The response to diphtheria toxin of two sensitive cell lines, KB and HeLa, was investigated. Inhibition of the incorporation of radioactively labeled amino acids into protein was the earliest detectable effect of diphtheria toxin. It was observed that, during the period of intoxication, the cell membrane was morphologically intact and retained its semi-permeable character, although it was rendered fragile and more easily disrupted by mechanical manipulations than the normal cell. The transport of amino acids continued even after intoxicated cells had ceased to synthesize protein, and the levels accumulated were equal to those of control cells. It was observed that cultural conditions, age, and handling of cells affected their response to toxin. In early log phase cells subjected to a minimum of handling before application of the toxin, the normally observed latent period preceding detectable effects was reduced to 15 min for KB cells and 30 min for HeLa cells, shorter times than previously reported. The data are consistent with the hypothesis that diphtheria toxin enters susceptible cells, possibly by pinocytosis, and there acts upon cytoplasmic sites of protein synthesis.

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