PENTOXIFYLLINE SYNERGIZES WITH ALL-TRANS-RETINOIC ACID TO INDUCE DIFFERENTIATION OF HL-60 MYELOCYTIC CELLS, BUT SUPPRESSES TRA-AUGMENTED CLONAL GROWTH OF NORMAL CFU-GM

All-trans retinoic acid (tRA) has been shown to promote terminal diffe rentiation of promyelocytic leukemia cells, but frequently induce hype rleukocytosis and pulmonary leakage syndrome. Employing pentoxifylline (PTX), a phosphodiesterase inhibitor which could raise intracellular cAMP and modulate leukocyte activation, we sought to investigate if PT X could enhance tRA-induced promyelocytic leukemic cell differentiatio n but suppress tRA-augmented growth and activation of human granulocyt es, tRA could significantly suppress clonal. growth of U937 and HL-60 leukemic cells but enhanced the CFU-GM formation of normal bone marrow cells (22 +/- 6 vs. 90 +/- 16 CFU/ well). PTX significantly augmented tRA suppression of clonal growth of U937 and HL-60 leukemic cells but suppressed tRA-augmented CFU-GM formation of normal bone marrow cells (90 +/- 16 vs. 25 +/- 9 CFU/well). In addition, PTX enhanced tRA-indu ced growth inhibition and differentiation of promyelocytic HL-60 leuke mic cells, but suppressed respiratory burst activation by the immature granulocytic HL-60 cells and suppressed CD11b adhesion molecule expre ssion by mature granulocytes. PTX similar to dibutyric cAMP promoted H L-60 myelocytic leukemic cell differentiation and growth inhibition, w hereas PTX, in contrast to dibutyric cAMP which could augment phorbol myristate acetate (PMA)-elicited respiratory burst activity by immatur e granulocytes, suppressed the PMA-elicited respiratory burst activity by immature and mature granulocytes. PTX did not raise the intracellu lar cAMP level of HL-60 cells, but partly suppressed the dibutyric cAM P-elicited elevation of intracellular cAMP level. Results from these s tudies suggest that PTX might act through different signaling pathways to enhance tRA-induced myelocytic leukemic cell differentiation but p revent from hyperreactive normal granulopoiesis and granulocyte activa tion.