title: CP-115,953 stimulates cytokine production by lymphocytes.
abstract: The cytotoxic quinolone CP-115,953 specifically exerts its inhibitory effect upon eukaryotic topoisomerase II. CP-115,953 stimulates DNA cleavage mediated by topoisomerase II with a potency approximately 600 times greater than that of ciprofloxacin, a quinolone antibacterial agent that currently is in clinical use. Because ciprofloxacin has been reported to strongly enhance interleukin-2 production, we considered it important to study the effect of CP-115,953 on interleukin-2 and gamma interferon (IFN-gamma) mRNA and protein expression in mitogen-stimulated human peripheral blood lymphocytes. For comparison, novobiocin and the antineoplastic drug etoposide were also included in the study. CP-115,953 (25 microM) enhanced interleukin-2 mRNA levels up to 8-fold and IFN-gamma mRNA concentrations up to 6.5-fold. In contrast, ciprofloxacin (282 microM) induced mRNAs for interleukin-2 and IFN-gamma up to 20-fold and 7.8-fold, respectively. However, CP-115,953 showed more prolonged kinetics of IFN-gamma mRNA production than ciprofloxacin. At high concentrations (> or = 141 microM), ciprofloxacin was a greater inducer of interleukin-2 production and exhibited a higher level of stimulatory action than CP-115,953 on IFN-gamma synthesis. At low concentrations, however, CP-115,953 (< or = 25 microM) was more potent than ciprofloxacin in inducing interleukin-2 and IFN-gamma synthesis. Etoposide or novobiocin did not influence cytokine mRNA expression. Thus, among the topoisomerase II inhibitors tested, fluoroquinolones are unique in stimulating cytokine synthesis in lymphocyte cultures.
authors.affiliation: Department of Medical Microbiology, Lund University, Malmö General Hospital, Sweden.
authors.forename: K
authors.initials: K
authors.lastname: Riesbeck
authors.forename: A
authors.initials: A
authors.lastname: Forsgren
mesh_terms: D000890:Anti-Infective Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D004249:DNA Damage; D005047:Etoposide / Q000494:pharmacology; D024841:Fluoroquinolones; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000187:drug effects; D009675:Novobiocin / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D013936:Thymidine / Q000378:metabolism; D059005:Topoisomerase II Inhibitors
chemical_list: D000890:Anti-Infective Agents; D016207:Cytokines; D024841:Fluoroquinolones; D007376:Interleukin-2; D015363:Quinolones; D012333:RNA, Messenger; D059005:Topoisomerase II Inhibitors; C070116:CP 115953; D009675:Novobiocin; D005047:Etoposide; D007371:Interferon-gamma; D013936:Thymidine