Different susceptibilities of postmitotic checkpoint-proficient and -deficient Balb/3T3 cells to ICRF-193, a catalytic inhibitor of DNA topoisomeraseII

Citation
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
Citations number
43
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Onconogenesis & Cancer Research
Journal title
JAPANESE JOURNAL OF CANCER RESEARCH
ISSN journal
0910-5050 → ACNP
Volume
92
Issue
2
Year of publication
2001
Pages
193 - 202
Database
ISI
SICI code
0910-5050(200102)92:2<193:DSOPCA>2.0.ZU;2-T
Abstract
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.