LISOFYLLINE INHIBITS TRANSFORMING GROWTH-FACTOR-BETA RELEASE AND ENHANCES TRILINEAGE HEMATOPOIETIC RECOVERY AFTER 5-FLUOROURACIL TREATMENT IN MICE

The effectiveness of endogenous or exogenously administered colony-sti mulating factors may be modulated by the presence of hematopoietic inh ibitory molecules. Cytotoxic therapy may result in the induction of he matopoietic inhibitors contributing to prolonged myelosuppression, whe reas preventing the induction of such inhibitors may accelerate multil ineage recovery. Lisofylline [LSF; (R)-1-(5-hydroxyhexyl)-3,7, dimethy l-xanthine], inhibits the signaling and/or release of certain hematopo ietic inhibitory molecules such as tumor necrosis factor alpha, macrop hage inflammatory protein 1 alpha, transforming growth factor beta, an d IFN-gamma. Treatment of murine bone marrow cells with the cytotoxic agent 5-fluorouracil (5-FU) results in the release of a nondialyzable inhibitor of progenitor (colony-forming unit-granulocyte macrophage; C FU-GM) proliferation. When murine bone marrow cells were treated with 5-FU plus LSF, release of this inhibitor of CFU-GM proliferation was b locked. Neutralizing antibody and Western blot analysis indicated that the inhibitor was TGF-beta. We tested the effect of LSF (100 mg/kg i. p., b.i.d.) on multilineage regeneration after high-dose 5-FU or thiot epa treatment in BALB/c mice. In 4 of 5 experiments, LSF significantly accelerated neutrophil recovery (P less than or equal to 0.05, Wilcox on paired-signed test). In addition, platelet, reticulocyte, and CFU-G M regeneration were significantly accelerated in mice treated with LSF compared to control mice (P less than or equal to 0.05). LSF had no s ignificant effects on the ability of 5;FU to kill hematopoietic progen itor cells, nor did LSF stimulate or inhibit proliferation of CFU-GM. LSF had no effect on chemotherapy-induced killing of tumor cells ill v itro, nor on the antitumor activity of 5-FU or thiotepa in BALB/c mice implanted with P388 leukemia cells. Inhibition of hematopoietic inhib itor release may accelerate multilineage recovery after cytotoxic ther apy and, as such, may represent an alternative or additional therapy t o the use of positively acting lineage specific colony-stimulating fac tors.