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Hydroxycarbamide in combination with azacitidine or decitabine is antagonistic on DNA methylation inhibition.
- Source :
-
British journal of haematology [Br J Haematol] 2007 Sep; Vol. 138 (5), pp. 616-23. - Publication Year :
- 2007
-
Abstract
- Azacitidine and decitabine are cytidine analogues that inhibit DNA methylation, and are used to treat myeloid haematological malignancies. Hydroxycarbamide (HC) (also known as hydroxyurea), a ribonucleotide reductase (RR) inhibitor, blocks the conversion of ribonucleotides to deoxyribonucleotides, and is also used to treat leukaemia and sickle-cell disease. Azacitidine is a ribonucleoside and decitabine is a deoxyribonucleoside; therefore, we hypothesized that inhibition of RR by HC would be antagonistic to azacitidine and synergistic to decitabine. HL-60 and T24 cancer cell lines were treated with azacitidine or decitabine in combination with HC and DNA methylation of LRE1, MAGEA1 and CDKN2A was quantitatively measured by bisulphite-polymerase chain reaction pyrosequencing. Surprisingly, we found that HC blocked the ability of both azacitidine and decitabine to inhibit DNA methylation and this antagonistic effect was attributable to the arrest of the cell cycle induced by HC. However, this antagonism could be avoided with sequential treatment of HC followed by azacitidine or decitabine. This data suggest that concurrent combination of HC blocks the ability of azacitidine and decitabine to inhibit DNA methylation and therefore these drugs should be used sequentially.
- Subjects :
- Antimetabolites, Antineoplastic administration & dosage
Antimetabolites, Antineoplastic pharmacology
Antineoplastic Combined Chemotherapy Protocols administration & dosage
Aphidicolin pharmacology
Azacitidine administration & dosage
Azacitidine pharmacology
Cell Cycle drug effects
DNA, Neoplasm metabolism
Decitabine
Dose-Response Relationship, Drug
Drug Administration Schedule
Enzyme Inhibitors administration & dosage
Enzyme Inhibitors pharmacology
Humans
Hydroxyurea administration & dosage
Tumor Cells, Cultured
Antineoplastic Combined Chemotherapy Protocols pharmacology
Azacitidine analogs & derivatives
Azacitidine antagonists & inhibitors
DNA Methylation drug effects
Hydroxyurea pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0007-1048
- Volume :
- 138
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- British journal of haematology
- Publication Type :
- Academic Journal
- Accession number :
- 17686055
- Full Text :
- https://doi.org/10.1111/j.1365-2141.2007.06707.x