INFLUENCE OF N-METHYLFORMAMIDE ON THE INTRACELLULAR-TRANSPORT OF DOXORUBICIN

The polar solvent N-methylformamide proved to be capable of enhancing the cytotoxic potential of various antitumoral compounds, both in vitr o and in vivo. In many cases, this ability depended on the sequence of treatment, and the enhancement of the cytotoxic effect occurred only when N-methylformamide administration succeeded anticancer drug treatm ent, The results obtained in the present study indicate that N-methylf ormamide interferes with the mechanisms of intracellular transport and efflux of the antitumoral drug doxorubicin. In particular, laser scan ning confocal microscopy observations performed on melanoma cells (M14 ) after N-methylformamide administration revealed evident alterations of the microtubular network, including numerous interruptions of the m icrotubules. Moreover, when doxorubicin-treated cells were recovered i n the presence of the polar solvent, the normal efflux of the anthracy clinic antibiotic appeared to be hampered, and the drug was localized mainly in well delimited perinuclear regions. Double staining experime nts demonstrated the colocalization of the doxorubicin molecules and t he WGA-stained regions as well as a close structural relationship betw een them and the microtubule system. These results indicate that N-met hylformamide interferes with the doxorubicin transport inducing a dama ge in the microtubular network and the consequent persistence and entr apment of the drug in the regions likely occupied by the Golgi apparat us of tumor cells. This finding could account for the chemosensitizing properties exerted by N-methylformamide.