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Bleomycin, an Apoptosis-mimetic Drug That Induces Two Types of Cell Death Depending on the Number of Molecules Internalized¹

Laboratoire de Biochimie-Enzymologie (U.R.A. 147 Centre National de la Recherche Scientifique; U. 140 INSERM) Institut Gustave Roussy, 94805 Villejuif, France

Bleomycin (BLM), a compound currently used in anticancer therapy, is unable to cross the plasma membrane efficiently. Electropermeabilization allows a defined number of BLM molecules to enter directly into the cell cytoplasm. Such a procedure has revealed that BLM is intrinsicly highly cytotoxic. Here we show that the mechanisms of the cell death caused by BLM are closely related to the number of BLM molecules introduced into the cell cytoplasm. When only a few thousand BLM molecules are internalized, cells display an arrest in the G₂-M phase of the cell cycle and become enlarged and polynucleated before dying. These observations parallel the "mitotic death" seen with ionizing radiations. By contrast, when several million molecules of BLM are internalized, morphological changes identical to those usually associated with apoptosis are observed as well as very rapid DNA fragmentation into oligonucleosomal-sized fragments. We demonstrate that this fragmentation, which occurs within a few seconds after BLM internalization, is consistent with the direct internucleosomal cleavage of chromatin by BLM. Our findings reinforce the importance of DNA digestion as an early and essential step in the morphological changes associated with apoptosis.

¹ This work was supported by a grant from the Association pour la Recherche sur le Cancer.

Received 4/26/93. Accepted 9/13/93.

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