Effects of Bouvardin (NSC 259968), a Cyclic Hexapeptide from Bouvardia ternifolia, on the Progression Capacity of Cultured Chinese Hamster Cells¹

Bouvardin (NSC 259968) was examined for effects on survival and cell cycle progression capacity in exponentially growing populations of line CHO Chinese hamster cells. Cells were slowed in their ability to traverse the cell cycle by concentrations of Bouvardin as low as 0.2 µg/ml, with complete inhibition observed at concentrations in excess of 1.0 µg/ml. Flow cytometric analysis indicated that there was very little rearrangement of cells around the cell cycle in treated cultures, suggesting that Bouvardin arrested cell progression uniformly throughout the entire cell cycle. Cells treated for prolonged periods of time with levels of Bouvardin inducing a total inhibition of cell division were highly resistant to drug-specific cytotoxicity (i.e., 58% of the cells continuously exposed to Bouvardin (2.0 µg/ml) for 62 hr were capable of forming colonies). Cells entering mitosis either in the presence of the drug or following drug removal were free of chromosome aberrations. Asynchronous cells exposed to Bouvardin exhibited a terminal point of inhibition of traverse capacity situated 20 min prior to prophase. Concentrations of Bouvardin that affected cell cycle traverse capacity drastically reduced the incorporation of labeled leucine into acid-precipitable material, both in whole cells and in a cell-free, protein-synthesizing system. Consideration of both the incorporation data and the cell kinetic response and terminal point of action measurements led to the conclusion that Bouvardin was acting as a protein synthesis inhibitor. In view of these kinetic and cytotoxic properties, questions are raised concerning the value of Bouvardin as a chemotherapeutic agent.