Different susceptibilities of postmitotic checkpoint-proficient and -deficient Balb/3T3 cells to ICRF-193, a catalytic inhibitor of DNA topoisomeraseII
K. Nishida et al., Different susceptibilities of postmitotic checkpoint-proficient and -deficient Balb/3T3 cells to ICRF-193, a catalytic inhibitor of DNA topoisomeraseII, JPN J CANC, 92(2), 2001, pp. 193-202
Two distinct types of Balb/3T3 cells were isolated which exhibit either 4 N
DNA or both 4 N and 8 N DNA after exposure to colcemid for 48 h. They were
found to differ with respect to the postmitotic checkpoint, but not the mi
totic checkpoint. Firstly, the checkpoint-proficient and -deficient cells e
xhibited the same accumulation and subsequent decrease in the number of mit
otic cells following exposure to microtubule inhibitors. Secondly, after ex
it from abnormal mitosis in the presence of ICRF (Imperial Cancer Research
Fund)-193, the checkpoint-proficient cells were arrested in the next cycle
G1, while the checkpoint-deficient cells progressed into S and G2 phase. Wh
en either mitotic or asynchronous cells were ex-posed to ICRF-193, the chec
kpoint-proficient cells proved more sensitive to the cytotoxic effect of th
is agent than the checkpoint-deficient cells. The different susceptibilitie
s of the two types of cells to ICRF-193 were not caused by variation in top
oisomerase (topo) II function since both the biochemical activity of this e
nzyme and chromosome segregation were inhibited by similar concentrations o
f ICRF-193 in both checkpoint-proficient and -deficient cells. We propose t
hat the inhibition of chromosome segregation by ICRF-193 is monitored by th
e next G1 checkpoint, resulting in an irreversible G1 block in the case of
postmitotic checkpoint-proficient cells. As the checkpoint-deficient cells
can escape this G1 block, these cells have an increased survival capacity.
In summary, ICRF-193 may prove to be a very useful drug for examination of
the postmitotic checkpoint.