Age-dependent cell inactivation by vincristine alone or in combination with 1-propargyl-5-chloropyrimidin-2-one

Inactivating effects caused by vincristine alone or in combination with another mitotic inhibitor, 1-propargyl-5-chloropyrimidin-2-one, were studied as loss of colony-forming ability in exponentially growing or synchronized populations of the human cell line NHIK 3025. Treatment with 4 ng vincristine per ml(4.3 nM) in G2 led to irreversible mitotic arrest. Both mitotic arrest and lethal damage due to vincristine were primarily induced when cells were exposed in late S and G2, suggesting a correlation between the cell cycle-inhibitory and inactivating effect of this drug at clinically relevant concentrations. No repair of sublethal damage after vincristine treatment could be detected within 5 hr. A common feature in the age response of NHIK 3025 cells to the two mitotic inhibitors is drug resistance in G1. However, while mitosis is the most sensitive stage in the cycle with respect to inactivation by 1-propargyl-5-chloropyrimidin-2-one, mitotic cells are relatively resistant to treatment with vincristine. The combined inactivating effect of vincristine and 1-propargyl-5-chloropyrimidin-2-one was purely additive during interphase. In mitosis, the two drugs demonstrated a striking synergistic effect.