title: Blockade of bulky lymphoma-associated CD55 expression by RNA interference overcomes resistance to complement-dependent cytotoxicity with rituximab.
abstract: Recently, anti-CD20 (rituximab) and anti-Her2/neu (trastuzumab) antibodies have been developed and applied to the treatment of malignant lymphoma and breast cancer, respectively. However, bulky lymphoma is known to be resistant to rituximab therapy, and this needs to be overcome. Fresh lymphoma cells were collected from 30 patients with non-Hodgkin's lymphoma, the expression of CD20 and CD55 was examined by flow cytometry, and complement-dependent cytotoxicity (CDC) assays were carried out. Susceptibility to CDC with rituximab was decreased in a tumor size-dependent manner (r=-0.895, P<0.0001), but not in a CD20-dependent manner (r=-0.076, P=0.6807) using clinical samples. One complement-inhibitory protein, CD55, contributed to bulky lymphoma-related resistance to CDC with rituximab. A decrease in susceptibility to CDC with rituximab was statistically dependent on CD55 expression (r=-0.927, P<0.0001) and the relationship between tumor size and CD55 expression showed a significant positive correlation (r=0.921, P<0.0001) using clinical samples. To overcome the resistance to rituximab by high expression of CD55 in bulky lymphoma masses, small interfering RNA (siRNA) was designed from the DNA sequence corresponding to nucleic acids 1-380 of the CD55 cDNA. Introduction of this siRNA decreased CD55 expression in the breast cancer cell line SK-BR3 and in CD20-positive cells of patients with recurrent lymphoma; resistance to CDC was also inhibited. This observation gives us a novel strategy to suppress bulky disease-related resistance to monoclonal antibody treatment.
authors.affiliation: Division of Clinical Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Terui
authors.forename: Takuma
authors.initials: T
authors.lastname: Sakurai
authors.forename: Yuko
authors.initials: Y
authors.lastname: Mishima
authors.forename: Yuji
authors.initials: Y
authors.lastname: Mishima
authors.forename: Natsuhiko
authors.initials: N
authors.lastname: Sugimura
authors.forename: Chino
authors.initials: C
authors.lastname: Sasaoka
authors.forename: Kiyotsugu
authors.initials: K
authors.lastname: Kojima
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yokoyama
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Mizunuma
authors.forename: Shunji
authors.initials: S
authors.lastname: Takahashi
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Ito
authors.forename: Kiyohiko
authors.initials: K
authors.lastname: Hatake
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D058846:Antibodies, Monoclonal, Murine-Derived; D018958:CD55 Antigens / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D003165:Complement System Proteins / Q000187:drug effects* / Q000276:immunology; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology / Q000473:pathology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D000069283:Rituximab
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018958:CD55 Antigens; D034741:RNA, Small Interfering; D000069283:Rituximab; D003165:Complement System Proteins