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 differentiation of promyelocytic leukemia cells, but frequently induce hyperleukocytosis and pulmonary leakage syndrome. Employing pentoxifylline (PTX), a phosphodiesterase inhibitor which could raise intracellular cAMP and modulate leukocyte activation, we sought to investigate if PTX could enhance tRA-induced promyelocytic leukemic cell differentiation but suppress tRA-augmented growth and activation of human granulocytes. 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-induced growth inhibition and differentiation of promyelocytic HL-60 leukemic cells, but suppressed respiratory burst activation by the immature granulocytic HL-60 cells and suppressed CD11b adhesion molecule expression by mature granulocytes. PTX similar to dibutyric cAMP promoted HL-60 myelocytic leukemic cell differentiation and growth inhibition, whereas PTX, in contrast to dibutyric cAMP which could augment phorbol myristate acetate (PMA)-elicited respiratory burst activity by immature granulocytes, suppressed the PMA-elicited respiratory burst activity by immature and mature granulocytes. PTX did not raise the intracellular cAMP level of HL-60 cells, but partly suppressed the dibutyric cAMP-elicited elevation of intracellular cAMP level. Results from these studies suggest that PTX might act through different signaling pathways to enhance tRA-induced myelocytic leukemic cell differentiation but prevent from hyperreactive normal granulopoiesis and granulocyte activation.