Interaction of 5-aza-2'-deoxycytidine with amsacrine or 1,25-dihydroxyvitamin D3 on HL-60 myeloid leukemic cells and inhibitors of cytidine deaminase.
5-aza-2'-deoxycytidine (5-Aza-CdR) is an experimental anti-leukemic agent that can induce the differentiation of myeloid leukemic cells and is currently under investigation in clinical trials in patients with leukemia. The objective of this study was to investigate the in vitro interaction of 5-Aza-CdR with different agents which may increase its clinical efficacy. Since 5-Aza-CdR has been used in combination with amsacrine in patients with relapsed leukemia, we have investigated the in vitro antileukemic activity of these agents in combination on human HL-60 myeloid leukemic cells. For a 24-hour drug exposure, we observed that the interaction of 5-Aza-CdR with amsacrine was subadditive to was synergistic with respect to the loss of clonogenicity of the HL-60 leukemic cells as demonstrated by a colony assay. We have also investigated the interaction of 5-Aza-CdR with 1,25-dihydroxyvitamin D3, an agent that can induce in vitro differentiation of myeloid leukemic cells. The combination of 5-Aza-CdR with 1,25-dihydroxyvitamin D3 produced a synergistic reduction in the clonogenicity of the HL-60 leukemic cells. These results indicate that 5-Aza-CdR can interact synergistically with both cytotoxic agents and agents that induce differentiation, and can provide some rationale for clinical investigations on these combinations in patients with acute leukemia. We have also explored other approaches to increase the clinical effectiveness of 5-Aza-CdR by investigating the in vitro effect of different inhibitors of human cytidine deaminase, the enzyme responsible for the rapid in vivo inactivation of this analogue.
Momparler
R L
RL
Departement de Pharmacologie, Université de Montréal, Québec, Canada.
Doré
B T
BT
Labiberté
J
J
Momparler
L F
LF
D000677:Amsacrine / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002117:Calcitriol / Q000494:pharmacology*; D000077209:Decitabine; D004347:Drug Interactions; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy*; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
D000970:Antineoplastic Agents; D000677:Amsacrine; D000077209:Decitabine; D002117:Calcitriol; D001374:Azacitidine