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.
Xu
Y J
YJ
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing.
Li
D D
DD
Zhen
Y S
YS
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis; D004249:DNA Damage; D053281:Enediynes; D005434:Flow Cytometry; D006801:Humans; D008940:Mitotic Index / Q000187:drug effects; D011506:Proteins / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014529:Uridine / Q000378:metabolism
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D000903:Antibiotics, Antineoplastic; D053281:Enediynes; D011506:Proteins; C058024:C 1027; D004247:DNA; D013936:Thymidine; D014529:Uridine