Abstract
The purine nucleoside analogues (PNAs), fludarabine (FA), 2-CdA (2-chlorodeoxyadenosine, 2-CdA) and pentostatin (2-deoxycoformycin, DCF) represent a group of cytotoxic agents with high activity in lymphoid and myeloid malignancies. PNAs share similar chemical structure and mechanism of action. Several mechanisms could be responsible for their cytotoxicity both in proliferating and quiescent cells, such as inhibition of DNA synthesis, inhibition of DNA repair and accumulation of DNA strand breaks. Induction of apoptosis through the mitochondrial pathway, direct binding to apoptosome or modulation of p53 expression all lead to apoptosis, which is the main end-point of PNA action. However, individual PNAs exhibit significant differences, especially in their interaction with enzymes involved in adenosine and deoxyadenosine metabolism. Synergistic interactions between PNAs and other cytotoxic agents (alkylating agents, anthracycline antitumor antibiotics, cytarabine, monoclonal antibodies) have been demonstrated in both preclinical and clinical studies. PNAs are highly effective in chronic lymphoid leukemias and low grade B- and T-cell non-Hodgkins lymphomas, including Waldenströms macroglobulinemia. DCF and 2-CdA are currently the drugs of choice in hairy cell leukemia. Moreover, clinical studies have confirmed the efficacy of PNAs alone or in combination protocols in the treatment of acute myeloid leukemia and myelodysplastic syndromes. Finally, PNAs, especially FA, play an important role in non-myeloablative conditioning regimens for allogenic stem cell transplantation in high-risk patients. The toxicity profiles of PNAs are similar for all agents and consist mainly of dose-limiting myelotoxicity and prolonged immunosuppression. Three other compounds: clofarabine, nelarabine and immucillin-H are currently being evaluated clinically.
Keywords: cladribine, fludarabine, pentostatin, clofarabine, nelarabine, immucillin h, leukemia, lymphoma
Current Cancer Drug Targets
Title: Purine Nucleoside Analogues for the Treatment of Hematological Malignancies: Pharmacology and Clinical Applications
Volume: 5 Issue: 6
Author(s): T. Robak, A. Korycka, M. Kasznicki, A. Wrzesien-Kus and P. Smolewski
Affiliation:
Keywords: cladribine, fludarabine, pentostatin, clofarabine, nelarabine, immucillin h, leukemia, lymphoma
Abstract: The purine nucleoside analogues (PNAs), fludarabine (FA), 2-CdA (2-chlorodeoxyadenosine, 2-CdA) and pentostatin (2-deoxycoformycin, DCF) represent a group of cytotoxic agents with high activity in lymphoid and myeloid malignancies. PNAs share similar chemical structure and mechanism of action. Several mechanisms could be responsible for their cytotoxicity both in proliferating and quiescent cells, such as inhibition of DNA synthesis, inhibition of DNA repair and accumulation of DNA strand breaks. Induction of apoptosis through the mitochondrial pathway, direct binding to apoptosome or modulation of p53 expression all lead to apoptosis, which is the main end-point of PNA action. However, individual PNAs exhibit significant differences, especially in their interaction with enzymes involved in adenosine and deoxyadenosine metabolism. Synergistic interactions between PNAs and other cytotoxic agents (alkylating agents, anthracycline antitumor antibiotics, cytarabine, monoclonal antibodies) have been demonstrated in both preclinical and clinical studies. PNAs are highly effective in chronic lymphoid leukemias and low grade B- and T-cell non-Hodgkins lymphomas, including Waldenströms macroglobulinemia. DCF and 2-CdA are currently the drugs of choice in hairy cell leukemia. Moreover, clinical studies have confirmed the efficacy of PNAs alone or in combination protocols in the treatment of acute myeloid leukemia and myelodysplastic syndromes. Finally, PNAs, especially FA, play an important role in non-myeloablative conditioning regimens for allogenic stem cell transplantation in high-risk patients. The toxicity profiles of PNAs are similar for all agents and consist mainly of dose-limiting myelotoxicity and prolonged immunosuppression. Three other compounds: clofarabine, nelarabine and immucillin-H are currently being evaluated clinically.
