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Intracellular Uptake of 7-con-O-Methylnogarol and Adriamycin by Cells in Culture and Its Relationship to Cell Survival

Cancer Research, The Upjohn Company, Kalamazoo, Michigan 49001

7-con-O-Methylnogarol (7-OMEN) is a new anthracycline antitumor agent with significant activity in vivo against murine P388 and L1210 leukemia (140% increase in life span) and B16 melanoma (114% increase in life span). We report here the complex relationship that exists between intracellular drug concentration and killing of Chinese hamster ovary (CHO), B16, and L1210 cells in culture by 7-OMEN and Adriamycin.

The uptake of 7-OMEN and Adriamycin by CHO, B16, and L1210 cells was proportional to the extracellular concentration (µg/ml medium) of the drug. At similar concentrations, CHO and B16 cells accumulated more 7-OMEN than Adriamycin. Based on intracellular concentration in CHO cells, Adriamycin was more lethal [lethal dose for 90% of the cells (LD₉₀), 0.02 µg/10⁶ cells] than was 7-OMEN (LD₉₀, 0.1 µg/10⁶ cells). However, based on concentration in CHO cells extracellular 7-OMEN was more lethal (LD₉₀, 0.6 µg/ml) than was Adriamycin (LD₉₀, 2.5 µg/ml). This was probably due to the very low level of uptake of Adriamycin by CHO cells.

For both 7-OMEN and Adriamycin, cell kill increased with increasing intracellular concentration. In contrast to the linear relationship between intracellular concentration and cell kill with Adriamycin, a biphasic relationship was seen with 7-OMEN. For 7-OMEN, cell kill was proportional to intracellular concentration up to approximately 0.04 µg/10⁶ cells. Further increase in intracellular concentration did not result in proportional increase in cell kill.

Exponentially growing cells not only accumulated more 7-OMEN than did plateau-phase cells but were also inherently more sensitive to the drug. This latter conclusion was based on the observation that, even at similar intracellular concentration, more exponentially growing than plateau-phase cells were killed.

Fluorescence microscopy showed that 7-OMEN accumulated predominantly in the cytoplasm, whereas Adriamycin accumulated in the nucleus. The significance of this observation to the mode of action of these drugs is discussed.

¹ To whom requests for reprints should be addressed.

Received 4/ 1/80. Accepted 11/13/80.