Comparison of the antileukaemic activity of 5 aza-2-deoxycytidine and arabinofuranosyl-cytosine in rats with myelocytic leukaemia.
Using a Brown Norway rat leukaemia model (BNML), which is a realistic model of human myelocytic leukaemia, we compared the antileukaemic activity, influence on cell cycle kinetics and effect on normal haematopoiesis of 5 aza-2-deoxycytidine (aza-dC) and arabinofuranosyl-cytosine (ara-C). The antileukaemic activity was evaluated by means of a survival study. For aza-dC a dose-response relationship was demonstrated for doses up to 50 mg kg-1 (3 times q 12 h); a higher dose resulted in only a slight increase in median survival time (MST). For ara-C a weak dose-response relationship was observed. At the maximum dose of aza-dC and ara-C tested, aza-dC induced a 10-day longer survival time than ara-C, which means 2 logs more of leukaemic cell kill for aza-dC. By means of flow cytometric analysis and a 3HTdR uptake study it was shown that aza-dC does not influence the cell cycle kinetics in the first 24 h after exposure, in contrast to ara-C which caused the characteristic G1/S blockage and synchronization. The influence of aza-dC and ara-C on normal haematopoiesis was evaluated with the CFU-S assay. The dose-response curve for CFU-S did not show a significant difference in stem cell cytotoxicity between aza-dC and ara-C. In the BNML model aza-dC is a much more effective antileukaemic agent than ara-C, while the toxic effect on normal haematopoiesis is comparable to that of ara-C.
Richel
D J
DJ
Division of Hematology, University Hospital Leiden, The Netherlands.
Colly
L P
LP
Lurvink
E
E
Willemze
R
R
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D001853:Bone Marrow / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D003114:Colony-Forming Units Assay; D003561:Cytarabine / Q000627:therapeutic use*; D004247:DNA / Q000096:biosynthesis; D000077209:Decitabine; D004305:Dose-Response Relationship, Drug; D005260:Female; D007951:Leukemia, Myeloid / Q000188:drug therapy*; D051381:Rats; D011914:Rats, Inbred BN; D013997:Time Factors
D000970:Antineoplastic Agents; D003561:Cytarabine; D000077209:Decitabine; D004247:DNA; D001374:Azacitidine