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 mu M), 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 mu M [3'-H-3]-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 Ic(50) values of 3'-dA against phytohemagglutinin (PHA)-activated and resting peripheral blood mononuclear cells (PBM) (N = 5) were 8 and 32 mu M, 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. (C) 1999 Elsevier Science Inc.