Enhanced antitumor activity of a combination treatment with a mouse/human chimeric anti-MK-1 antibody and lymphokine-activated killer cells in vitro and in a severe combined immunodeficient mouse xenograft model |
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| Authors: | Takafumi Yamamoto Fumiko Arakawa Ken Nakamura Tarumi Senba Yoshihiro Tomita Seiyo Ikeda Masahide Kuroki |
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| Institution: | (1) First Department of Biochemistry, School of Medicine, Fukuoka University, 7-45-1, Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan e-mail: kurokima@fukuoka-u.ac.jp Tel.: +81-92-801-1011 (ext. 3240) Fax: +81-92-801-3600, JP;(2) First Department of Surgery, School of Medicine, Fukuoka University, 7-45-1, Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan, JP |
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| Abstract: | Mouse monoclonal antibody FU-MK-1, raised against a human gastric adenocarcinoma, recognizes a glycoprotein antigen (termed
MK-1 antigen) present on most carcinomas and seems to be valuable in immunodiagnosis and immunotherapy of various cancers.
In a recent study, we constructed a mouse/human chimeric antibody, designated Ch FU-MK-1, by fusing the FU-MK-1 VH and Vκ genes to the human Cγ1 and Cκ genes, respectively. In the present study, we tested combination immunotherapy of Ch
FU-MK-1 with human lymphokine-activated killer (LAK) cells in vitro and in mice with severe combined immunodeficiency (SCID)
bearing human MK-1-expressing tumors. In in vitro experiments, Ch FU-MK-1 effectively mediated antibody-dependent cell-mediated
cytotoxicity (ADCC) against MK-1-expressing MKN-74 cells, which was completely blocked by an anti-FcR antibody. Since the
apoptotic pathway as well as the necrotic pathway have been shown to be utilized in various cytotoxic effector mechanisms,
we investigated the role of apoptosis in ADCC mediated by LAK cells and Ch FU-MK-1 against MKN-74 cells. The implication of
the apoptosis during ADCC was demonstrated by means of both a terminal-deoxynucleotidyltransferase-mediated dUTP-biotin nick-end-labeling
assay and a propidium iodide staining method. In vivo antitumor activity of combination treatment with LAK cells and Ch FU-MK-1
was estimated using SCID mice inoculated s.c. with MKN-74 cells. The i.v. administration of LAK cells and i.p. administration
of Ch FU-MK-1 and interleukin-2 (IL-2) produced a marked growth inhibition of MKN-74 tumors in SCID mice. When the actual
tumor weights were measured 16 days after initiation of treatment, more than 70% reduction was observed in the group receiving
LAK cells plus Ch FU-MK-1 plus IL-2 as compared to the control untreated group. Together these results suggest that Ch FU-MK-1
may serve as a potentially useful immunotherapeutic reagent for human MK-1-expressing tumors.
Received: 27 November 1998 / Accepted: 23 February 1999 |
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| Keywords: | Immunotherapy MK-1 antigen Chimeric antibody ADCC Apoptosis |
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