A novel therapeutic strategy against monocytic leukemia with deoxyadenosine analogs and adenosine deaminase inhibitors.
The adenosine deaminase inhibitor 2'-deoxycoformycin (dCF) significantly inhibits the proliferation of leukemia and lymphoma cells in the presence of either 2'-deoxyadenosine (dAdo) or its analog adenine arabinoside (araA). The concentration of dCF required to induce apoptosis of monocytoid leukemia cells is much lower than that required for myeloid, erythroid, or lymphoma cells. dATP effectively induces caspase-3 activation in cytosol from monocytoid cells, but not in that from non-monocytoid cells, suggesting that dATP-dependent caspase-3 activation is involved in the preferential induction of apoptosis in monocytoid leukemia cells. Athymic nude mice inoculated with human monocytoid leukemia U937 cells show significantly prolonged survival following combined treatment with dCF and araA. The clinical usefulness of the combination of adenosine deaminase inhibitor and dAdo analog is discussed.
Honma
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Saitama Cancer Center Research Institute, Ina, Japan. honma@cancer-c.pref.saitama.jp
D058892:Adenosine Deaminase Inhibitors; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D003839:Deoxyadenosines / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000473:pathology
D058892:Adenosine Deaminase Inhibitors; D003839:Deoxyadenosines; D004791:Enzyme Inhibitors