ICRF-193 MODIFIES ETOPOSIDE-INDUCED APOPTOSIS IN THYMOCYTES

Etoposide (VP-16), one of the topoisomerase II (Topoll) inhibitors, in terferes with Topoll by inducing the formation of and stabilizing a cl eavable enzyme-DNA complex. VP-16 has been demonstrated to induce apop tosis in murine thymocytes. To clarify the mechanism of action of VP-1 6, we examined the in vitro effect of a non-cleavable-complex-forming type Topoll inhibitor, ICRF-193 which inhibits the DNA strand breakage induced by VP-16, on murine thymocytes in which apoptosis had been in duced 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 Topoll 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 cou rse of DNA fragmentation caused by ICRF-193 was different from that of VP-16.