[Bleomycin is an antineoplastic agent capable of mimicking apoptosis]

Bleomycin (BLM), a currently used anticancer drug, crosses the plasma membrane poorly. Electropermeabilization allows a defined number of BLM molecules to enter directly into the cell cytoplasm. Such a procedure has revealed that BLM is endowed with a very high intrinsic cytotoxicity. Here we show that 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 a direct internucleosomal cleavage of chromatin by BLM. This result reinforces the importance of DNA digestion as an early and essential step in the morphological changes associated with apoptosis. Our study also demonstrates that BLM cytotoxicity is actually due to the DNA double strand breaks generated by this drug.