplatin doses were calculated using a pharmacokinetic formula on an area under the curve (AUC) basis. Four doses of carboplatin were planned for each patient. The first cohort of patients received an AUC of 5 mg/mL x min every 3 weeks. Subsequently four additional cohorts received AUCs of 5, 7, 9, and 8 every 2 weeks. Non-hematologic toxicities were mild and not significant. The dose-limiting toxicity was thrombocytopenia and occurred at an AUC of 9. Most patients could complete treatment at an AUC of 7. Results for AUC 8 are awaited. Complete and partial responses were seen in most patients at all dose levels.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Carboplatino/uso terapéutico , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Adenocarcinoma/patología , Adulto , Carboplatino/efectos adversos , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Filgrastim , Factor Estimulante de Colonias de Granulocitos/efectos adversos , Humanos , Recuento de Leucocitos/efectos de los fármacos , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Ováricas/patología , Transfusión de Plaquetas , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/uso terapéutico , Trombocitopenia/inducido químicamente , Trombocitopenia/terapia , Resultado del TratamientoRESUMEN
A specific and sensitive radioimmunoassay has been developed for pregnancy-associated endometrial alpha 2-globulin (alpha 2-PEG), the major secretory protein of the human endometrium during the mid- to late-luteal phase of the menstrual cycle and first trimester of pregnancy. This assay enabled alpha 2-PEG to be measured in the cytosolic extracts of endometrium, amniotic fluid, seminal plasma and in pregnancy sera. The concentration of alpha 2-PEG in cytosols prepared from mid-secretory endometrium was 44-fold higher than in those from proliferative endometrium and a further 30-fold increase during the first trimester in comparison with mid-secretory endometrium. Levels of alpha 2-PEG in amniotic fluid (15-20 weeks) and seminal plasma were 15 +/- 4 and 55 +/- 7 micrograms/ml, respectively. With the exception of sera, where alpha 2-PEG was undetectable using rocket immunoelectrophoresis, estimates of alpha 2-PEG levels in these compartments, measured by rocket immunoelectrophoretic and RIA assays were comparable, although for seminal plasma 2.5-fold higher estimates were obtained by RIA. Detectable levels of alpha 2-PEG were obtained in 253 of 275 (92%) pregnancy sera tested. During pregnancy, peak levels were detected between weeks 6 and 11 but these represented only 2% of the levels detected in amniotic fluid. These observations support evidence from in vitro studies that alpha 2-PEG is a product of the secretory glandular epithelium, a tissue prominent in the first trimester and whose principal secretory route during pregnancy is into the amniotic fluid.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Endometrio/análisis , Proteínas Gestacionales/análisis , Radioinmunoensayo/métodos , Líquido Amniótico/análisis , Citosol/análisis , Femenino , Humanos , Masculino , Embarazo , Semen/análisisRESUMEN
Pregnancy-associated endometrial alpha 2-globulin (alpha 2-PEG), the major secretory protein of the human endometrium as assessed by in vitro de novo synthesis and secretion, during the mid- to late-luteal phase of the menstrual cycle and early first trimester pregnancy, has now been detected immunochemically in uterine luminal flushings during the luteal phase of the menstrual cycle. Physicochemical characterization of this immunoreactive alpha 2-PEG demonstrated that it exhibited identical properties to the protein isolated from either the cytosol of pregnancy endometrium or medium from in vitro cultures of pregnancy endometrium, i.e. native Mr 56 K, subunit Mr 28 K, eluted from an anion exchange column at 0.11 M NaCl and bound to concanavalin A. These findings, together with other evidence, suggest that a major route of secretion of alpha 2-PEG during the luteal phase of the menstrual cycle in vivo is into the lumen of the uterus. These results are discussed with reference to the hypothesis that alpha 2-PEG, derived from the endometrial glandular epithelium, may represent the human functional analogue of uteroglobin and to the implications for the human of the hypothesized immunosuppressive role of uteroglobin and transglutaminase (Factor XIII) in masking Class I MHC antigens on gametes and the conceptus.