[Suppression of granulopoiesis by vesnarinone]

The effects of vesnarinone (3,4-dihydro-6-[4(3,4-dimethoxybenzoyl)-1-piperanizyl]-2 (1H)-quinolinone) on the hematopoietic precursors in 5 healthy volunteers and leukemic blast progenitors in 11 acute myeloid leukemia (AML) patients, 1 chronic myelocytic leukemia patient (CML) in blast crisis, and 3 leukemic cell lines were studied in methylcellulose and suspension cultures. Normal erythroid precursors (colony-forming unit erythroid: CFU-E and burst-forming unit erythroid: BFU-E) and granulopoietic precursors (colony-forming unit granulocyte/macrophage: CFU-GM) were suppressed in methylcellulose culture by vesnarinone in a dose-dependent manner. Leukemic blast progenitors may replicate themselves and/or undergo terminal divisions with limited differentiation. The plating efficiency of primary blast colony formation (PE1) in methylcellulose, which is considered to reflect the terminal divisions of leukemic blast progenitors, was suppressed by vesnarinone in a dose-dependent manner in all cases tested. The plating efficiency of secondary blast colony-formation (PE2) in methylcellulose culture and the recovery of clonogenic cells in the suspension culture, which are considered to reflect the self-replication function of leukemic blast progenitors, were also suppressed by vesnarinone in a dose-dependent manner in all cases tested. The results suggest that vesnarinone inhibits the growth of normal and leukemic hematopoietic progenitors. To determine the mechanism by which vesnarinone inhibits hematopoiesis, the effect of the agent on apoptosis (programmed cell death) of leukemic cells was studied. DNA ladder formation was recognized in OCI/AML 1 a cells after exposure to 100 micrograms/ml vesnarinone for 18 hours; this means that vesnarinone induced apoptosis in this cell line. Therefore, vesnarinone is considered to be the cause of apoptosis of granulopoietic precursors.