CC-1065 (NSC 298223), a Most Potent Antitumor Agent: Kinetics of Inhibition of Growth, DNA Synthesis, and Cell Survival

Abstract CC-1065 (NSC 298223) is the most cytotoxic agent tested against cells in culture in our laboratory. The 50% lethal doses for exponentially growing B16 melanoma and Chinese hamster ovary cells were 0.44 and 0.14 ng/ml, respectively, as compared to 35 and 500 ng/ml for Adriamycin. In the human tumor-cloning assay, 1-hr exposure to CC-1065 (0.1 ng/ml) caused ⩾50% lethality in a broad spectrum of tumors. The dose-survival curves for B16 and Chinese hamster ovary cells were characterized by an initial shoulder followed by an exponential decline with increasing dose. CC-1065 was more lethal to exponentially growing B16 cells (50% lethal dose = 0.44 ng/ml) than to plateau-phase cells (50% lethal dose = 1.2 ng/ml). CC-1065 inhibited DNA synthesis much more than did RNA or protein synthesis. After a 2-hr incubation with drug, inhibition of DNA synthesis was low immediately (0 hr) after drug exposure and reached maximum inhibition about 20 hr later. The doses for 50% inhibition of growth (0.18 ng/ml), survival (0.44 ng/ml), and DNA synthesis (0.15 ng/ml) were in the same range, whereas RNA synthesis was inhibited 50% at a much higher dose (5 ng/ml).