Deoxyuridine analog nucleotides in deoxycytidine analog treatment: secondary active metabolites?
Deoxycytidine analogs (dCa's) are nucleosides widely used in anticancer and anti (retro) viral therapies. Intracellularly phosphorylated dCa anabolites are considered to be their main active metabolites. This article reviews the literature on the formation and pharmacological activity of deaminated dCa nucleotides. Most dCa's are rapidly deaminated into deoxyuridine analogs (dUa's) which are only slowly phosphorylated and therefore relatively inactive. dUa nucleotides are, however, also formed via deamination of dCa monophosphates by deoxycytidine monophosphate deaminase (dCMPD). dUa-monophosphates can interact with thymidylate synthase (TS), whereas dUa-triphosphates are incorporated into nucleic acids and interfere with polymerases. Administration of dCa's as monophosphate prodrugs or co-administration of the cytidine deaminase inhibitor tetrahydrouridine (THU) does not prevent dUa nucleotide formation which is, on the other hand, influenced by the dose and dCMPD activity. Taken together, these observations show that the formation of dUa nucleotides is a common phenomenon in treatment with dCa's and these compounds may play a role in treatment outcome. We conclude that more attention should be given to these relatively unknown, but potentially important metabolites.
Jansen
Robert S
RS
Department of Pharmacy & Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Louwesweg 6, 1066 EC Amsterdam, The Netherlands. Robert.jansen@slz.nl
Rosing
Hilde
H
Schellens
Jan H M
JH
Beijnen
Jos H
JH
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism; D000998:Antiviral Agents / Q000008:administration & dosage / Q000378:metabolism; D003844:DCMP Deaminase / Q000378:metabolism*; D003641:Deamination; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism*; D003856:Deoxyuracil Nucleotides / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D010766:Phosphorylation
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D003856:Deoxyuracil Nucleotides; D003841:Deoxycytidine; D003844:DCMP Deaminase