Selective inhibition of translation in transformed cells

Cancer chemotherapy is based mainly on agents that, although cell-cycle specific inhibitors, do not normally show a selective effect on transformed, as opposed to normal-growing, cells [I]_ Under special conditions, however, some compounds act selectively on transformed cells. For instance, compounds that arrest normal cells in the Gl phase of the cell-cycle combined with S phase inhibitors selectively kill transformed proliferating cells [2-6). Unfortunately, many of these selective methods use agents too toxic for cancer therapy. Several procedures are now available to reversibly permeabilize mammalian cells to low molecular weight compounds [7,8]. One of these methods, which uses ATP combined with a saline buffer, specifically permeabilizes transformed cells [7]. However, both normal and transformed cells exposed to the permeabilizing conditions are equally viable when replaced in normal culture medium. We reasoned that this selective permeabilization could provide a method for specifically killing tr~sformed cells with inhibitors to which normal or transformed untreated cells are normally impermeable. An inhibitor of this kind is hygromycin B, an aminoglycoside antibiotic produced by Srreptomyces hygroscopicus. Although this compound powerfully blocks protein synthesis in cefl-free systems [9], it is ineffective in intact mammalian cells, owing to failure to penetrate the plasma membrane [IO]. We have shown that this antibiotic readily inhibits translation in virus-infected cells, as these cells have modified permeability to low molecular weight compounds [lo,1 11.