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Effect of 7-con-O-Methylnogarol on DNA Synthesis, Survival, and Cell Cycle Progression of Chinese Hamster Ovary Cells

Cancer Research, The Upjohn Company, Kalamazoo, Michigan 49001

The effect of 7-con-O-methylnogarol (7-OMEN) on the survival of exponentially growing and plateau-phase Chinese hamster ovary cells was determined in a cloning assay. After 2 hr of exposure, the 50% lethal dose for exponential and plateauphase cells was 0.3 and 1.5 µg/ml, respectively. Drug doses for cell progression studies were based upon drug lethality; therefore, higher doses were used for plateau than for exponential populations. The effect of 7-OMEN on cell progression was studied by DNA flow cytometry under the following conditions: (a) during 24 hr of continuous exposure of exponentially growing cells; (b) during recovery of exponential cells after 2 or 7 hr of drug exposure; and (c) during recovery of plateau-phase cells after 2 hr of exposure. Exponential cells exposed continuously for 24 hr progressed normally from M to G₁ phase and from G₁ to S phase, progression through S phase was slowed, and cells were ultimately blocked in G₂ + M. Inhibition of S-phase progression was dose dependent, 0.2 µg/ml having only slight effect and 1.0 µg/ml accumulating a large fraction in S phase. Inhibition of S-phase progression correlated with DNA synthesis inhibition. Similar inhibitory effects were observed after pulsed (2- or 7-hr) exposure of exponential cells. 7-OMEN also blocked plateau-phase cells in G₂ + M after 2 hr of exposure, but higher doses (3.0 µg/ml) were required.

Simultaneous exposure of exponential cells to Colcemid (which blocks cells in metaphase) and 1.0 µg 7-OMEN per ml completely inhibited the expected increase in mitotic index, indicating that the G₂ + M block observed by DNA flow cytometry was a block in G₂ or prophase.

¹ To whom requests for reprints should be addressed.

Received 6/11/81. Accepted 9/ 9/81.