Open AccessApoptotic cell death triggered by camptothecin or teniposide. The cell cycle specificity and effects of ionizing radiation
Author(s) -
Bino G. Del,
Bruno S.,
Yi P. N.,
Darzynkiewicz Z.
Publication year - 1992
Publication title -
cell proliferation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.647
H-Index - 74
eISSN - 1365-2184
pISSN - 0960-7722
DOI - 10.1111/j.1365-2184.1992.tb01458.x
Subject(s) - teniposide , camptothecin , cell cycle , topoisomerase , biology , apoptosis , dna replication , microbiology and biotechnology , cell culture , programmed cell death , dna damage , cell , amsacrine , mitosis , dna , genetics , biochemistry , etoposide , chemotherapy
. We have previously observed that the DNA topoisomerase I inhibitor camptothecin (CAM), or DNA topoisomerase II inhibitors teniposide (TEN) and amsacrine ( m ‐AMSA) trigger endonucleolytic activity in myelogenous (HL‐60 or KGl), but not lymphocytic (MOLT‐4) leukaemic cell lines. DNA degradation and other signs of apoptotic death were seen as early as 2–4 h after cell exposure to these inhibitors. Cells replicating DNA (S phase) were selectively sensitive whereas cells in G 1 were resistant; the sensitivity of G 2 or M cells could not be assessed in these studies. The present studies were aimed at revealing whether DNA repair replication induced by ionizing radiation can sensitize the cells, and to probe the sensitivity of cells arrested in G 2 or M, to these inhibitors. The data show that γ‐irradiation (0.5–15 Gy) of HL‐60 cells does not alter their pattern of sensitivity, i.e. G 1 cells, although engaged in DNA repair replication, still remain resistant to CAM compared with the S phase cells. Likewise, irradiation of MOLT‐4 cells also does not render them sensitive to either CAM or TEN, regardless of their position in the cell cycle. Irradiation, however, by slowing the rate of cell progression through S, increased the proportion of S phase cells, and thus made the whole cell population more sensitive to CAM. HL‐60 cells arrested in G 2 either by irradiation or treatments with Hoechst 33342 or doxorubicin appear to be more resistant to CAM relative to S phase cells. Also resistant are cells arrested in M by vinblastine. The data suggest that some factor(s) exist exclusively in S phase cells, which precondition them to respond to the inhibitors of DNA topoisomerases by rapid activation of endogenous nuclease(s) and subsequent death by apoptosis. HL‐60 cells in G 1 , G 2 or M, or MOLT‐4 cells, regardless of the phase of the cycle, appear to be protected from such a mechanism, and even induction of DNA repair replication cannot initiate DNA degradation in response to DNA topoisomerase inhibitors. These data, together with the evidence in the literature that topoisomerase I may be involved in DNA repair, suggest that a combination of these inhibitors with treatments that synchronize cells in the S phase and/or recruit quiescent cells to proliferation, including radiation, may be of value in the clinic.