title: Novel role of triazenes in haematological malignancies: pilot study of Temozolomide, Lomeguatrib and IL-2 in the chemo-immunotherapy of acute leukaemia.
abstract: Previous studies indicated that dacarbazine and Temozolomide could be highly effective against refractory acute leukaemia. Their activity relies mainly on the generation of methyl adducts at the O(6)-position of guanine in DNA. High levels of O(6)-methylguanine-DNA methyltransferase (MGMT) or a defective mismatch repair (MMR) system, are associated with cellular resistance to triazenes. The MGMT inhibitor, O(6)-(4-bromothenyl)guanine (Lomeguatrib), can restore in vitro sensitivity to Temozolomide in MMR-proficient blasts. In the early 1970s we discovered that, in vivo, triazene compounds induce the appearance of novel transplantation antigens in murine leukaemia ("Chemical Xenogenization", CX). Non-self peptides presented by class I MHC molecules are generated by triazene-induced somatic mutations, affecting retroviral sequences that are detectable in the mouse genome. Moreover, preliminary experiments suggested that human cancer cells can also undergo CX. Therefore, we designed a chemo-immunotherapy strategy in leukaemic patients as follows: (a) cytoreduction and a hypothetical CX phase, i.e. treatment with Lomeguatrib (to suppress MGMT activity) and Temozolomide (to kill sensitive blasts and to presumably induce CX in resistant leukaemic cells); (b) immune response recovery phase using interleukin-2 (to possibly restore an immune response and take advantage of the hypothetical, triazene-induced CX). Here we present the results of pilot study which is in progress in patients with refractory/relapsed acute leukaemia. In all tested cases, Lomeguatrib suppressed MGMT activity in vivo. Six out of eight patients showed partial or complete disappearance of blast cells in peripheral blood or in bone marrow. We observed severe and long-lasting myelosuppression, accompanied by limited non-haematological toxicity. Up to now, two patients are alive (after 9 and 10 months, respectively), four died of opportunistic infections and two of progressive disease. This investigation confirms the potential role of triazenes in leukaemia and highlights the contribution of Lomeguatrib in overcoming drug resistance. Further studies are required to establish whether Temozolomide can induce CX in human leukaemia, and thus offer a new approach to control minimal residual disease.
authors.affiliation: Laboratory of Molecular Oncology, Istituto Dermopatico dell'Immacolata-IRCCS, Via dei Monti di Creta 104, 00167 Rome, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Caporaso
authors.forename: Mario
authors.initials: M
authors.lastname: Turriziani
authors.forename: Adriano
authors.initials: A
authors.lastname: Venditti
authors.forename: Francesco
authors.initials: F
authors.lastname: Marchesi
authors.forename: Francesco
authors.initials: F
authors.lastname: Buccisano
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Tirindelli
authors.forename: Ester
authors.initials: E
authors.lastname: Alvino
authors.forename: Alberto
authors.initials: A
authors.lastname: Garbin
authors.forename: Grazia
authors.initials: G
authors.lastname: Tortorelli
authors.forename: Laura
authors.initials: L
authors.lastname: Toppo
authors.forename: Enzo
authors.initials: E
authors.lastname: Bonmassar
authors.forename: Stefania
authors.initials: S
authors.lastname: D'Atri
authors.forename: Sergio
authors.initials: S
authors.lastname: Amadori
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D003131:Combined Modality Therapy; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000037:antagonists & inhibitors; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006801:Humans; D007167:Immunotherapy; D007376:Interleukin-2 / Q000627:therapeutic use*; D007938:Leukemia / Q000188:drug therapy* / Q000628:therapy*; D051379:Mice; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000037:antagonists & inhibitors; D010865:Pilot Projects; D011687:Purines / Q000627:therapeutic use*; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004791:Enzyme Inhibitors; D007376:Interleukin-2; D011687:Purines; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D019853:O(6)-Methylguanine-DNA Methyltransferase; D045643:DNA Repair Enzymes; C521206:lomeguatrib; D000077204:Temozolomide