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DIFFERENTIAL ANTIPROLIFERATIVE ACTIONS OF 2′,5′ OLIGO A TRIMER CORE AND ITS CORDYCEPIN ANALOGUE ON HUMAN TUMOR CELLS
Author(s) -
HUBBELL Howard R.,
PEQUIGNOT Edward C.,
WILLIS David H.,
LEE Choongeun,
SUHADOLNIK Robert J.
Publication year - 1985
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.1985.36.3.389
Subject(s) - cordycepin , adenosine , deoxycoformycin , adenosine deaminase inhibitor , intracellular , cell culture , deoxyadenosine , chemistry , adenosine deaminase , biochemistry , prodrug , nucleoside , microbiology and biotechnology , biology , genetics
The antiproliferative effect of 2′, 5′A 3 core and 2′5′‐3′dA 3 (cordycepin trimer) core was measured in 8 human tumor cell lines. Cells were treated in a dose‐response manner for 72 hr and the concentration of drug necessary to inhibit cell growth 50% (Gl 50 ) was determined. A wide range of sensitivities to these drugs was found, even among tumors of the same histological type. The cell lines showed different sensitivities and dose‐response curves to the 2′, 5′A 3 and 2′, 5′‐3′dA 3 cores. Uptake studies of the 2′,5′A 3 and 2′,5′‐3′ dA 3 cores, using high‐pressure liquid chromatography , demonstrated that both cores were rapidly degraded in the tissue culture medium and taken up as adenosine or cordycepin, respectively. There was a direct correlation between the uptake of cordycepin and the antiproliferative effect . In contrast, there was no correlation between cell sensitivity and the uptake of the 2′,5′A 3 core degradation products. Analysis of intracellular nucleosides and nucleotides indicated that differences in intracellular metabolism of adenosine might explain the different sensitivities of the various cell lines to 2′,5′A 3 core. Molar equivalent concentrations of adenosine and cordycepin inhibited cell growth; however, equimolar concentrations of these nucleosides were not effective. In addition, the anti‐proliferative effect of both core compounds and their corresponding nucleosides could be potentiated by the addition of the adenosine deaminase inhibitor, deoxycoformycin . The results indicate that these cores act prodrugs and that the active metabolites are their corresponding nucleosides.