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

Abstract

Summary 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 2mM. 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 lOpM cis-DDP in combination with 2mM 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 I 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.

The role of apoptosis in cell killing by cisplatin: a flow cytometric study

“…In order to be arrested in G2, damage to DNA alone is insufficient; there must also be replication of DNA on the damaged template -an effect which has also been observed in cells treated with alkylating agents (Roberts, 1978). It has been suggested that cells are more sensitive to cisplatin in GI (Roberts & Fraval, 1980) or at the GI/S boundary (Dornish et al, 1987) compared with S-phase. If the G2 block is a critical step in cell death, then our observation that cells treated in GI become blocked in G2 while those treated in S-phase move through G2 and divide is consistent with this suggestion.…”

Direct Cellular Responses to Platinum-Induced DNA Damage

“…Evidence for a role of active transporters in the uptake and efflux of cisplatin and other platinum compounds has been available in the literature for some time . For example, multiple studies demonstrated that reactive aldehydes inhibit cisplatin accumulation in cells, possibly by modifying membrane proteins. , Recently, a series of experiments have indicated a direct link between copper transporters and the uptake and efflux of platinum compounds . The first clue came when cisplatin resistance was observed following transfection of a copper-transporting P-type ATPase (ATP7B), a key player in copper homeostasis, into human epidermoid carcinoma cells, which enhanced the efflux of the drug .…”

Cellular accumulation of the anticancer agent cisplatin: A review

“…In another group of experiments, this group has found that the mitotic inhibitor l-propargyl-5-chloropyrimidin-2-one (NY 3170) synergistically enhances DDP toxicity (Dornish et al, 1987 . In order to determine if the decreased uptake could be explained by a change in the plasma membrane, Mann et al.…”