Inhibition of human DNA polymerase beta activity by the anticancer prodrug Cloretazine

Biochem Biophys Res Commun. 2009 Jan 16;378(3):419-23. doi: 10.1016/j.bbrc.2008.11.042. Epub 2008 Nov 21.


The antineoplastic prodrug Cloretazine exerts its cytotoxicity via a synergism between 2-chloroethylating and carbamoylating activities that are cogenerated upon activation in situ. Cloretazine is reported here to inhibit the nucleotidyl-transferase activity of purified human DNA polymerase beta (Pol beta), a principal enzyme of DNA base excision repair (BER). The 2-chloroethylating activity of Cloretazine alkylates DNA at the O(6) position of guanine bases resulting in 2-chloroethoxyguanine monoadducts, which further react to form cytotoxic interstrand DNA crosslinks. Alkylated DNA is often repaired via BER in vivo. Inhibition of the polymerase activity of Pol beta may account for some of the synergism between Cloretazine's two reactive subspecies in cytotoxicity assays. This inhibition was only observed using agents with carbamoylating activity. Furthermore, while therapeutically relevant concentrations of Cloretazine inhibited the polymerase activity of Pol beta, the enzyme's lyase activity, which may also participate in BER, was not significantly inhibited.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • DNA Polymerase I / antagonists & inhibitors
  • DNA Polymerase beta / antagonists & inhibitors*
  • DNA Repair / drug effects
  • Humans
  • Hydrazines / pharmacology*
  • Inhibitory Concentration 50
  • Prodrugs / pharmacology*
  • Sulfonamides / pharmacology*


  • Antineoplastic Agents
  • Hydrazines
  • Prodrugs
  • Sulfonamides
  • laromustine
  • DNA Polymerase I
  • DNA Polymerase beta