Metabolism and mechanism of action of 1-B-D-arabinosyl-5-azacytosine
1-B-D-arabinofuranosyl-5-azacytosine (ara-5-aza-Cyd) is an analog of 1-B-D-arabinofuranosylcytozine (ara-C) which is currently being considered for clinical trial. Ara-5-aza-Cyd reduced clonogenic survival of human T-lymphoblastic cells (Molt-4) in culture by 50% and 98% at initial concentrations of 10/sup -7/ M and 10/sup -6/ M, respectively, compared to 3 x 10/sup -8/ M and 10/sup -6/ M, respectively, for the same effect with ara-C. The analog is chemically unstable, with a T l/1 = 12 hr for the nucleoside and 5 hr for the triphosphate in phosphate-buffered saline (PBS) at 37/sup 0/C. Ara-5-aza-Cyd was incorporated in a dose-dependent manner into DNA, but not RNA, primarily in internucleotide linkage as the parent nucleoside, rather than the chemical breakdown product. Incorporation into the DNA of Molt-4 cells was 3-5-fold higher at 5-8 hr than ara-C incorporation. With gapped duplex DNA as a substrate for purified human DNA polymerases alpha and beta, inhibition of (/sup 3/H)-dCTP incorporation by ara-5-aza-CTP and ara-CTP was competitive, with Ki values for polymerase alpha of 11 and 1.5 ..mu..M, respectively. Ki values for polymerase beta were 39 and 7.6 uM, respectively.
- Research Organization:
- North Carolina Univ., Chapel Hill (USA)
- OSTI ID:
- 7001949
- Resource Relation:
- Other Information: Thesis (Ph. D.)
- Country of Publication:
- United States
- Language:
- English
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AMINES
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550501* - Metabolism- Tracer Techniques