Reduced Inhibition of DNA Synthesis and G(2) Arrest during the Cell Cycle of Resistant HeLa Cells in Response to cis-Diamminedichloroplatinum.

Abstract

The influence of cisplatin, an anticancer agent, on DNA synthesis and cell cycle progression of a cisplatin-resistant cell line was investigated. Cell cycle analysis using flow cytometry showed that cytotoxic concentrations of cisplatin caused a transient inhibition of parental HeLa cells at S phase, followed by accumulation at G(2) phase. In contrast, the resistant cells progressed through the cell cycle without being affected by the same treatment. However, cell cycle distributions were the same in the resistant and the parental cells at IC( 50), the drug concentration inhibiting cell growth by 50%. Studies using a [(3)H]thymidine incorporation technique also demonstrated a transient inhibition of DNA synthesis in HeLa cells by cisplatin; such inhibition was greatly reduced in the resistant cells. These data argue for the hypothesis that the inhibition of DNA synthesis is important in determining cisplatin-induced cytotoxicity. In addition, the accumulation of cells at G(o)/G(1) by serum starvation was not effective in the resistant cells compared to the parental cells, suggesting that the control of cell cycle exiting is also altered in the resistant cells. Taken together, these results support the notion that alterations in cell cycle control, in particular G(2) arrest, are important in determining the sensitivity or resistance of mammalian cells to cisplatin and may have a role in clinical protocols. Copyright 1994 S. Karger AG, Basel