Novel role of triazenes in haematological malignancies: Pilot study of Temozolomide, Lomeguatrib and IL-2 in the chemo-immunotherapy of acute leukaemia

Patrizia Caporaso, Mario Turriziani, Adriano Venditti, Francesco Marchesi, Francesco Buccisano, Maria Cristina Tirindelli, Ester Alvino, Alberto Garbin, Grazia Tortorelli, Laura Toppo, Enzo Bonmassar, Stefania D'Atri, Sergio Amadori

Research output: Contribution to journalArticle

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 O6-position of guanine in DNA. High levels of O6-methylguanine-DNA methyltransferase (MGMT) or a defective mismatch repair (MMR) system, are associated with cellular resistance to triazenes. The MGMT inhibitor, O6-(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.

Original languageEnglish
Pages (from-to)1179-1186
Number of pages8
JournalDNA Repair
Volume6
Issue number8
DOIs
Publication statusPublished - Aug 1 2007

Keywords

  • IL-2
  • Leukaemia
  • Lomeguatrib
  • MGMT
  • MMR
  • Temozolomide

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

Fingerprint Dive into the research topics of 'Novel role of triazenes in haematological malignancies: Pilot study of Temozolomide, Lomeguatrib and IL-2 in the chemo-immunotherapy of acute leukaemia'. Together they form a unique fingerprint.

  • Cite this

    Caporaso, P., Turriziani, M., Venditti, A., Marchesi, F., Buccisano, F., Tirindelli, M. C., Alvino, E., Garbin, A., Tortorelli, G., Toppo, L., Bonmassar, E., D'Atri, S., & Amadori, S. (2007). Novel role of triazenes in haematological malignancies: Pilot study of Temozolomide, Lomeguatrib and IL-2 in the chemo-immunotherapy of acute leukaemia. DNA Repair, 6(8), 1179-1186. https://doi.org/10.1016/j.dnarep.2007.03.016