RESUMEN
BACKGROUND: Paclitaxel-carboplatin is used as the standard regimen for patients with advanced or metastatic non-small-cell lung cancer (NSCLC). This trial was designed to compare gemcitabine + carboplatin or gemcitabine + paclitaxel to the standard regimen. PATIENTS AND METHODS: A total of 1135 chemonaive patients with stage IIIB or IV NSCLC were randomly allocated to receive gemcitabine 1000 mg/m(2) on days 1 and 8 plus carboplatin area under the concentration-time curve (AUC) 5.5 on day 1 (GC), gemcitabine 1000 mg/m(2) on days 1 and 8 plus paclitaxel 200 mg/m(2) on day 1 (GP), or paclitaxel 225 mg/m(2) plus carboplatin AUC 6.0 on day 1 (PC). Stratification was based on disease stage, baseline weight loss, and presence or absence of brain metastases. Cycles were repeated every 21 days for up to six cycles or disease progression. RESULTS: Median survival (months) with GC was 7.9 compared with 8.5 for GP and 8.7 for PC. Response rates (RRs) were as follows: GC, 25.3%; GP, 32.1%; and PC, 29.8%. The GC arm was associated with a greater incidence of grade 3 or 4 hematologic events but a lower rate of neurotoxicity and alopecia when compared with GP and PC. CONCLUSIONS: Non-platinum and non-paclitaxel gemcitabine-containing doublets demonstrate similar overall survival and RR compared with the standard PC regimen. However, the treatment arms had distinct toxicity profiles.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Encefálicas/secundario , Carboplatino/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/patología , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Femenino , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Paclitaxel/administración & dosificación , Estudios Prospectivos , Tasa de Supervivencia , Resultado del Tratamiento , GemcitabinaRESUMEN
Our study was designed to evaluate the pharmacokinetics, tissue distribution, toxicity and therapeutic efficacy of liposome-encapsulated paclitaxel (LET) in comparison to conventional paclitaxel. In normal mice, LET was much less toxic than the conventional drug. A dose of 32.5 mg/kg of conventional paclitaxel administered i.v. on three consecutive days produced 100% mortality by day three, while liposomal paclitaxel exhibited no mortality. The control group which received Diluent 12 (Chremophor EL and ethanol; 1:1 v/v), a vehicle used in conventional paclitaxel, 30% mortality was observed at this dosage level. In murine ascitic L1210 leukemia model, liposomal paclitaxel and conventional paclitaxel showed comparable antitumor activity. The pharmacokinetics of conventional paclitaxel and LET was studied in mice at dose levels of 5 mg/kg and 20 mg/kg. After intravenous administration of conventional paclitaxel at a dose of 5 mg/kg, the area under the plasma-concentration-time curve (AUC) was 2-fold lower and, the elimination half-life was 2-times shorter compared to LET. At a dose of 20 mg/kg, the terminal half-lives were comparable, however, conventional paclitaxel displayed non-linear pharmacokinetics with disproportionate increase in AUC. At the two dose levels studied, LET demonstrated linear kinetics. Tissue distribution of paclitaxel after administration of LET showed levels 10-fold higher in spleen and 3.5-fold higher in liver as compared to conventional paclitaxel. The significant decrease in toxicity shown by LET, coupled with an increase in plasma AUC and half-life indicates that LET may be a viable alternative to the therapeutic use of the conventional preparation of paclitaxel.
Asunto(s)
Leucemia L1210/tratamiento farmacológico , Paclitaxel/farmacocinética , Paclitaxel/toxicidad , Animales , Portadores de Fármacos , Femenino , Semivida , Liposomas , Masculino , Tasa de Depuración Metabólica , Ratones , Ratones Endogámicos DBA , Ratones Endogámicos , Paclitaxel/administración & dosificación , Paclitaxel/uso terapéutico , Distribución TisularRESUMEN
Kaposi's sarcoma is associated with an increased frequency of HLA-DR5. The hypothesized model of a susceptibility gene in linkage disequilibrium with DR5 may be tested by haplotype analysis in familial Kaposi's sarcoma. Our finding of no common haplotype among afflicted members of a family provides evidence against the hypothesized linkage.
