CP-115,953 STIMULATES CYTOKINE PRODUCTION BY LYMPHOCYTES

The cytotoxic quinolone CP-115,953 specifically exerts its inhibitory effect upon eukaryotic topoisomerase II. CP-115,953 stimulates DNA cle avage mediated bg topoisomerase II with a potency approximately 600 ti mes greater than that of ciprofloxacin, a quinolone antibacterial agen t that currently is in clinical use. Because ciprofloxacin has been re ported 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-stimula ted human peripheral blood lymphocytes. For comparison, novobiocin and the antineoplastic drug etoposide were also included in the study. CP -115,953 (25 mu M) enhanced interleukin-2 mRNA levels up to 8-fold and IFN-gamma mRNA concentrations up to 6.5-fold. In contrast, ciprofloxa cin (282 mu M) induced mRNAs for interleukin-2 and IFN-gamma up to 20- fold and 7.8-fold, respectively. However, CP-115,953 showed more prolo nged kinetics of IFN-gamma mRNA production than ciprofloxacin. At high concentrations (greater than or equal to 141 mu M), 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 (less than or equal to 25 mu M) was more potent than ciprofloxacin in inducing interleukin-2 and IF N-gamma synthesis. Etoposide or novobiocin did not influence cytokine mRNA expression. Thus, among the topoisomerase II inhibitors tested, f luoroquinolones are unique in stimulating cytokine synthesis in lympho cyte cultures.