Comparative evaluation of C1311 cytotoxic activity and interference with cell cycle progression in a panel of human...

The cytotoxic activity of the imidazoacridinone C1311 was related to its effect on cell cycle progression in 16 human cell lines from different solid tumour types and leukaemias. A 72-h exposure to C1311 induced a wide range of growth inhibition (IC50 values ranging from 0.0094 to 0.8 microM; median, 0.279 microM), with the highest activity in the 2 gastric cancer cell lines (IC50, 0.0094 and 0.0098 microM). No significant association was found between in vitro sensitivtity to C1311 and doxorubicin or taxol. Moreover, the activity of C1311 was independent of the p53 gene status of the cell line. Twenty-four-hour exposure to C1311 led to a marked increase in the number of cells in the G2M phase in the majority of cell lines, although the extent of such accumulation was independent of the level of drug cytotoxic activity. C1311 did not generally affect the expression level of cyclin B1 or Cdk1 (p34cdc2) proteins. Conversely, when normalised on the basis of the number of cells arrested in the G2M compartment, Cdk1 kinase activity appeared lower than that of untreated cells in the 4 cell lines showing the most pronounced accumulation in G2M. Overall, such data show that C1311 is active against a variety of human tumour cell lines and strongly support further evaluation of the drug in clinical trials.