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.
Keywords: Acute myeloid leukaemia, lomeguatrib, O6-Methylguanine-DNA methyltransferase (MGMT), MGMT inhibitors, Temozolomide (TMZ), triazene compounds, chemical xenogenization (CX).
Current Medicinal Chemistry
Title:Triazene Compounds in the Treatment of Acute Myeloid Leukemia: A Short Review and a Case Report
Volume: 20 Issue: 19
Author(s): L. Bonmassar, F. Marchesi, E. Pascale, O. Franzese, G.P. Margison, A. Bianchi, S. D’Atri, S. Bernardini, D. Lattuada, E. Bonmassar and A. Aquino
Affiliation:
Keywords: Acute myeloid leukaemia, lomeguatrib, O6-Methylguanine-DNA methyltransferase (MGMT), MGMT inhibitors, Temozolomide (TMZ), triazene compounds, chemical xenogenization (CX).
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.
Export Options
About this article
Cite this article as:
Bonmassar L., Marchesi F., Pascale E., Franzese O., Margison G.P., Bianchi A., D’Atri S., Bernardini S., Lattuada D., Bonmassar E. and Aquino A., Triazene Compounds in the Treatment of Acute Myeloid Leukemia: A Short Review and a Case Report, Current Medicinal Chemistry 2013; 20 (19) . https://dx.doi.org/10.2174/0929867311320190001
DOI https://dx.doi.org/10.2174/0929867311320190001 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...read more
Current advances in inherited cardiomyopathy
Describe in detail all novel advances in multimodality imaging related to inherited cardiomyopathy diagnosis and prognosis. Shed light to deeper phenotypic characterization. Acknowledge recent advances in genetics, genomics and precision medicineread more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Microwave Assisted Synthesis, Biological Characterization and Docking Studies of Pyrimidine Derivatives
Current Microwave Chemistry Working Hypothesis: Elimination of Cancer Stem Cells in Solid Tumors by Immuno-Gene Therapy Using Cancer Vaccines and Created-Inhibitory RNA
Current Cancer Therapy Reviews Multidisciplinary Cancer Therapy with Telomerase-Specific Oncolytic Adenovirus
Current Cancer Therapy Reviews Editorial [Hot topic: Role of Inflammation in Neurological and Psychiatric Disorders (Guest Editor: Mohtashem Samsam)]
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry APE1/Ref-1Role in Redox Signaling: Translational Applications of Targeting the Redox Function of the DNA Repair/Redox Protein APE1/Ref-1
Current Molecular Pharmacology Synergism of Temozolomide, Metformin, and Epigallocatechin Gallate Promotes Oxidative Stress-Induced Apoptosis in Glioma Cells
Current Drug Therapy A Novel Lily-of-the-Valley Fragrance Contrast Agent for Magnetic Resonance and Fluorescence Imaging of Prostate Cancer Cells
Current Pharmaceutical Biotechnology Pyruvate Dehydrogenase Kinases in the Nervous System: Their Principal Functions in Neuronal-glial Metabolic Interaction and Neuro-metabolic Disorders
Current Neuropharmacology Integrins as Novel Drug Targets for Overcoming Innate Drug Resistance
Current Cancer Drug Targets Endogenous Angiogenesis Inhibitors as Therapeutic Agents: Historical Perspective and Future Direction
Recent Patents on Anti-Cancer Drug Discovery Use of Topiceuticals (Topically Applied, Peripherally Acting Drugs) in the Treatment of Chronic Pain
Current Drug Therapy Sphingosine Kinases Signalling in Carcinogenesis
Mini-Reviews in Medicinal Chemistry Minocycline and Doxycycline: More Than Antibiotics
Current Molecular Pharmacology Recent Advances in the Development of Thioredoxin Reductase Inhibitors as Anticancer Agents
Current Drug Targets The Development of Future Research Strategies from Reviewing Antiemetic Trials for Chemotherapy Induced Emesis
Reviews on Recent Clinical Trials Peptide Self-Assemblies for Drug Delivery
Current Topics in Medicinal Chemistry Immune Checkpoint Inhibitors: Basics and Challenges
Current Medicinal Chemistry Prospective Role of Polyphenolic Compounds in the Treatment of Neurodegenerative Diseases
CNS & Neurological Disorders - Drug Targets Oleuropein Mediated Targeting of Signaling Network in Cancer
Current Topics in Medicinal Chemistry An Integrative Informatics Approach to Explain the Mechanism of Action of N1-(Anthraquinon-2-yl) Amidrazones as BCR/ABL Inhibitors
Current Computer-Aided Drug Design