Chemotherapy of L1210 and L1210/ARA-C leukemia with 5-aza-2?-deoxycytidine and 3-deazauridine

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Abstract
The in vitro and in vivo antineoplastic activity of 5-aza-2′-deoxycytidine (5-AZA-dCyd) and 3-deazauridine (3-DU) against L1210 and L1210/ARA-C (resistant to cytosine arabinoside) leukemic cells were investigated. L1210/ARA-C cells were more sensitive to the inhibitory effects of 3-DU than L1210 cells. Deoxycytidine completely reversed the in vitro cytotoxic effects produced by 3-DU on L1210 cells, but not those produced in L1210/ARA-C cells. L1210/ARA-C cells, which are deficient in deoxycytidine kinase, were completely resistant to the antileukemic effects of 5-AZA-dCyd, whereas this analogue produced a very potent antileukemic effect against L1210 cells. To study the in vivo interaction of 5-AZA-dCyd and 3-DU with respect to drug resistance, mice were simultaneously injected i. v. with 104 L1210 cells plus 102 L1210/ARA-C cells. A 9-h i. v. infusion of 5-AZA-dCyd (12.8 mg/kg) or 3-DU (186 mg/kg) produced an increase in life span of 56% and 26%, respectively. However, the sequential administration of 5-AZA-dCyd followed by 3-DU produced a 265% increase in life span and 7/10 longterm survivor, a very potent antileukemic effect. These results suggest that 3-DU is an excellent agent for use in combination chemotherapy to overcome drug resistance to the deoxycytidine analogue, 5-AZA-dCyd.