title: Neutrophil influx and chemokine production during the early phases of the antitumor response to the vascular disrupting agent DMXAA (ASA404).
abstract: 5,6-Dimethylxanthenone-4-acetic acid (DMXAA) acts through tumor vascular disruption and cytokine production and is the first of its class to enter phase 3 trials. We characterized leukocytes and cytokines in murine Colon 38 tumors before and after DMXAA treatment. Tumor mass declined 50% 24 hours after DMXAA administration, but the leukocyte count per gram of tumor increased threefold owing to a large influx of Ly6G(+)CD11b(+)F4/80(-) cells with the morphology of neutrophils. However, B and T lymphocytes, natural killer cells, and macrophages in the tumor all decreased in numbers. Seven chemokines were substantially induced in the tumor, spleen, and serum 4 hours after DMXAA administration. Using cultured spleen cell subpopulations, CD11b(+) cells (largely monocytes and macrophages) were shown to be the primary producers of tumor necrosis factor alpha, interleukin 6 (IL-6), and macrophage inflammatory 1alpha (MIP-1alpha). CD49b(+) natural killer cells produced IP-10, whereas CD45R(+) B lymphocytes produced regulated upon activation normal T cell express sequence. T lymphocytes were not major producers of cytokines in the response to DMXAA. Murine peripheral blood leukocytes (PBLs) produced a similar panel of cytokines in culture to that detected in mouse serum after DMXAA treatment. Cytokines in human PBL cultures were subsequently measured with the aim of identifying potential serum markers of the human response to DMXAA. IP-10 (P < .001), monocyte chemoattractant protein 1 (P < .001), and sCD40L (P < .01) were decreased, whereas IL-8 (P < .001) and MIP-1alpha (P = .03) were increased in DMXAA-treated compared with untreated PBL cultures from a group of 12 donors.
authors: Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand.
authors: Liang-Chuan S
authors: LC
authors: Wang
authors: Lotte
authors: L
authors: Thomsen
authors: Rachel
authors: R
authors: Sutherland
authors: Charu B
authors: CB
authors: Reddy
authors: Sofian M
authors: SM
authors: Tijono
authors: Chun-Jen J
authors: CJ
authors: Chen
authors: Catherine E
authors: CE
authors: Angel
authors: P Rod
authors: PR
authors: Dunbar
authors: Lai-Ming
authors: LM
authors: Ching
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000187:drug effects*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration / Q000187:drug effects*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D044004:Xanthones / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D044004:Xanthones; C066668:vadimezan