muramidase and vesnarinone

It has been reported that vesnarinone, a new inotropic agent used in the treatment of cardiac failure, causes agranulocytosis as a side effect. To study the mechanisms by which this complication occurs, vesnarinone was introduced into a coculture system of HL60 and bone marrow (BM) stromal cells, in which HL60 cells were able to differentiate into mature granulocytes with no inducible exogenous factors added to the culture. When HL60 cells were cocultured with the human BM-derived stromal cell line LP101, HL60 cells were induced to differentiate into mature granulocytes, and expression of the mature granulocyte-macrophage surface antigen, CD11b was increased. Conditioned medium (CM) obtained from LP101 cells also showed the capacity to induce the maturation of HL60 cells, in a dose- and time-dependent manner. The differentiation of HL60 cells induced by CM was also determined by morphological analysis, expression of myeloperoxidase, and a nitroblue tetrazolium (NBT) reduction test. When HL60 cells were cocultured with LP101 in the presence of vesnarinone, the CD11b expression was greatly suppressed. CM obtained from vesnarinone-treated LP101 (ves-CM) lost the capacity to induce the differentiation of HL60 cells, at a concentration of 1 microg/mL of vesnarinone. Vesnarinone itself did not affect the proliferation of HL60 cells. Furthermore, the addition of vesnarinone or ves-CM to HL60 cultures incubated with CM did not alter the induction of CD11b expression, suggesting that vesnarinone has no effect on HL60 cells, but that it inhibits stromal cells from producing soluble factor(s) required for the differentiation of HL60 cells to mature granulocytes. All these findings indicate that vesnarinone causes the hematopoietic disorder agranulocytosis, via impairment of stromal function.

Topics: Bone Marrow; Bone Marrow Cells; Cardiotonic Agents; Cell Differentiation; Cell Division; Cells, Cultured; Gene Expression; HL-60 Cells; Humans; Macrophage-1 Antigen; Muramidase; Oxidation-Reduction; Peroxidase; Pyrazines; Quinolines

We examined the effect of vesnarinone, an oral cardiotonic, on the growth and differentiation of human myeloid leukemia cells. Vesnarinone alone markedly induced erythroid differentiation of HEL cells. All-trans-retinoic acid also induced erythroid differentiation of the cells, and the differentiation was greatly enhanced by combined treatment with vesnarinone and retinoic acid. HEL cells are highly resistant to some anticancer drugs, including vincristine, but treatment with vesnarinone greatly increased the sensitivity of HEL cells to vincristine. Enhancement of vincristine sensitivity by vesnarinone was not as significant for other leukemia cells. Expression of P-glycoprotein in HEL cells was effectively inhibited by vesnarinone, suggesting that the restoration of vincristine sensitivity is associated with decrease of P-glycoprotein expression in HEL cells. The plasma level of vesnarinone required to induce differentiation of leukemia cells is 30 micrograms/mL, which could be achieved with oral administration. These results suggest that vesnarinone should be useful in differentiation therapy for some types of myelogenous leukemia.

Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Calcium; Cardiotonic Agents; Cell Differentiation; Drug Interactions; Drug Resistance; Humans; Leukemia, Erythroblastic, Acute; Leukemia, Myeloid; Muramidase; Pyrazines; Quinolines; Stimulation, Chemical; Tretinoin; Tumor Cells, Cultured; Vincristine