title: Stromal cells in bone marrow play important roles in pro-inflammatory cytokine secretion causing fever following bortezomib administration in patients with multiple myeloma.
abstract: Bortezomib blocks the activation of nuclear factor-kappaB-mediated pro-inflammatory cytokines, however, systemic inflammatory symptoms following bortezomib administration have been reported, although their mechanisms remain elusive. Serum samples were obtained from five patients, who participated in a phase I/II study of Japanese patients with relapsed or refractory multiple myeloma (MM), and developed cyclic fever following bortezomib administration, to measure cytokine levels. Significant correlations between interleukin (IL)-6 or interferon (IFN)-gamma and the body temperature were observed in two patients each. Furthermore, we found that IL-6 elevation was not observed after the addition of bortezomib to any examined MM cells alone, but was noted in a case of bone marrow stromal cells (BMSCs) of macrophage origin alone or co-cultured with MM cells. Similarly, a marked increase in IFN-gamma levels was induced by adding bortezomib to BMSCs of fibroblast origin. Although this investigation was a preliminary study with a small number of patients, our results suggested that pro-inflammatory cytokines causing bortezomib-associated fever were secreted from BMSCs rather than MM cells.
authors.affiliation: Hematology and Stem Cell Transplantation Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Dai
authors.initials: D
authors.lastname: Maruyama
authors.affiliation: Hematology and Stem Cell Transplantation Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. takawata@ncc.go.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Hematology and Stem Cell Transplantation Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Heike
authors.affiliation: Hematology and Stem Cell Transplantation Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Nagase
authors.affiliation: Hematology and Stem Cell Transplantation Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Takahashi
authors.affiliation: Hematology and Stem Cell Transplantation Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamasaki
authors.affiliation: Hematology and Stem Cell Transplantation Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Fusako
authors.initials: F
authors.lastname: Waki
authors.affiliation: Hematology and Stem Cell Transplantation Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yokoyama
authors.affiliation: Hematology and Stem Cell Transplantation Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Sung-Won
authors.initials: SW
authors.lastname: Kim
authors.affiliation: Hematology and Stem Cell Transplantation Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kobayashi
authors.affiliation: Department of Functional Morphology, Nihon University School of Medicine, Tokyo, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Aizawa
authors.affiliation: Hematology and Stem Cell Transplantation Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Kensei
authors.initials: K
authors.lastname: Tobinai
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D001854:Bone Marrow Cells / Q000378:metabolism*; D001897:Boronic Acids / Q000008:administration & dosage / Q000009:adverse effects*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D016207:Cytokines / Q000097:blood* / Q000378:metabolism; D005260:Female; D005334:Fever / Q000097:blood* / Q000139:chemically induced*; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood*; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000097:blood* / Q000188:drug therapy; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects*; D017154:Stromal Cells / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D016207:Cytokines; D018836:Inflammation Mediators; D011719:Pyrazines; D000069286:Bortezomib