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 with inhibitory effects on hematopoiesis and if lisofylline (LSF), a novel antiinflammatory compound, suppresses this induction. Materials and Methods. Mice were treated with cytosine beta-d-arabinofuranoside (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, erythroid, megakaryocytic, and beta-lymphoid lineages, LSF (100 mg/kg), administered either simultaneously with or up to 48 hours before the cytotoxic agents, suppressed the release of this inhibitory activity. Treatment of inhibitory Chi with neutralizing antibodies against known growth inhibitory cytokines, including tumor necrosis factor alpha, transforming growth factor beta, 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 LSF. These findings suggest a mechanism whereby I,SF can accelerate recovery of hematopoiesis following cytotoxic therapies, (C) 2000 International Society for Experimental Hematology. Published by Elsevier Science.