title: A humanized anti-CD26 monoclonal antibody inhibits cell growth of malignant mesothelioma via retarded G2/M cell cycle transition.
abstract: BACKGROUND
  Malignant Mesothelioma (MM) is a highly aggressive tumor with poor prognosis. Multimodal treatments and novel molecular targeted therapies against MM are in high demand in order treat this disease effectively. We have developed a humanized monoclonal antibody YS110 against CD26 expressed in 85 % of MM cases. CD26 is thought to be involved in tumor growth and invasion by interacting with collagen and fibronectin, or affecting signal transduction processes.
  
  
  METHODS
  We evaluated the direct anti-tumor effect of YS110 against MM cell lines, NCI-H2452 and JMN, and investigated its effects on cell cycle and on the cell cycle regulator molecules. In addition, we investigated synergistic effects of YS110 and anti-tumor agent pemetrexed (PMX) against MM cell line both in vitro and in vivo.
  
  
  RESULTS
  YS110 suppressed the proliferation of NCI-H2452 cells by approximately 20 % in 48 h. Based on cell cycle analysis, percentage of cells in G2/M phase increased 8.0 % on the average after YS110 treatment; in addition, cell cycle regulator p21 cip/waf1 was increased and cyclin B1 was decreased after YS110 treatment. Inhibitory phosphorylation of both cdc2 (Tyr15) and cdc25C (Ser216) were elevated. Furthermore, activating phosphorylation of p38 MAPK (Thr180/Tyr182) and ERK1/2 (Thr202/Tyr204) were augmented at 24 h after YS110 treatment. PMX rapidly induced CD26 expression on cell surface and the treatment with both YS110 and PMX inhibited in vivo tumor growth accompanied by a synergistic reduction in the MIB-1 index.
  
  
  CONCLUSIONS
  This is a first report of a novel anti-proliferative mechanism of the humanized anti-CD26 monoclonal antibody YS110, which resulted in G2/M cell cycle delay through regulation of quantity and activity of various cell cycle regulating molecules.
authors.affiliation: Department of Pathology, Keio University School of Medicine, 35 Shinanomachi, Tokyo, Shinjuku-ku 160-8582 Japan ; Department of Pediatrics, Keio University School of Medicine, 35 Shinanomachi, Tokyo, Shinjuku-ku 160-8582 Japan.
authors.forename: Mutsumi
authors.initials: M
authors.lastname: Hayashi
authors.affiliation: Department of Pathology, Keio University School of Medicine, 35 Shinanomachi, Tokyo, Shinjuku-ku 160-8582 Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Madokoro
authors.affiliation: Laboratory of Nuclear Transport Dynamics, National Insititute of Biomedical Innovation, 7-6-8 Saito-Asagi, Ibaraki City, Osaka Prefecture 567-0085 Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Yamada
authors.affiliation: Department of Pathology, Keio University School of Medicine, 35 Shinanomachi, Tokyo, Shinjuku-ku 160-8582 Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Nishida
authors.affiliation: Department of Therapy Development and Innovation for Immune Disorders and Cancers, Juntendo University, 2-1-2 Hongo, Tokyo, Bunkyo-ku 113-8421 Japan.
authors.forename: Chikao
authors.initials: C
authors.lastname: Morimoto
authors.affiliation: Department of Pathology, Keio University School of Medicine, 35 Shinanomachi, Tokyo, Shinjuku-ku 160-8582 Japan.
authors.forename: Michiie
authors.initials: M
authors.lastname: Sakamoto
authors.affiliation: Department of Pathology, Keio University School of Medicine, 35 Shinanomachi, Tokyo, Shinjuku-ku 160-8582 Japan ; Department of Pathology, Saitama Medical University, 38 Morohongo, Saitama, Moroyama-machi 350-0495 Japan.
authors.forename: Taketo
authors.initials: T
authors.lastname: Yamada
keywords: CD26; G2/M transition; Mesothelioma; Monoclonal antibody; Pemetrexed