title: Lisofylline suppresses ex vivo release by murine spleen cells of hematopoietic inhibitors induced by cancer chemotherapeutic agents.
abstract: 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. Mice were treated with cytosine beta-d-arabinofuranoside (AraC), cis-platinum(II)diammine-dichloride (CisP), etoposide (VP-16), or melphalan at clinically relevant doses, with or without LSF. 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 bone marrow progenitors belonging to the myeloid, erythroid, megakaryocytic, and B-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 CM with neutralizing antibodies against known growth inhibitory cytokines, including tumor necrosis factor alpha, transforming growth factor beta, and macrophage inflammatory protein-1alpha, resulted in enhanced colony growth. 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 LSF can accelerate recovery of hematopoiesis following cytotoxic therapies.
authors.affiliation: Cell Therapeutics, Inc., Seattle, WA 98119, USA. pdevries@ctiseattle.com
authors.forename: P
authors.initials: P
authors.lastname: de Vries
authors.forename: J W
authors.initials: JW
authors.lastname: Singer
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000906:Antibodies / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects; D002455:Cell Division; D054407:Chemokine CCL4; D002945:Cisplatin / Q000494:pharmacology; D003114:Colony-Forming Units Assay; D017077:Culture Media, Conditioned; D003561:Cytarabine / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D006131:Growth Inhibitors / Q000276:immunology / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects; D019402:Macrophage Inflammatory Proteins / Q000494:pharmacology; D008558:Melphalan / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D010431:Pentoxifylline / Q000031:analogs & derivatives* / Q000494:pharmacology*; D013154:Spleen / Q000187:drug effects* / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000906:Antibodies; D000970:Antineoplastic Agents; D054407:Chemokine CCL4; D017077:Culture Media, Conditioned; D006131:Growth Inhibitors; D019402:Macrophage Inflammatory Proteins; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D003561:Cytarabine; D005047:Etoposide; C025189:lisofylline; D002945:Cisplatin; D008558:Melphalan; D010431:Pentoxifylline