6th ESACP Congress, Heidelberg, April 7-11, 1999

A009
CELL CYCLE SPECIFICITY IN INDUCTION OF APOPTOSIS BY ANTITUMOR AGENTS
Darzynkiewicz Z

Brander Cancer Research Institute, Hawthorne, N.Y. USA

New methods adaptable to flow- and laser scanning- cytometry habe been developed to identify apoptotic cells and reveal whether apoptosis is selective to particular phases of the cell cycle. These methods enabled us to characterize several antitumor drugs of different classes in terms of their cell cycle specificity in vitro. Using these methods it was possible to assess apoptosis and correlate it with the cell cycle position in clinical samples during treatment of acute leukemias (AML, ALL, CML in blastic crisis). These in vitro and clinical observations provided rationale for new antitumor strategies. The respective strategies are based on: (i)drug combinations and sequences that recruit cells to the sensitive phase of the cycle; (ii) suppression of normal cells proliferation by agents that arrest in Go phase combined with the drugs that target other phases of the cycle: the cells that are unable to postmitotically enter Go, namely the tumor cells, are then preferentially undergoing apoptosis; (iii) potentiation of apoptosis when DNA damaging drugs are followed by inducers of differentiation, and (iv) suppression of induction of cell survival genes which are triggered by nuclear factor kappa B, selectively in tumor cells. Some of these strategies are being tested in clinical trials in our Institute.