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Enhancement of anti‐neoplastic activity of cytosine arabinoside against human HL‐60 myeloid leukemic cells by 3‐deazauridine
Author(s) -
Momparler Richard L.,
Bouffard David Y.,
Momparler Louise F.,
Marquet Jeanine,
Zittoun Jacqueline,
Marie JeanPierre,
Zittoun Robert
Publication year - 1991
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.2910490417
Subject(s) - deoxycytidine kinase , cytarabine , myeloid leukemia , deoxycytidine , cytosine , chemotherapy , leukemia , cancer research , drug , cytotoxic t cell , uridine , pharmacology , myeloid , chemistry , in vitro , biology , biochemistry , immunology , dna , rna , genetics , gemcitabine , gene
Drug resistance is one of the major reasons for failure of chemotherapy of acute leukemia with cytosine arabinoside (ARA‐C). In order to overcome this problem we have investigated the interaction of ARA‐C with 3‐deazauridine (3‐DU) against HL‐60 myeloid leukemic cells. 3‐DU is an interesting agent to use in combination with ARA‐C, since drug‐resistant cells that are deficient in deoxycytidine kinase are very sensitive to this uridine analogue. We have observed that for both short and long drug exposure there was a potent synergistic interaction between ARA‐C and 3‐DU with respect to their cytotoxic effects on HL‐60 leukemic cells. This synergy could be explained by an increased cellular uptake of ARA‐C to ARA‐CTP by the leukemic cells in the presence of 3‐DU, due to the reduction in the pool of dCTP produced by this latter analogue. Since dCTP is a potent feedback inhibitor of the phosphorylation of ARA‐C by deoxycytidine kinase, the reduction in the dCTP produced by 3‐DU results in an increased rate of phosphorylation of the arabinosyl analogue. Our results suggest that ARA‐C and 3‐DU may be an interesting drug combination to circumvent drug resistance in the chemotherapy of acute leukemia.