RESUMEN
PURPOSE: The induction of polyamine catabolism has been directly associated with the cytotoxic response of various tumor types to the antitumor polyamine analogues. Initially, human polyamine catabolism was assumed to be under the control of a rate-limiting spermidine/spermine N1-acetyltransferase (SSAT) that provides substrate for an acetylpolyamine oxidase (PAO). We have recently cloned a new polyamine analogue-inducible human polyamine oxidase (PAOh1/SMO) that efficiently uses spermine as a substrate. The induction of PAOh1/SMO in response to multiple polyamine analogues was examined in representative lung tumor cell lines. METHODS: Representatives of three different classes of antitumor polyamine analogues were examined for their ability to induce PAOh1/SMO. RESULTS: The human adenocarcinoma line, NCI A549 was found to be the most responsive line with respect to induction of PAOh1/SMO in response to analogue exposure. Similar to previous observations with SSAT expression, PAOh1/SMO induction was found to occur primarily in non-small-cell lung cancers cell lines. Using a series of polyamine analogues, it was found that the most potent inducers of PAOh1/SMO possessed multiple three-carbon linkers between nitrogens, as typified by N1,N11-bis(ethyl)norspermine. CONCLUSIONS: Since PAOh1/SMO is an analogue-inducible enzyme that produces H2O2 as a metabolic product, it may play a significant role in determining the sensitivity of various human tumors to specific polyamine analogues.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/enzimología , Carcinoma de Células Pequeñas/enzimología , Neoplasias Pulmonares/enzimología , Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH/biosíntesis , Poliaminas/farmacología , Acetiltransferasas/metabolismo , Northern Blotting , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Inducción Enzimática/efectos de los fármacos , Humanos , Poliaminas/metabolismo , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Especificidad por Sustrato , Factores de Tiempo , Poliamino OxidasaRESUMEN
The synthesis of symmetric and asymmetric piperazinyl-linked dimers of the fluoroquinolone class of antibiotics is described. Specific dimers are shown to possess potent antibacterial activity against drug-resistant strains of Staphylococcus aureus, including strains possessing resistance due to the NorA multidrug efflux pump and a mutation in the quinolone resistance-determining region of topoisomerase IV.