Selective Protection by Anguidine of Normal versus Transformed Cells against 1-ß-D-Arabinofuranosylcytosine and Adriamycin

Anguidine, a protein synthesis inhibitor, has been shown previously to induce a reversible arrest of cell progression through all phases of the mitotic cycle without inducing appreciable cell kill. This “frozen” cell cycle state provided protection of Chinese hamster ovary cells against the lethal effects of 1-ß-D-arabinofuranosylcytosine, Adriamycin, hydroxyurea, 5-fluorouracil, and hyperthermia. We now report on the preferential induction of cytostasis by anguidine in normal WI-38 fibroblasts, occurring at one-tenth of the dosage required to inhibit the cycle progression of WI-38 VA13 cells, the SV40 transformant. Pretreatment with anguidine at a concentration producing effective inhibition of normal cell cycle traverse while permitting sustained proliferation of transformed cells resulted in almost complete protection of WI-38 normal cells against the growth-inhibitory effects of 1-ß-D-arabinofuranosylcytosine and Adriamycin, without reducing the antiproliferative effects of these two agents against WI-38 VA13 transformed cells. Thus, this cytokinetic concept of preferential normal tissue protection should be explored in vivo to increase the therapeutic index of cancer chemotherapy.