Antileukemic activity and mechanism of action of cordycepin against terminal deoxynucleotidyl transferase-positive (TdT+) leukemic cells

Eiichi N. Kodama, Ronald P. McCaffrey, Keisuke Yusa, Hiroaki Mitsuya

研究成果: Article査読

103 被引用数 (Scopus)

抄録

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 μM), 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/106 cells) and TdT- K562 cells (49 pmol/106 cells) when cultured with 1 μM [3'-3H]- labeled 3'-dA. A substantial level of 3'-dATP was detected in TdT- HUT-102 cells (27 pmol/106 cells), whereas the level of 3'-dATP in TdT+ MOLT-4 cells was low (0.3 pmol/106 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 μM, respectively. There was a modest level of 3'-dATP (7 pmol/106 cells) in PHA-PBM, whereas a lower level of 3'-dATP was detected in resting PBM (2.5 pmol/106 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.

本文言語English
ページ(範囲)273-281
ページ数9
ジャーナルBiochemical Pharmacology
59
3
DOI
出版ステータスPublished - 2000 2 1
外部発表はい

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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