Antileukemic activity and mechanism of action of cordycepin against terminal deoxynucleotidyl transferase-positive (TdT+) leukemic cells.
The nucleoside analogue cordycepin (3'-deoxyadenosine, 3'-dA) is substantially more cytotoxic to terminal deoxynucleotidyl transferase positive (TdT+) leukemic cells than to TdT leukemic cells in vitro in the presence of an adenosine deaminase inhibitor, deoxycoformycin (dCF), and has been considered as a therapeutic agent for TdT+ leukemia. The intracellular metabolism of 3'-dA was examined with HPLC, and the mechanism of its anti-TdT+ leukemic activity was analyzed. In the presence of dCF (2.5 microM), TdT+ leukemic cells (N = 5) were sensitive to the cytotoxic effect of 3'-dA, whereas TdT (N = 6) cells were not. A high level of 3'-dA-5'-triphosphate (3'-dATP) formation was detected in TdT+ NALM-6 cells (67 pmol/10(6) cells) and TdT- K562 cells (49 pmol/10(6) cells) when cultured with 1 microM [3'-3H]-labeled 3'-dA. A substantial level of 3'-dATP was detected in TdT HUT-102 cells (27 pmol/10(6) cells), whereas the level of 3'-dATP in TdT+ MOLT-4 cells was low (0.3 pmol/10(6) cells). The mean IC50 values of 3'-dA against phytohemagglutinin (PHA)-activated and resting peripheral blood mononuclear cells (PBM) (N = 5) were 8 and 32 microM, respectively. There was a modest level of 3'-dATP (7 pmol/10(6) cells) in PHA-PBM, whereas a lower level of 3'-dATP was detected in resting PBM (2.5 pmol/10(6) cells). These data suggest that the presence of 3'-dATP is not sufficient for the antileukemic effect of 3'-dA, but that TdT positivity is essential, and that PBM are significantly less sensitive to the cytotoxicity of 3'-dA in vitro. Further development of 3'-dA as a potential antileukemic agent to treat patients with TdT+ leukemia is warranted.
Kodama
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Experimental Retrovirology Section, Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
McCaffrey
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Yusa
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Mitsuya
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D000243:Adenosine Deaminase / Q000187:drug effects / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004253:DNA Nucleotidylexotransferase / Q000187:drug effects / Q000378:metabolism*; D003641:Deamination; D003839:Deoxyadenosines / Q000494:pharmacology*; D006801:Humans; D007288:Inosine / Q000031:analogs & derivatives / Q000494:pharmacology; D007938:Leukemia; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D015649:Pentostatin / Q000494:pharmacology; D010766:Phosphorylation; D010835:Phytohemagglutinins / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D003839:Deoxyadenosines; D010835:Phytohemagglutinins; C070014:3'-deoxyinosine; D015649:Pentostatin; D007288:Inosine; D004253:DNA Nucleotidylexotransferase; D000243:Adenosine Deaminase; C058120:cordycepin