Triazene compounds in the treatment of acute myeloid leukemia: A short review and a case report

L. Bonmassar, F. Marchesi, E. Pascale, O. Franzese, G. P. Margison, A. Bianchi, S. D'Atri, S. Bernardini, D. Lattuada, E. Bonmassar, A. Aquino

Research output: Contribution to journalArticle

Abstract

Acute myeloid leukemia (AML) is a highly lethal disease, especially in old patients. Chemoresistance and the absence of host immune responses against autochthonous malignancy play a major role in the poor prognosis of AML. The triazene compounds Dacarbazine and Temozolomide are monofunctional alkylators that donate methyl groups to many sites in DNA, including the O6-position of guanine producing O6-methylguanine (O6-MeG). If not repaired, O6- MeG frequently mispairs with thymine during DNA duplication. O6-MeG:T mismatches can be recognized by the mismatch repair (MMR) system which activates a cascade of molecular events leading to cell cycle arrest and cell death. If MMR is defective, cells continue to divide and GC × AT transition mutations occur. In preclinical models, such mutations can lead to the appearance of abnormal proteins containing non-self peptides ('chemical xenogenization' CX) that can be recognized by host cell-mediated immunity. Repair of O6-MeG is achieved by the DNA repair protein, O6- methylguanine-DNA methyltransferase (MGMT), which removes the methyl adduct in an autoinactivating stoichiometric reaction. High MGMT levels attenuate the pharmacodynamic effects of triazenes. In the last few years, triazenes, alone or with MGMT inhibitors, have been tested in AML. In view of their potential activity as CX inducers, triazenes could offer the additional advantage of host anti-leukemia immune responses. The present paper describes several studies of leukemia treatment with triazenes and a case of acute refractory leukemia with massive skin infiltration by malignant cells. Treatment with Temozolomide and Lomeguatrib, a potent MGMT inhibitor, produced a huge, although transient, blastolysis and complete disappearance of all skin lesions.

Original languageEnglish
Pages (from-to)2389-2401
Number of pages13
JournalCurrent Medicinal Chemistry
Volume20
Issue number19
DOIs
Publication statusPublished - Jun 2013

Keywords

  • Acute myeloid leukaemia
  • Chemical xenogenization (CX)
  • Lomeguatrib
  • MGMT inhibitors
  • O6-Methylguanine-DNA methyltransferase (MGMT)
  • Temozolomide (TMZ)
  • Triazene compounds

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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  • Cite this

    Bonmassar, L., Marchesi, F., Pascale, E., Franzese, O., Margison, G. P., Bianchi, A., D'Atri, S., Bernardini, S., Lattuada, D., Bonmassar, E., & Aquino, A. (2013). Triazene compounds in the treatment of acute myeloid leukemia: A short review and a case report. Current Medicinal Chemistry, 20(19), 2389-2401. https://doi.org/10.2174/0929867311320190001