Compuestos selectivamente toxicos en hipoxia estudio in vitro de sus propiedades genotoxicas

Abstract

Compounds that are selectively activated in hypoxic celis are a class of anticáncer agents whose toxicity is directed against resistant hypoxic tumoural cells. Twenty eight new aromatic-N-oxide compounds have been evaluated for selective toxicity in v-79 cells. Nine of them were selectively toxic in hypoxia but di d not improve the in vi tro profile of 7-chloro-3-[[(N,N-dimethylami no)propyl]ami no]-2-qui noxali necarboni tri1e 1,4-di-N-oxide hydrochloride (Q-85). After determining the activity of Q-85 in 4 human tumoural celi Tines -Caco-2, HT-29, MCF-7 and tk-10-, Caco-2 celis were selected for elucidating the mechanism of action. Celis were treated with subtoxic concentration in hypoxia and normoxia, although the concentrations used in normoxia were 100-fold times higher than in hypoxia. Twenty-four hours after two hours of treatment, a decrease was observed in the number of viable cells which proliferated slowly thereafter. No apoptosis was detected, only necrosis. The comet assay showed that Q-85 generates dose-dependent single strand breaks (SSB) and oxidative DNA damage, in hypoxia and in normoxia. The majority of the lesions were repaired after 24 hours, with the exception of the oxidized pyrimidine bases and SSB-induced at the hiqhest concentration in hypoxia. vitamin C and vitamin E do not have any effect on DNA damage caused by Q-85. The acute toxicity of six quinoxalines showed that the intravenouse route was not useful because of the limited solubility, and by intraperitoneal route, LD50 was between 30 and more than 120 mg/Kg.