RESUMEN
A series of over 70 difluoropurine analogs was synthesized by varying the C-2, 6 and 8 substituents about the purine ring system. After initial in vitro and in vivo screening, testing concentrated on the 2,6-diaminopurine analog (dFdAP) and the guanosine analog (dFdG). dFDAP appears to be a prodrug for dFdG. Both compounds significantly inhibited mammary tumor growth in mice, caused a moderate inhibition in ovarian and lymphosarcoma models, and demonstrated no activity in lung and melanoma models. This is a narrower spectrum of activity than that of gemcitabine (dFdC). The antitumor activity of dFdAP in human xenografts that are refractory to standard clinical agents was comparable or superior to that of gemcitabine. However, during the preliminary toxicology testing, dFdG was associated with several deaths caused by cardiac toxicity. Therefore, although dFdG is a potentially useful oncolytic, further investigation is required.
Asunto(s)
2-Aminopurina/análogos & derivados , Antineoplásicos/farmacología , Desoxiadenosinas/química , Desoxiadenosinas/farmacología , Desoxiguanosina/análogos & derivados , Guanosina/análogos & derivados , Neoplasias Experimentales/tratamiento farmacológico , 2-Aminopurina/química , 2-Aminopurina/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Recuento de Células Sanguíneas/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Desoxiadenosinas/síntesis química , Desoxiguanosina/síntesis química , Desoxiguanosina/química , Desoxiguanosina/farmacología , Perros , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Corazón/efectos de los fármacos , Humanos , Técnicas In Vitro , Infusiones Intravenosas , Inyecciones Intraperitoneales , Hígado/efectos de los fármacos , Tejido Linfoide/efectos de los fármacos , Masculino , Ratones , Neoplasias Ováricas/tratamiento farmacológico , Relación Estructura-Actividad , Testículo/efectos de los fármacosRESUMEN
Human pancreatic carcinoma xenograft models were developed from established MIA PaCa-2 and PANC-1 cell lines (ATCC, Rockville, MD). Tumors were maintained by serial trocar implantation in CD1 nu/nu mice, and attempts were made to test all drugs under optimal schedules at maximum tolerated doses. In both models, adriamycin, cisplatin, and 5-fluorouracil were inactive (< 60% inhibition of tumor weight), whereas gemcitabine (LY188011] produced modest activity (69% inhibition in MIA PaCa-2 and 76% inhibition in PANC-1. Major differences in tumor sensitivity were noted with diarylsulfonylureas (DSU) and taxol. The DSU (Sulofenur [LY186641] and LY295501) produced complete inhibition in the MIA PaCa-2 xenograft, but were inactive in PANC-1. Conversely, taxol produced 80% inhibition of PANC-1 tumor growth, but was inactive against MIA PaCa-2. In general, in vivo antitumor activity roughly correlated with in vitro tumor cytotoxicity with the exception of DSU. We have previously shown that DSU are extensively bound to albumin and that in vitro cytotoxic activity in serum-containing medium is not predictive of in vivo antitumor activity. The MIA PaCa-2 and PANC-1 xenograft models may be useful for selecting potential candidates for therapy of human pancreatic cancer.