Cytotoxic activity and mechanism of action of 5-Aza-2'-deoxycytidine in human CML cells.

Abstract

We investigated the cytotoxic activity and some aspects of the mode of action of 5-aza-2'-deoxycytidine (Aza-dC) in 21 primary cultures of leukemic cells freshly obtained from patients with chronic myeloid leukemia (CML) in blast crisis. The cytotoxic potency of Aza-dC was comparable or even greater than that of 1-beta-D-arabinofuranosylcytosine (Ara-C) in most cases, suggesting that this drug has potential in the therapy of blast crisis of CML. Drug incorporation into DNA was evaluated by exposing leukemic cells simultaneously to 3H-Aza-dC at the concentration of 0.1 micrograms/ml and 14C-thymidine (TdR) used as internal standard. Incorporation of Aza-dC into DNA was detectable in all cases. In 17 samples we evaluated the DNA integrity of leukemic cells exposed to Aza-dC using alkaline elution techniques. The drug caused a detectable amount of DNA alkali labile sites (ALS). DNA-ALS increased in cells exposed to Aza-dC concentrations from 0.1 to 1 microgram/ml but did not further increase at 10 micrograms/ml. A plateau in the levels of DNA-ALS was also seen in human K562 cells exposed to increasing concentrations of Aza-dC from 5 to 10 micrograms/ml, whereas in these cells Aza-dC incorporation into DNA increased with increasing Aza-dC concentrations. Therefore, DNA-ALS caused by Aza-dC are not simply the result of the chemical decomposition of azacytosine molecules incorporated into DNA, but are presumably the result of a saturable DNA repair mechanism (e.g., glycosylases) leading to formation of the apyrimidinic sites.

• Authors: M Limonta, T Colombo, G Damia, C V Catapano, V Conter, M Gervasoni, G Masera, V Liso, G Specchia, G Giudici
• Journal: Leukemia research (Leuk Res) Vol. 17 Issue 11 Pg. 977-82 (Nov 1993) ISSN: 0145-2126 [Print] England
• PMID: 7694001 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• DNA, Neoplasm
• Cytarabine
• Decitabine
• Azacitidine

Topics

• Antineoplastic Agents (metabolism, pharmacology, therapeutic use)
• Azacitidine (analogs & derivatives, pharmacology, therapeutic use)
• Blast Crisis
• Cytarabine (pharmacology)
• DNA, Neoplasm (metabolism)
• Decitabine
• Humans
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy)
• Time Factors
• Tumor Cells, Cultured