DNA topoisomerase inhibitors induce reversible senescence in normal human fibroblasts

Inhibitors of DNA topoisomerases I and II induced arrest in cell division i n normal human fibroblasts depending on cell divisions. Arrested cells show ed morphology similar to those of normally senesced cells and strongly indu ced senescence-associated P-galactosidase. In these cells, p16(ink4a) was u pregulated, whereas p21(waf1) or p53 was not altered. Upon removal of the i nhibitors, the cells resumed growth but their cumulative population doublin gs were reduced dose dependently. Accelerated telomere shortening was not o bserved in the arrested cells. These results suggest that DNA topoisomerase inhibitors are efficient and reversible inducers of premature senescence i n normal human cells. (C) 1998 Academic Press.