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Induction of dna breaks and apoptosis in crosslink-hypersensitive v79 cells by the cytostatic drug β-d-glucosyl-ifosfamide mustard

British Journal of Cancer, ISSN: 0007-0920, Vol: 86, Issue: 1, Page: 130-135
2002
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Article Description

To study molecular aspects of cytotoxicity of the anticancer drug β-D-glucose-ifosfamide mustard we investigated the potential of the agent to induce apoptosis and DNA breakage. Since β-D-glucose-ifosfamide mustard generates DNA interstrand crosslinks, we used as an in vitro model system a pair of isogenic Chinese hamster V79 cells differing in their sensitivity to crosslinking agents. CL-V5B cells are dramatically more sensitive (30-fold based on D values) to the cytotoxic effects of β-D-glucose-ifosfamide mustard as compared to parental V79B cells. After 48 h of pulse-treatment with the agent, sensitive cells but not the resistant parental line undergo apoptosis and necrosis, with apoptosis being the predominant form of cell death (70 and 20% of apoptosis and necrosis, respectively). Apoptosis increased as a function of dose and was accompanied by induction of DNA double-strand breaks in the hypersensitive cells. Furthermore, a strong decline in the level of Bcl-2 protein and activation of caspases-3, -8 and -9 were observed. The resistant parental cells were refractory to all these parameters. Bcl-2 decline in the sensitive cells preceded apoptosis, and transfection-mediated overexpression of Bcl-2 protected at least in part from apoptosis. From the data we hypothesize that non-repaired crosslinks induced by β-D-glucose-ifosfamide mustard are transformed into double-strand breaks which trigger apoptosis via a Bcl-2 dependent pathway. © 2002 The Cancer Research Campaign All rights reserved.

Bibliographic Details

R. Becker; A. Ritter; U. Eichhorn; J. Lips; B. Kaina; B. Bertram; M. Wiessler; M. Z. Zdzienicka

Springer Science and Business Media LLC

Medicine; Biochemistry, Genetics and Molecular Biology

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