Antitumor imidazotetrazines--XV. Role of guanine O6 alkylation in the mechanism of cytotoxicity of imidazotetrazinones

Biochem Pharmacol. 1987 Feb 15;36(4):457-62. doi: 10.1016/0006-2952(87)90351-0.


Cell lines with constitutive levels of the DNA repair protein O6-methylguanine-DNA methyltransferase (O6MeGMT) (Mer+ phenotype) were less sensitive to the cytotoxic effects of the imidazotetrazinone mitozolomide and the methyl analogue (CCRG 81045) than cells lacking the repair enzyme (Mer-). In contrast neither chlorambucil or the ethylimidazotetrazinone (CCRG 82019) showed differential toxicity between Mer+ and Mer- cell lines. When Mer+ cell lines were incubated with the free base O6-methylguanine (O6MeG) for 16 hr there was a depletion of O6MeGMT, which was dose-related. Such cells showed an increased sensitivity to both mitozolamide and CCRG 81045, but not to CCRG 82019. The only Mer+ cell line not showing increased sensitization with O6MeG pretreatment was Raji, where O6MeGMT was shown to reappear after addition of CCRG 81045. These results suggest that the chloroethyl and methylimidazole-triazinones are similar to the nitrosoureas and triazenes in that cytotoxicity correlates with alkylation of the O6-position of guanine, while the ethyl analogues appear to produce an alternate cytotoxic lesion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy
  • Animals
  • Antineoplastic Agents / therapeutic use*
  • Cell Line
  • Chlorambucil / therapeutic use
  • Colonic Neoplasms / drug therapy
  • DNA Repair
  • Dacarbazine* / analogs & derivatives*
  • Dose-Response Relationship, Drug
  • Guanine / analogs & derivatives*
  • Guanine / metabolism
  • Humans
  • Imidazoles / therapeutic use*
  • Kinetics
  • Leukemia, Myeloid, Acute / drug therapy
  • Lung Neoplasms / drug therapy
  • Lymphoma / drug therapy
  • Methyltransferases / metabolism*
  • Mice
  • Nitrogen Mustard Compounds / therapeutic use*
  • O(6)-Methylguanine-DNA Methyltransferase
  • Phenotype
  • Temozolomide


  • Antineoplastic Agents
  • Imidazoles
  • Nitrogen Mustard Compounds
  • Chlorambucil
  • Guanine
  • Dacarbazine
  • ethazolastone
  • O-(6)-methylguanine
  • mitozolomide
  • Methyltransferases
  • O(6)-Methylguanine-DNA Methyltransferase
  • Temozolomide