Dynamics Of Cell Cycle Arrest And Apoptosis Induction By Topoisomerase II Inhibitors In B Cell Lymphomas.
SF Chin*, JV Watson1 and PJ Smith, Dept. of Pathology, University of Wales College of Medicine, Health Park, Cardiff, UK.; 1MRC Centre, Hills Road, Cambridge, 1UK
We have compared the action of DNA-damaging (VP-16 and doxorubicin [DOX]) and non-DNA-damaging (ICRF-193) topoisomerase II inhibitors in two human B cell lymphoma lines. The objective was to investigate the p53-and DNA damage-dependence of cycle arrest. The DoHH2 line (p53wt) was more sensitive than SUD4 (p53mut) to the cytostatic effects of all three drugs. Flow cytometry showed that VP-16 and DOX induced the same patterns of cell cycle arrest in both lines with low concentrations (VP-16<0.25 µM; DOX<0.05 µM) causing G2/M arrest and higher concentrations causing arrest earlier in the cycle. ICRF-193 (< 0.125 µg/ml) caused G2 delay/arrest in both lines but at higher concentrations induced polyploidy in SUD4 alone. ICRF-193-induced arrest of DoHH2 cells in G2 led to apoptosis whereas SUD4 showed no evidence of DNA fragmentation. We conclude that while the disruption of chromosome segregation can induce apoptosis in the absence of overt chromosome damage, the preceding phase of cell cycle arrest is p53-independent and not a consequence of DNA fragmentation. We suggest that the hypersensitivity of DoHH2 cells relates to the presence of wild-type p53.