MECHANISMS RESPONSIBLE FOR RESISTANCE OF SUBLINES DERIVED FROM LEUKEMIA-CELL LINES TO AN ANTITUMOR AGENT 9-BETA-D-ARABINOFURANOSYL-2-FLUOROADENINE

An agent 9-beta-D-arabinofuranosyl-2-fluoroadenine (2-F-Ara-A) is a ma in metabolite of fludarabine, a fluorinated purine analogue with antit umor activity in lymphoproliferative malignancies. In,this study, the mechanism responsible for the resistance of cancer cells to fludarabin e was examined using the 2-F-Ara-A-resistant sublines JOK-1/F-Ara-A an d L1210/F-Ara-A from a human hairy leukemic cell line (JOK-1) and a mo use leukemic cell line (L1210) respectively, which were established by continuous treatment of the parental cell lines with 2-F-AraA. JOK-1/ F-Ara-A and L1210/F-Ara-A cells were more than 55 and 29 times more re sistant to 2-F-Ara-A than were their parent cell lines, and showed a h igh cross-resistance to 1-beta-D-arabinofuranosylcytosine but not to d oxorubicin or vincristine. These resistant sublines intracellularly ac cumulated almost the same amount of 2-F-Ara-A as did their parent cell lines. However, the amount of 2-F-Ara-ATP, a cytotoxic metabolite of 2-F-Ara-A, decreased by 2.6% (JOK-1/F-Ara-A C3), 6% (L1210/F-Ara-A C1) and 3.7% (L1210/F-Ara-A. C7) relative to the levels in the parent cel l lines. Enzymatically, these resistant cells hardly activated deoxycy tidine (dCyd) and 2-F-Ara-A. In addition, the abilities to phosphoryla te deoxyadenosine and deoxyguanosine were also decreased in the resist ant cells in comparison with the parent cells. These findings suggest that the deficiency in activity of dCyd kinase may contribute to the r esistance of 2-F-Ara-A.