NEPLANOCIN-A, A POTENT INHIBITOR OF S-ADENOSYLHOMOCYSTEINE HYDROLASE,POTENTIATES GRANULOCYTIC DIFFERENTIATION OF ACUTE PROMYELOCYTIC LEUKEMIA-CELLS INDUCED BY ALL-TRANS-RETINOIC ACID

Several neplanocin A analogs were synthesized and their growth-inhibit ing and differentiation-inducing activities on myelogenous leukemia ce lls were examined. An adenosine kinase-ineffective analog of neplanoci n A was effective in inducing differentiation, suggesting that phospho rylation of the nucleoside is not essential for inducing the different iation of leukemia cells. Neplanocin A induced functional and morpholo gical differentiation of HL-60 cells, but did not effectively induce d ifferentiation of NB4, a cell line derived from a leukemia patient wit h t(15;17). However, these cells have been known to undergo granulocyt ic differentiation upon treatment with all-trans retinoic acid (ATRA), and are used as a model for differentiation therapy in acute promyelo cytic leukemia. Preexposure of NB4 cells to low concentrations of nepl anocin A greatly enhanced the ATRA-induced differentiation of the cell s, whereas representative antileukemic drugs such as cytosine arabinos ide and daunomycin did not enhance this differentiation. A clinical st rategy that combines intermittent treatment with neplanocin A analogs and a low dose of ATRA may increase the clinical response and decrease the adverse effects of ATRA.