ICRF-193, a catalytic inhibitor of DNA topoisomerase II, inhibits re-entry into the cell division cycle from quiescent state in mammalian cells.
BACKGROUND
To describe the requirement of DNA topoisomerase II (topo II) during transition from the quiescent state (G0 phase) to the cell division cycle in mammalian cells, we examined the influence of ICRF-193, a catalytic inhibitor of topo II, on re-entry into the cell division cycle of quiescent cells in response to appropriate growth stimuli.


RESULTS
The re-entry into the S phase of cultured cell lines arrested at the quiescent (G0) phase by serum-starvation was sensitive to 10 microm ICRF-193. DNA syntheses induced by lipopolysaccharide in murine spleen cells or by release from contact-inhibition were also inhibited by ICRF-193. The cell lines with a high-level of resistance toward ICRF-193 due to a point mutation in the topo IIalpha gene entered into the S phase from quiescence in the presence of ICRF-193. The drug did not inhibit entry into the S phase in cultured cells released from arrest at the metaphase or G1 phase.


CONCLUSIONS
There is an ICRF-193-sensitive step during re-entry of quiescent mammalian cells into the cell division cycle upon growth stimulation and the drug targets topo IIalpha during the process.
Hossain
Muktadir S
MS
Laboratory of Developmental Biochemistry, Faculty of Pharmaceutical Sciences, University of Tokyo, 3-1, 7-Chome, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Akimitsu
Nobuyoshi
N
Takaki
Tohru
T
Hirai
Hiroshi
H
Sekimizu
Kazuhisa
K
D016475:3T3 Cells; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003260:Contact Inhibition / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D054659:Diketopiperazines; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D016192:Resting Phase, Cell Cycle / Q000187:drug effects / Q000502:physiology*; D013154:Spleen; D059005:Topoisomerase II Inhibitors
D054659:Diketopiperazines; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D019384:Nucleic Acid Synthesis Inhibitors; D010879:Piperazines; D059005:Topoisomerase II Inhibitors; C070899:4,4'-(1,2-dimethyl-1,2-ethanediyl)bis-2,6-piperazinedione; D004247:DNA; D004250:DNA Topoisomerases, Type II