RESUMEN
The phylogenetically distant F344 and BN rat strains and their (BN x F344) F1 hybrids were compared for susceptibility to hepatocarcinogenesis using the 'resistant hepatocyte' model. Quantitative stereological analysis of frequency (number/liver) and size (mean volume and volume fraction) of placental form glutathione S-transferase (GST-P)-positive lesions was carried out at 8, 15 and 32 weeks after diethylnitrosamine initiation. The number/liver of GST-P-positive lesions at any time point was slightly higher in BN and (BN x F344) F1 rats than in F344 rats, but not statistically different. However, mean volume and volume fraction of GST-P positive lesions were much higher in F344 than in both BN and (BN x F344) F1 rats at any time point, with a difference of up to > 10-fold. GST-P-positive lesions exhibited a significantly higher labeling index and much lower remodeling in male F344 than in BN and (BN x F344) F1 rats. HCCs were present at 54-57 weeks after initiation in 77% of male F344 and in no (BN x F344) F1 rats and at 70 weeks HCCs were observed in 100% of male F344 and in 23% of (BN x F344) F1 rats. These results suggest that the BN rat strain is resistant to hepatocarcinogenesis and that its resistance is genetically transmitted as a dominant character to F1 hybrids of the BN strain with the F344 susceptible strain.
Asunto(s)
2-Acetilaminofluoreno/toxicidad , Carcinógenos/toxicidad , Genes Dominantes , Neoplasias Hepáticas Experimentales/inducido químicamente , Animales , Peso Corporal , Predisposición Genética a la Enfermedad , Glutatión Transferasa/metabolismo , Isoenzimas/metabolismo , Hígado/enzimología , Neoplasias Hepáticas Experimentales/genética , Masculino , Tamaño de los Órganos , Filogenia , Ratas , Ratas Endogámicas BN , Ratas Endogámicas F344 , Especificidad de la EspecieRESUMEN
Highly purified 5-l-methyltetrahydrofolate (m-THF) and 5-l-formyl-THF (f-THF) preparations were compared for rescuing from methotrexate (MTX) toxicity in DBA2 mice transplanted with L1210 leukemia. Mice received two doses of reduced folates (2 mg/kg, s.c.) 16 and 24 h after a single s.c. MTX dose. f-THF was 1.8 time more effective than m-THF in protecting tumor cells from MTX (800 mg/kg). This MTX dose caused a 57% fall in circulating polymorphonucleates, which was prevented by both reduced folates. Treatment with 800 mg/kg of MTX plus m-THF was 1.5 fold more effective than the same MTX dose plus f-THF in increasing survival time of tumor-bearing mice. These data suggest a higher selectivity and efficacy of l-m-THF with respect to l-f-THF in rescuing from MTX toxicity.