Chemotherapy of L1210 and L1210/ARA-C leukemia with 5-aza-2'-deoxycytidine and 3-deazauridine.
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 10(4) L1210 cells plus 10(2) 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.
Momparler
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Département de Pharmacologie, Université de Montréal, Québec, Canada.
Momparler
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LF
D015092:3-Deazauridine / Q000008:administration & dosage; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D002460:Cell Line / Q000187:drug effects; D003561:Cytarabine / Q000037:antagonists & inhibitors*; D000077209:Decitabine; D004347:Drug Interactions; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D007939:Leukemia L1210 / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D014407:Tumor Cells, Cultured / Q000187:drug effects
D003561:Cytarabine; D015092:3-Deazauridine; D000077209:Decitabine; D001374:Azacitidine