Export Options
About this article
Cite this article as:
Robak T., Korycka A., Kasznicki M., Wrzesien-Kus A. and Smolewski P., Purine Nucleoside Analogues for the Treatment of Hematological Malignancies: Pharmacology and Clinical Applications, Current Cancer Drug Targets 2005; 5 (6) . https://dx.doi.org/10.2174/1568009054863618
DOI https://dx.doi.org/10.2174/1568009054863618 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
Call for Papers in Thematic Issues
Advances in Cancer Biomarkers and Potential Drug Targets: From Diagnosis to Therapy
Cancer biomarkers play a crucial role in the diagnosis, prognosis, and treatment of cancer. They provide valuable information for cancer detection, risk assessment, treatment selection, and monitoring response to therapy. With advancements in molecular biology and high-throughput technologies, there has been an increasing interest in identifying and characterizing cancer biomarkers ...read more
Novel Therapeutic Approaches to Target Drug Resistant Tumors
With the development of disciplines such as chemical biology and molecular biology, the genes or proteins closely related to tumor occurrence and development have gradually become clear. Targeted therapies targeting these genes or proteins provide more effective methods for tumor treatment. Tumor targeted drugs generally only act on specific targets ...read more
ROLE OF IMMUNE AND GENOTOXIC RESPONSE BIOMARKERS IN TUMOR MICROENVIRONMENT IN CANCER DIAGNOSIS AND TREATMENT
Biological biomarkers have been used in medical research as an indicator of a normal or abnormal process inside the body, or of a disease. Nowadays, various researchers are in process to explore and investigate the biological markers for the early assessment of cancer. DNA Damage response (DDR) pathways and immune ...read more
Targeting the battlefield between host and tumor: basic research and clinical practice on reshaping tumor immune microenvironment
Immune system protects host against malignant tumors through effector cells and molecules. Cancer development and its response to therapy are regulated by inflammation, which either promotes or suppresses cancer progression. Chronic inflammation facilitates cancer progression and treatment resistance, whereas induction of acute inflammatory reactions often lead to anti-cancer immune responses. ...read 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
Related Articles
-
CypA: A Potential Target of Tumor Radiotherapy and/or Chemotherapy
Current Medicinal Chemistry Biologics for Extraintestinal Manifestations of IBD
Current Drug Targets Histone Modifications, Stem Cells and Prostate Cancer
Current Pharmaceutical Design Molecular Link Mechanisms between Inflammation and Cancer
Current Pharmaceutical Design Coinhibitory Molecule PD-1 as a Therapeutic Target in the Microenvironment of Multiple Myeloma
Current Cancer Drug Targets A Conceptual View on Glucocorticoid-Induced Apoptosis, Cell Cycle Arrest and Glucocorticoid Resistance in Lymphoblastic Leukemia
Current Molecular Medicine Cachexia and Herbal Medicine: Perspective
Current Pharmaceutical Design Recent Advances In Developing Novel Anti-Cancer Drugs Targeting Tumor Hypoxic and Acidic Microenvironments
Recent Patents on Anti-Cancer Drug Discovery Implication of Heat Shock Protein 90 (HSP90) in Tumor Angiogenesis: A Molecular Target for Anti-Angiogenic Therapy?
Current Cancer Drug Targets Exploratory Study on the Effects of Biodegradable Nanoparticles with Drugs on Malignant B Cells and on a Human/Mouse Model of Burkitt Lymphoma
Current Clinical Pharmacology Bypass Mechanisms of Resistance to Tyrosine Kinase Inhibition in Chronic Myelogenous Leukaemia
Current Drug Discovery Technologies Cytoprotection and Immunomodulation in Cancer Therapy
Current Medicinal Chemistry - Anti-Cancer Agents Developing Target Therapy Against Oncogenic Tyrosine Kinase in Myeloid Maliganacies
Current Pharmaceutical Biotechnology Potential New Targets for Antithrombotic Therapy
Current Pharmaceutical Design Randomised Trials of Graft Versus Host Disease Prophylaxis in Haemopoietic Stem Cell Transplantation
Reviews on Recent Clinical Trials The University of New Mexico Center for Molecular Discovery
Combinatorial Chemistry & High Throughput Screening Anabolic Androgenic Steroid (AAS) Related Deaths: Autoptic, Histopathological and Toxicological Findings
Current Neuropharmacology Advances in Oncolytic Virus Therapy for Glioma
Recent Patents on CNS Drug Discovery (Discontinued) Targeting the Ubiquitin-Mediated Proteasome Degradation of p53 for Cancer Therapy
Current Pharmaceutical Design Antiviral Drugs that Target Cellular Proteins May Play Major Roles in Combating HIV Resistance
Current Pharmaceutical Design