Mode of action of C-1027, a new macromolecular antitumor antibiotic with highly potent cytotoxicity, on human hepatoma BEL-7402 cells.

C-1027, a new macromolecular peptide antitumor antibiotic produced by a Streptomyces strain, was extremely cytotoxic to cultured cancer cells and markedly inhibited the growth of transplantable tumors in mice. As determined by tritium-labeled precursor-incorporation assay, C-1027 strongly inhibited DNA and RNA synthesis in hepatoma BEL-7402 cells without affecting protein synthesis. After incubation with the hepatoma cells for 4 h, IC50 values for [3H]-thymidine and [3H]-uridine incorporation were 0.00012 and 0.00032 microM, respectively. After 30 min incubation, C-1027 showed much stronger inhibition of [3H]-thymidine incorporation than did Adriamycin, mitomycin C or methotrexate, even at a concentration 10,000 times lower. The effect of C-1027 on pBR322 DNA suggested that the drug could cause single- or double-strand scission of DNA. As determined by flow cytometry, C-1027 delayed the progression of hepatoma cells through the S-phase and blocked the cells at G2+M. Cytological study showed that C-1027 caused a drastic reduction of the mitotic index within 1 h and that an overshot of the mitotic index occurred at 48 h. Our results indicate that C-1027 is an interesting compound with highly potent activity on cellular DNA.