bleomycin-a6 and Carcinoma--Hepatocellular

Boanmycin (bleomycin A6, BM), an antitumor antibiotic, was conjugated to monoclonal antibodies including R19, H111 and CCT2. The immunoconjugates exhibited selective cytotoxicity to related target cells including cecum cancer Hce-8693 cells, liver cancer BEL-7402 cells and leukemia CEM cells. They were highly effective against related human tumor xenografts in nude mice, and the inhibition rates by the conjugates were much higher than those by free BM. The inhibition rate by R19-BM conjugate against human cecum cancer xenografts reached 90%. BY immunoelectron microscopy, CCT2-BM conjugate showed specific binding and internalization in leukemia CEM cells. The results indicate that boanmycin-monoclonal antibody immunoconjugates are highly active both in vitro and in vivo.

Topics: Adenocarcinoma; Animals; Antibiotics, Antineoplastic; Antibodies, Monoclonal; Bleomycin; Carcinoma, Hepatocellular; Cecal Neoplasms; Humans; Immunotoxins; Liver Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Tumor Cells, Cultured

Bleomycin A6 (A6), a single component of bleomycin complex, is highly active against human liver cancer cells in vitro and xenografts in nude mice. A6 was conjugated to monoclonal antibody H111 directed against human hepatoma BEL - 7402 cells, using Dextran T40 as an intermediate. The conjugate consisted of a coupling molar ratio of 1:264 for H111 and A6, and retained 6.3% of A6 activity. As determined by clonogenic assay with hepatoma BEL - 7402 cells exposed to the agents for 1 h, the IC90 values for H111 - A6 conjugate, free A6 and M3 - A6 conjugate (an irrelevant conjugate) were 0.17 mu mol/L, 17 mu mol/L and 7 mu mol/L respectively. The cytotoxicity of Hill - A6 conjugate to target cells was markedly blocked by unconjugated H111 but not by irrelevant monoclonal antibody M3. The H111 - A6 conjugate exhibited 78% inhibition on the growth of hepatoma BEL - 7402 xenografts in nude mice, whereas the equivalent doses of free A6, M3 - A6 conjugate and H111 plus A6 mixture showed approximately 30% inhibition. Histopathological examination showed no toxic changes in the liver, lung, kidney and bone marrow in the H111 - A6 conjugate--treated animals. These results suggest that the conjugate of monoclonal antibody and bleomycin A6 exhibits specific cytotoxicity to target liver cancer cells and the conjugate is highly effective against liver cancer xenografts in nude mice with more marked tumor inhibition than free A6 at comparable dose levels.

Topics: Animals; Antibodies, Monoclonal; Bleomycin; Carcinoma, Hepatocellular; Humans; Immunotoxins; Liver Neoplasms; Male; Mice; Mice, Nude; Neoplasm Transplantation; Pharyngeal Neoplasms; Tumor Cells, Cultured; Tumor Stem Cell Assay

Topics: Animals; Antibiotics, Antineoplastic; Bleomycin; Carcinoma, Hepatocellular; Colony-Forming Units Assay; Humans; Interphase; Liver Neoplasms; Mice; Mice, Nude; Neoplasm Transplantation; Tumor Cells, Cultured; Tumor Stem Cell Assay