Lisofylline suppresses ex vivo release by murine spleen cells of hematopoietic inhibitors induced by cancer chemotherapeutic agents

Objective. Many cytotoxic cancer therapeutic drugs activate stress response signaling pathways that transcriptionally activate a variety of genes. We decided to determine if cytotoxic therapies induce inflammatory cytokines w ith inhibitory effects on hematopoiesis and if lisofylline (LSF), a novel a ntiinflammatory compound, suppresses this induction. Materials and Methods. Mice were treated with cytosine beta-d-arabinofurano side (AraC), cisplatinum(II)diammine-dichloride (CisP), etoposide (VF-16), or melphalan at clinically relevant doses, with or without LSF, Results. Spleen cell conditioned media (CM) derived from mice treated with cytotoxic agents, but not from control or LSF treated mice, reduced colony formation by murine hone marrow progenitors belonging to the myeloid, eryth roid, megakaryocytic, and beta-lymphoid lineages, LSF (100 mg/kg), administ ered either simultaneously with or up to 48 hours before the cytotoxic agen ts, suppressed the release of this inhibitory activity. Treatment of inhibi tory Chi with neutralizing antibodies against known growth inhibitory cytok ines, including tumor necrosis factor alpha, transforming growth factor bet a, and macrophage inflammatory protein-1 alpha, resulted in enhanced colony growth. Conclusion. We conclude that treatment of mice with chemotherapeutic drugs induces the ex vivo production of multilineage hematopoietic inhibitors and that induction of these Inhibitors could be abrogated by treatment with LS F. These findings suggest a mechanism whereby I,SF can accelerate recovery of hematopoiesis following cytotoxic therapies, (C) 2000 International Soci ety for Experimental Hematology. Published by Elsevier Science.