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-inhibiting and differentiation-inducing activities on myelogenous leukemia cells were examined. An adenosine kinase-ineffective analog of neplanocin A was effective in inducing differentiation, suggesting that phosphorylation of the nucleoside is not essential for inducing the differentiation of leukemia cells. Neplanocin A induced functional and morphological differentiation of HL-60 cells, but did not effectively induce differentiation of NB4, a cell line derived from a leukemia patient with t(15;17). However, these cells have been known to undergo granulocytic differentiation upon treatment with all-trans retinoic acid (ATRA), and are used as a model for differentiation therapy in acute promyelocytic leukemia. Preexposure of NB4 cells to low concentrations of neplanocin A greatly enhanced the ATRA-induced differentiation of the cells, whereas representative antileukemic drugs such as cytosine arabinoside and daunomycin did not enhance this differentiation. A clinical strategy 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.
Niitsu
N
N
Department of Chemotherapy, Saitama Cancer Center Research Institute, Ina, Japan.
Yamamoto-Yamaguchi
Y
Y
Kanatani
Y
Y
Shuto
S
S
Matsuda
A
A
Umeda
M
M
Honma
Y
Y
D000241:Adenosine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D043383:Adenosylhomocysteinase; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D003561:Cytarabine / Q000494:pharmacology; D004273:DNA, Neoplasm / Q000032:analysis; D003630:Daunorubicin / Q000008:administration & dosage; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006098:Granulocytes / Q000166:cytology*; D006801:Humans; D006867:Hydrolases / Q000037:antagonists & inhibitors*; D015473:Leukemia, Promyelocytic, Acute / Q000473:pathology*; D019891:Leukopoiesis / Q000187:drug effects; D014212:Tretinoin / Q000008:administration & dosage*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D003561:Cytarabine; D014212:Tretinoin; C031096:neplanocin A; D006867:Hydrolases; D043383:Adenosylhomocysteinase; D000241:Adenosine; D003630:Daunorubicin