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.