RESUMEN
A collaborative study was conducted to evaluate whether a replicative DNA synthesis (RDS) test using the rat liver can detect nongenotoxic (Ames-negative) hepatocarcinogens with three or seven daily administrations at dose-levels effective in long-term bioassays. The assay methods were well-validated by the 14 participants. Of six compounds tested, carbon tetrachloride (50 and 100 mg/kg), clofibrate (125 and 250 mg/kg), diethylstilbestrol (0.125 and 0.25 mg/kg) and urethane (100 mg/kg) gave positive results, methyl carbamate (200 and 400 mg/kg) exerted equivocal effects, and D,L-ethionine (125 mg/kg) failed to elevate RDS. These findings suggest that the RDS test can detect many nongenotoxic rat hepatocarcinogens with short-term administration at dose-levels used in long-term bioassays.
Asunto(s)
Pruebas de Carcinogenicidad/métodos , Replicación del ADN/efectos de los fármacos , ADN/biosíntesis , Hígado/metabolismo , Pruebas de Mutagenicidad/métodos , Animales , Antimetabolitos Antineoplásicos/toxicidad , Bromodesoxiuridina/toxicidad , Inmunohistoquímica , Hígado/citología , Hígado/efectos de los fármacos , Masculino , Ratas , Ratas Endogámicas F344RESUMEN
We studied the antileishmanial activity of 3'-deoxy-3'-fluoroinosine (3'-FI) against Leishmania tropica and L. donovani. In in vitro cultivation, the EC50 values (the concentration of drug necessary to inhibit the growth rate of cells to 50% of the control value) obtained for 3'-FI against the promastigotes of L. tropica and L. donovani were 2.3 x 10(-7) and 1.0 x 10(-6) M, respectively. It was less toxic toward mouse mammary-tumor FM3A cells, a model host; the EC50 value was 1.9 x 10(-4) M. Leishmania promastigote metabolized 3'-FI to 3'-deoxy-3'-fluoroadenosine 5'-triphosphate (3'-FATP) but FM3A cells did not. 3'-FI was effective against L. donovani amastigotes in J774.1 cells in an in vitro cultivation system under conditions similar to those used in the in vivo assay. 3'-FI (50 mg/kg, given i.v.) showed a cytotoxic effect against the amastigotes of L. donovani in mice.
Asunto(s)
Antiprotozoarios/metabolismo , Antiprotozoarios/toxicidad , Inosina/análogos & derivados , Leishmania donovani/efectos de los fármacos , Leishmania tropica/efectos de los fármacos , Leishmaniasis Visceral/tratamiento farmacológico , Animales , Antiprotozoarios/uso terapéutico , Cromatografía Líquida de Alta Presión , Relación Dosis-Respuesta a Droga , Inosina/metabolismo , Inosina/uso terapéutico , Inosina/toxicidad , Leishmania donovani/crecimiento & desarrollo , Leishmania tropica/crecimiento & desarrollo , Masculino , Ratones , Ratones Endogámicos BALB C , Factores de TiempoRESUMEN
3'-Deoxy-3'-fluoroinosine is a potent inhibitor for the growth of the promastigote form of Leishmania tropica and Leishmania donovani. In culture, the EC50 values of 3'-deoxy-3'-fluoroinosine are 2.3 x 10(-7) and 1.0 x 10(-6) M for the promastigotes of L. tropica and L. donovani, respectively. It is less toxic towards mouse mammary tumor FM3A cells: the EC50 value is 2.0 x 10(-4) M. 3'-Deoxy-3'-fluoroinosine is metabolized by Leishmania promastigotes to give 3'-deoxy-3'-fluoroadenosine-5'-triphosphate. This metabolic conversion provides a mechanism for the parasite-selective toxicity of 3'-deoxy-3'-fluoroinosine.