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Neplanocin A, a potent inhibitor of S-adenosylhomocysteine hydrolase, potentiates granulocytic differentiation of acute promyelocytic leukemia cells induced by all-trans retinoic acid.

Abstract
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.
AuthorsN Niitsu, Y Yamamoto-Yamaguchi, Y Kanatani, S Shuto, A Matsuda, M Umeda, Y Honma
JournalExperimental hematology (Exp Hematol) Vol. 25 Issue 12 Pg. 1296-303 (Nov 1997) ISSN: 0301-472X [Print] Netherlands
PMID9357974 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antibiotics, Antineoplastic
  • Antineoplastic Agents
  • DNA, Neoplasm
  • Enzyme Inhibitors
  • Cytarabine
  • Tretinoin
  • neplanocin A
  • Hydrolases
  • Adenosylhomocysteinase
  • Adenosine
  • Daunorubicin
Topics
  • Adenosine (administration & dosage, analogs & derivatives)
  • Adenosylhomocysteinase
  • Antibiotics, Antineoplastic (pharmacology)
  • Antineoplastic Agents (pharmacology)
  • Cell Cycle (drug effects)
  • Cell Differentiation (drug effects)
  • Cytarabine (pharmacology)
  • DNA, Neoplasm (analysis)
  • Daunorubicin (administration & dosage)
  • Drug Synergism
  • Enzyme Inhibitors (pharmacology)
  • Granulocytes (cytology)
  • Humans
  • Hydrolases (antagonists & inhibitors)
  • Leukemia, Promyelocytic, Acute (pathology)
  • Leukopoiesis (drug effects)
  • Tretinoin (administration & dosage)
  • Tumor Cells, Cultured (drug effects)

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