RESUMEN
The anticancer efficacy of methionine γ-lyase (MGL) from Clostridium sporogenes (C. sporogenes) is described. MGL was active against cancer cells in vitro and in vivo. Doxorubicin (DOX) and MGL were more effective on A549 human lung-cancer growth inhibition than either agent alone in vitro and in vivo.
Asunto(s)
Antineoplásicos/aislamiento & purificación , Liasas de Carbono-Azufre/metabolismo , Clostridium/enzimología , Ensayos Antitumor por Modelo de Xenoinjerto , Células A549 , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Liasas de Carbono-Azufre/aislamiento & purificación , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cisplatino/farmacología , Cisplatino/uso terapéutico , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Pruebas de Enzimas , Humanos , Células MCF-7 , Ratones , Resultado del TratamientoRESUMEN
PK studies were carried out after a single i.v. administration of 500 and 1000 U/kg by measuring of MGL activity in plasma samples. L-methionine concentration was measured by mass spectrometry. After single i.v. injection of 500U/kg the circulating T1/2 of enzymes in mice varies from 73 to 123min. The AUC0-tinf values determined for MGL 500U/kg from C. freundii, C. tetani and C. sporogenes are 8.21±0.28, 9.04±0.33 and 13.88±0.39U/(ml×h), respectively. Comparison of PK parameters of three MGL sources in the dose of 500U/kg indicated the MGL C. sporogenes to have better PK parameters: clearance 0.83(95%CI: 0.779-0.871) - was lower than C. tetanii 1.27(95%CI: 1.18-1.36) and C. freundii 1.39(95%CI: 1.30-1.49). Mice plasma methionine decreased to undetectable level 10min after MGL 1000 U/kg injection. After MGL C. sporogenes 500U/kg injection plasma methionine level completely omitted after 10min till 6h, assuming the sustainability of negligible levels of methionine (<5µM) in plasma of mice for about 6h. The recovery of methionine concentration showed the advantageous efficiency of MGL from C. sporogenes: 95% 0.010-0.022 vs 0.023-0.061 for MGL C. freundii and 0.036-0.056 for MGL C. tetani. There are no significant differences between methionine cleavage after MGL C. tetani and MGL C. sporogenes i.v. injection at all doses. MGL from C. sporogenes may be considered as promising enzyme for further investigation as potential anticancer agent.