ICRF 159-induced cell-cycle perturbation in vitro: its relationship to inhibition of colony-forming ability.

The effects of single doses of ICRF 159 (Razoxane) on the cell-cycle kinetics of lines of BKH 21S cells in vitro were studied by means of flow micro-fluorometry (FMF). A characteristic accumulation of cells in the 4n DNA region after 6 h in the presence of ICRF 159 was evident in cells which were sensitive to the cytotoxic effects of the agents, as judged by colony-forming assays. The subsequent accumulation of 8n cells as the major population within 24 h indicates that this 6 h effect is associated with the induction of tetraploidy through abnormal mitosis, rather than reflecting a G2 block of potential value in combination therapy. In ICRF 159-resistant sublines, the cell-cycle distributions were similarly affected, but only the doses of the drug high enough to reduce their surviving fraction. Somatic cell hybrids from crosses between sensitive and resistant cells demonstrated intermediate responses in ICRF 159, both in terms of cell-cycle kinetics and impairment of reproductive integrity. These data suggest a relationship between the 2 manifestations of the cellular action of ICRF 159, and also a possible predictive role for FMF in the assessment of response to this particular agent.