ICRF-193 modifies etoposide-induced apoptosis in thymocytes.
Etoposide (VP-16), one of the topoisomerase II (TopoII) inhibitors, interferes with TopoII by inducing the formation of and stabilizing a cleavable enzyme-DNA complex. VP-16 has been demonstrated to induce apoptosis in murine thymocytes. To clarify the mechanism of action of VP-16, we examined the in vitro effect of a non-cleavable-complex-forming type TopoII inhibitor, ICRF-193 which inhibits the DNA strand breakage induced by VP-16, on murine thymocytes in which apoptosis had been induced with VP-16. DNA fragmentation is characteristic of apoptosis. In the early stages, ICRF-193 decreased DNA fragmentation induced by VP-16, although this inhibitory effect decreased in the later. These data suggest that TopoII inhibitors induce apoptosis in murine thymocytes in two ways: with DNA-strand breaks in the early stage or without them. ICRF-193 itself induced apoptosis in murine thymocytes. The time course of DNA fragmentation caused by ICRF-193 was different from that of VP-16.
Tanimoto
C
C
Third Department of Internal Medicine, Okayama University Medical School, Japan.
Hirakawa
S
S
Kawasaki
H
H
Hayakawa
N
N
Ota
Z
Z
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D004247:DNA / Q000187:drug effects / Q000378:metabolism*; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins; D054659:Diketopiperazines; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005047:Etoposide / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008856:Microscopy, Fluorescence; D010879:Piperazines / Q000494:pharmacology*; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D059005:Topoisomerase II Inhibitors
D000972:Antineoplastic Agents, Phytogenic; D004268:DNA-Binding Proteins; D054659:Diketopiperazines; D004791:Enzyme Inhibitors; D010879:Piperazines; D059005:Topoisomerase II Inhibitors; C070899:4,4'-(1,2-dimethyl-1,2-ethanediyl)bis-2,6-piperazinedione; D005047:Etoposide; D004247:DNA; D004250:DNA Topoisomerases, Type II