title: Lipopolysaccharide-Induced CXCL10 mRNA Level and Six Stimulant-mRNA Combinations in Whole Blood: Novel Biomarkers for Bortezomib Responses Obtained from a Prospective Multicenter Trial for Patients with Multiple Myeloma.
abstract: To identify predictive biomarkers for clinical responses to bortezomib treatment, 0.06 mL of each whole blood without any cell separation procedures was stimulated ex vivo using five agents, and eight mRNAs were quantified. In six centers, heparinized peripheral blood was prospectively obtained from 80 previously treated or untreated, symptomatic multiple myeloma (MM) patients with measurable levels of M-proteins. The blood sample was procured prior to treatment as well as 2-3 days and 1-3 weeks after the first dose of bortezomib, which was intravenously administered biweekly or weekly, during the first cycle. Six stimulant-mRNA combinations; that is, lipopolysaccharide (LPS)-granulocyte-macrophage colony-stimulating factor (GM-CSF), LPS-CXCL chemokine 10 (CXCL10), LPS-CCL chemokine 4 (CCL4), phytohemagglutinin-CCL4, zymosan A (ZA)-GMCSF and ZA-CCL4 showed significantly higher induction in the complete and very good partial response group than in the stable and progressive disease group, as determined by both parametric (t-test) and non-parametric (unpaired Mann-Whitney test) tests. Moreover, LPS-induced CXCL10 mRNA expression was significantly suppressed 2-3 days after the first dose of bortezomib in all patients, as determined by both parametric (t-test) and non-parametric (paired Wilcoxon test) tests, whereas the complete and very good partial response group showed sustained suppression 1-3 weeks after the first dose. Thus, pretreatment LPS-CXCL10 mRNA and/or the six combinations may serve as potential biomarkers for the response to bortezomib treatment in MM patients.
authors.affiliation: Hematology Division, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Hitachi Chemical Research Center, Inc., Irvine, California, United States of America.
authors.forename: Masato
authors.initials: M
authors.lastname: Mitsuhashi
authors.affiliation: Department of Hematology, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan.
authors.forename: Morihiko
authors.initials: M
authors.lastname: Sagawa
authors.affiliation: Department of Medical Oncology and Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Ri
authors.affiliation: Department of Hematology, Japanese Red Cross Medical Center, Tokyo, Japan.
authors.forename: Kenshi
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Department of Hematology, Endocrinology and Metabolism Instutute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Abe
authors.affiliation: Division of Hematology/Oncology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Ohmachi
authors.affiliation: Department of Hematology, Japanese Red Cross Medical Center, Tokyo, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Nakagawa
authors.affiliation: Department of Hematology, Endocrinology and Metabolism Instutute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Shingen
authors.initials: S
authors.lastname: Nakamura
authors.affiliation: Hematology Division, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Mizuki
authors.initials: M
authors.lastname: Chosa
authors.affiliation: Department of Medical Oncology and Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Iida
authors.affiliation: Department of Hematology, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kizaki
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D015415:Biomarkers; D000069286:Bortezomib / Q000494:pharmacology / Q000627:therapeutic use; D054407:Chemokine CCL4 / Q000235:genetics; D054357:Chemokine CXCL10 / Q000097:blood / Q000235:genetics*; D002986:Clinical Trials as Topic; D005260:Female; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D054407:Chemokine CCL4; D054357:Chemokine CXCL10; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D000069286:Bortezomib