Synergistic cell inactivation by cis-dichlorodiammineplatinum in combination with 1-propargyl-5-chloropyrimidin-2-one

Abstract

A synergistic effect with respect to inactivation of human NHIK 3025 cells cultured in vitro was displayed when treatment with cis-dichlorodiammineplatinum(II) (cis-DDP) and the mitotic inhibitor 1-propargyl-5-chloropyrimidin-2-one (NY 3170) were given in simultaneous combination. Cell inactivation was measured by loss of colony-forming ability. Treatment with NY 3170 alone produced no significant inactivation at concentrations up to 2 mM. However, treatment with NY 3170 in combination with cis-DDP induced increased cell inactivating effects equal to a doubling of either the concentration of cis-DDP or treatment time. Scheduling of NY 3170 treatment in relationship to a 1 h cis-DDP pulse revealed that synergism occurred only when the two drugs were present simultaneously. The inactivating effect of 10 microM cis-DDP in combination with 2 mM NY 3170 given to synchronized NHIK 3025 cells at various stages of the cell cycle was also determined. For cells treated in S or in G2 + M cell survival was reduced by a factor of 5 after a 1 h treatment with the drug combination as compared to similar treatment with cis-DDP alone. The cells appeared to be most sensitive at the time of initiation of DNA synthesis. Here cell survival was reduced by a factor of 100 following treatment with the drug combination than following treatment with cis-DDP alone. Measurement of cell-associated platinum by atomic absorption spectroscopy indicated that cellular uptake of cis-DDP was increased when NY 3170 was simultaneously present during drug treatment.