Anticellular and Antitumor Activity of Duocarmycins, Novel Antitumor Antibiotics

The anticellular and antitumor activities of novel antitumor antibiotics, duocarmycins (DUMs), were examined against human and murine tumor cells. DUMs consist of live compounds, A, B(1), B(2), C(1), and C(2), which possess a pharmacophore similar to that of CC‐1065, a previously isolated antibiotic. Among them, DUMA exhibited ultrapotent growth‐inhibitory activity with an IC(50) value of 6 pM against human uterine cervix carcinoma HeLa S(3) cells. DUMA and DUMB1 also inhibited the growth of adriamycin (ADM)‐resistant lines of human nasopharynx carcinoma KB cells and breast carcinoma MCF‐7 cells as well as their sensitive lines. DUMs inhibited the growth of s.c.‐inoculated murine tumors such as B16 melanoma, sarcoma 180, M5076 sarcoma and colon 26. DUMs were also significantly effective in increasing the lifespan of i.p.‐inoculated B16 melanoma‐bearing mice, although their effect was marginal against other i.p.‐inoculated tumors. As a whole, DUMB1 exhibited superior activity to the other four compounds. DUMB1 rapidly inhibited the incorporation of [(3)H]‐TdR into macromolecules of HeLa S(3) cells as compared with that of [(3)H]UR or [(3)H]leucine. DNA strand breaks were detected in DUMB1 ‐treated HeLa S(3) cells by agarose gel electrophoresis with a contour‐clamped homogeneous electric field apparatus. These results indicate that DUMs possess interesting biological activities as DNA‐targeting antitumor antibiotics.