RESUMEN
UNLABELLED: Peritoneal disseminated cancer is highly treatment resistant. We here report the efficacy of intraperitoneal (i.p.) administration of tumor-targeting Salmonella typhimurium A1-R in a nude mouse model of disseminated human ovarian cancer. The mouse model was established by intraperitoneal injection of the human ovarian cancer cell line SKOV3-GFP. Seven days after implantation, mice were treated with S. typhimurium A1-R via intravenous (i.v.) or i.p. administration at the same dose, 5 × 10(7) CFU, once per week. Both i.v. and i.p. treatments effected prolonged survival compared with the untreated control group (P=0.025 and P<0.001, respectively). However, i.p. treatment was less toxic than i.v. TREATMENT: Tumor-specific targeting of S. typhimurium A1-R was confirmed with bacterial culture from tumors and various organs and tumor or organ colony formation after i.v. or i.p. injection. Selective tumor targeting was most effective with i.p. administration. The results of the present study show S. typhimurium A1-R has promising clinical potential for disseminated ovarian cancer, especially via i.p. administration.
Asunto(s)
Terapia Biológica/métodos , Neoplasias Ováricas/terapia , Neoplasias Peritoneales/terapia , Salmonella typhimurium/patogenicidad , Animales , Carga Bacteriana , Línea Celular Tumoral , Femenino , Humanos , Inyecciones Intraperitoneales , Inyecciones Intravenosas , Ratones Desnudos , Neoplasias Ováricas/microbiología , Neoplasias Ováricas/patología , Neoplasias Peritoneales/microbiología , Neoplasias Peritoneales/patología , Salmonella typhimurium/crecimiento & desarrollo , Factores de Tiempo , Virulencia , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Herein we report the development of novel, potent and non-peptide luteinizing hormone releasing hormone (LHRH) antagonists. The optimization towards derivatives free from mechanism-based CYP3A4 inhibition is described. The identification of a main metabolite guided us towards structural modifications of the benzyl moiety, which resulted in significant improvements of the CYP3A4 profile, while maintaining potent LHRH antagonist activity.