Asunto(s)
Antígeno HLA-DR5/genética , Sarcoma de Kaposi/genética , Anciano , Anciano de 80 o más Años , Susceptibilidad a Enfermedades , Femenino , Haplotipos , Prueba de Histocompatibilidad , Humanos , Masculino , Linaje , Sarcoma de Kaposi/inmunologíaRESUMEN
A phase I and II clinical trial of intraperitoneally administered liposome-encapsulated doxorubicin in patients with advanced ovarian cancer is being evaluated. Doxyrubicin liposomes were prepared with cardiolipin, phosphatidyl choline, cholesterol, and sterarylamine and sized by flow cytometry before administration. Fifteen patients have been treated with 42 cycles of intraperitoneal liposome-encapsulated doxrubicin. Liposome-encapsulated doxorubicin in 2 L of normal saline solution was infused over 1 hour through an infusaport into the peritoneal cavity with a dwell time of 4 hours every 21 days. Liposome-encapsulated doxorubicin has been administered at escalating doses up to 100 mg/2 L and has been well tolerated. Increased bowel motility with mild-to-moderate abdominal distress has been encountered during the first 24 hours after administration. There has been one patient with presumed chemically induced peritonitis after a temperature elevation to 39.5 degrees C. There has been no myelosuppression, abnormalities of liver function tests, or alopecia. Nausea and vomiting were minimal. Liposome-encapsulated doxorubicin was extravasated in two patients without sequelae. Drug levels were measured after completion of infusion. At a dose of 70 mg, the peak intraperitoneal concentration was 28.6 micrograms/microliter, which was reduced to 23.6 micrograms/microliter by 2 hours. Concurrent plasma levels were in the range of 0.2 to 0.5 micrograms/microliter. A similar pattern was observed at other doses. The maximum tolerable dose has not yet been obtained. There were three responders in the 10 evaluable patients. The preliminary experience with intraperitoneal liposome-encapsulated doxorubicin is encouraging.
Asunto(s)
Doxorrubicina/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Cardiolipinas , Doxorrubicina/administración & dosificación , Doxorrubicina/toxicidad , Portadores de Fármacos , Evaluación de Medicamentos , Femenino , Humanos , Inyecciones Intraperitoneales/métodos , Liposomas , Persona de Mediana EdadRESUMEN
Fibroblast cultures derived from uninjured and reparative rabbit buccal mucosa were compared in terms of extracellular glycosaminoglycan (GAG) content and cellular response to interleukin-1 (IL-1). Under identical growth conditions, proliferation of both cell lines was the same. Both lines incorporated [3H]-glucosamine into GAG in cellular, pericellular, and medium fractions, with the majority of incorporated label residing in the medium. Dermatan sulfate (DS) was the predominant GAG in the medium fraction of both normal and wound fibroblast cultures; however, the two cell lines differed in the identity of the medium fraction's secondary GAG: chondroitin sulfate (CS) for normal fibroblasts and hyaluronic acid (HA) for wound-derived cells. The GAG content of the pericellular matrix for all cultures was the same regardless of the tissue of origin: heparan sulfate (HS) accompanied by a very small amount of CS. Exposure to IL-1 produced limited but highly specific effects: It was not mitogenic for either cell line but did cause a quantitative change (increase) in overall incorporation into GAG for medium and pericellular fractions for both cell lines. Further, IL-1 induced a qualitative change in GAG composition for normal mucosal fibroblastic medium fractions by causing the synthesis/release of heparan sulfate (HS) and a variant form of DS. These data support the hypothesis that different fibroblastic substrains can populate a given oral site as a function of variables such as injury and/or healing status.