In vivo and in vitro antitumor activity of mitomycin C conjugates at 7-N position through a linker containing thiocarbamate bond with CD10 monoclonal antibody.
Through a linker containing thiocarbomate bound to the 7-N position of mitomycin C (MMC), conjugates with a monoclonal antibody to CD10 (NL-1) were prepared, and their antitumor activities were examined. All five conjugates, except one, showed in vitro cytotoxicity to two CD10+ lymphoid cell lines superior to MMC. The conjugate displaying the highest cytotoxicity was selected and further tested against three CD10+ and two CD10- lymphoid cell lines in vitro. The conjugate with NL-1 antibody demonstrated higher cytotoxic activity against CD10+ tumor cells than the control conjugate with normal immunoglobulin, while there was no significant difference, when tested against CD10- tumors. The cytotoxic activity of the NL-1 conjugate to CD10+ tumors was significantly blocked by NL-1 antibody. In vivo antitumor activity of the NL-1 conjugate was then tested against a CD10+ tumor transplanted to nude mice, and side effects were recorded. The NL-1 conjugate (4 mg/kg) showed an in vivo antitumor effect similar to MMC (2 mg/kg), which is at nearly maximal tolerable dose; the latter induced decreases in numbers of leukocytes and platelets, while the former did not, suggesting less side effect by the NL-1 conjugate. Since MMC demonstrates a broad spectrum of antitumor activity, the conjugate, as such, may be applicable for the treatment of cancer patients.
Shida
Y
Y
Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.
Okabe
M
M
Kuroda
T
T
Morimoto
M
M
Ueda
R
R
Takahashi
T
T
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000627:therapeutic use; D000943:Antigens, Differentiation / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000276:immunology*; D007074:Immunoglobulin G / Q000276:immunology; D016393:Lymphoma, B-Cell / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016685:Mitomycin / Q000737:chemistry / Q000627:therapeutic use*; D015260:Neprilysin; D013859:Thiocarbamates / Q000737:chemistry; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D000943:Antigens, Differentiation; D000951:Antigens, Neoplasm; D007074:Immunoglobulin G; D013859:Thiocarbamates; D016685:Mitomycin; D015260:Neprilysin