Several
adenosine analogs induce the functional and morphological differentiation of myelomonocytic
leukemia cells. They can be classified into two types; i.e., those that do/do not require phosphorylation to induce the differentiation of
leukemia cells.
Neplanocin A, a potent
S-adenosylhomocysteine hydrolase inhibitor, induces the differentiation of some
leukemia cells without phosphorylation. On the other hand,
deoxycoformycin (dCF), a potent
adenosine deaminase inhibitor, also induces the myelomonocytic differentiation of
leukemia cells when it is treated with
deoxyadenosine (dAdo). This differentiation is inhibited by 5'-amino-deoxyadenosine, an inhibitor of (deoxy)
adenosine kinase, suggesting that
kinase-dependent phosphorylation is involved in the differentiation-inducing effect of dCF plus dAdo.
Retinoids induce the differentiation of NB4 cells, a cell line derived from human promyelocytic
leukemia. When used in combination with
all-trans retinoic acid (ATRA), both NPA and dCF plus dAdo greatly enhance the granulocytic differentiation of NB4 cells. This enhancing effect is greatest when the cells are pretreated with NPA and then with ATRA. On the other hand, pre-exposure of NB4 cells to ATRA greatly potentiates the differentiation induced by dCF plus dAdo, while pretreatment with dCF plus dAdo before exposure to ATRA is less effective. The ATRA-induced differentiation of NB4 cells is effectively augmented by clinically applicable concentrations of these analogs. A clinical strategy that combines intermittent treatment with these analogs and a low dose of ATRA may increase the clinical response and decrease the adverse effects of ATRA.