Cellular pharmacokinetics and pharmacodynamics of the deoxycytidine analog 2'-C-cyano-2'-deoxy-1-beta-D-arabino-pentofuranosylcytosine (CNDAC).

Abstract

The pharmacokinetics and pharmacodynamics of the novel clinical candidate 2'-C-cyano-2'-deoxy-1-beta-D-arabino-pentofuranosylcytosine (CNDAC) were investigated in human lymphoblastoid CCRF-CEM cells and human myeloblastic leukemia ML-1 cells. Formation of CNDAC 5'-mono-, di-, and triphosphate (CNDACTP) was concentration-dependent; nucleotide accumulation was greater in the lymphoid cells than in the myeloid cells. The nucleotides were eliminated with linear kinetics from both lines, but were retained more effectively by the ML-1 cells. DNA synthesis was selectively inhibited by a 4-hr treatment with CNDAC in CCRF-CEM and ML-1 cells; the IC(50) values were 1 and 0.8 microM, respectively. Evaluation of the polymerization reaction of a primer on an M13mp19(+) template by human DNA polymerase alpha indicated that CNDACTP was incorporated effectively (K(m) = 0.22 microM) opposite a complementary dGMP in the template strand. CNDACTP competed with the normal substrate, dCTP, for incorporation, and the two nucleotides showed similar substrate efficiencies (V(max)/K(m): dCTP = 0.91; CNDACTP = 0.77). Primer extension was potently inhibited by CNDAC triphosphate (K(i) = 23 nM); once the analog had been incorporated, further extension was not observed in vitro, suggesting that primers containing a 3'-terminal nucleotide analog were high K(m) substrates for polymerase alpha. Thus, the ability of human leukemia cells to effectively accumulate and retain CNDACTP, coupled with the favorable kinetics of competition for incorporation into DNA, and the relatively strong ability of the analog to terminate further extension, are likely to contribute to the cytotoxic action of CNDAC.

• Authors: A Azuma, P Huang, A Matsuda, W Plunkett
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 61 Issue 12 Pg. 1497-507 (Jun 15 2001) ISSN: 0006-2952 [Print] England
• PMID: 11377379 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Deoxycytosine Nucleotides
• Deoxyribonucleotides
• Cytarabine
• 2'-cyano-2'-deoxyarabinofuranosylcytosine
• 2'-deoxycytidine 5'-triphosphate
• RNA
• DNA

Topics

• Antineoplastic Agents (metabolism, pharmacology)
• Cell Division (drug effects)
• Cytarabine (analogs & derivatives, metabolism, pharmacology)
• DNA (biosynthesis, drug effects)
• Deoxycytosine Nucleotides (metabolism)
• Deoxyribonucleotides (metabolism)
• Humans
• RNA (biosynthesis, drug effects)
• Tumor Cells, Cultured