Abstract
Camptothecins are still among the most widely prescribed and effective anticancer drugs. Unfortunately, important drawbacks including water insolubility, lactone instability, reversibility of the drug–target interaction, drug resistance and toxicity are responsible for treatment failure and often require suspension of the drug administration itself. In order to overcome such drawbacks, several options in chemical manipulation of natural camptothecin have been explored, and effective compounds have been identified in a novel series of 7- oxyiminomethyl derivatives. Among the compounds of this series, the hydrophilic derivative namitecan (7 (2-aminoethoxy) iminomethyl camptothecin) has been selected for further development. The relevant features of namitecan are: 1) marked cytotoxic potency - likely related to multiple factors, including i) a potent inhibition of topoisomerase I, ii) a persistent stabilization of the cleavable complex, iii) an increased intracellular accumulation, and iv) a peculiar subcellular localization; 2) enhanced lactone stability and favorable pharmacokinetics; 3) remarkable antitumor efficacy in a large panel of human tumor xenografts (including tumor models relatively resistant to topotecan and irinotecan), particularly on squamous cell carcinomas. The clinical development of namitecan is currently ongoing. Namitecan exhibited an acceptable toxicity profile, with neutropenia being the dose-limiting toxic effect, and clinical benefit was appreciable in patients with different tumor types, particularly bladder and endometrium carcinomas. In this article, we review the relevant features of namitecan, with particular reference to its advantages compared with the two analogues (topotecan and irinotecan) approved for clinical use.
Keywords: Antitumor therapy, Camptothecins, Cellular pharmacology, Clinical studies, Drug resistance, Gimatecan, Namitecan, 7- oxyiminomethyl derivatives, Topoisomerase I, Tumor cells
Current Medicinal Chemistry
Title:Namitecan: a Hydrophilic Camptothecin with a Promising Preclinical Profile
Volume: 19 Issue: 21
Author(s): G. L. Beretta, V. Zuco, M. De Cesare, P. Perego and N. Zaffaroni
Affiliation:
Keywords: Antitumor therapy, Camptothecins, Cellular pharmacology, Clinical studies, Drug resistance, Gimatecan, Namitecan, 7- oxyiminomethyl derivatives, Topoisomerase I, Tumor cells
Abstract: Camptothecins are still among the most widely prescribed and effective anticancer drugs. Unfortunately, important drawbacks including water insolubility, lactone instability, reversibility of the drug–target interaction, drug resistance and toxicity are responsible for treatment failure and often require suspension of the drug administration itself. In order to overcome such drawbacks, several options in chemical manipulation of natural camptothecin have been explored, and effective compounds have been identified in a novel series of 7- oxyiminomethyl derivatives. Among the compounds of this series, the hydrophilic derivative namitecan (7 (2-aminoethoxy) iminomethyl camptothecin) has been selected for further development. The relevant features of namitecan are: 1) marked cytotoxic potency - likely related to multiple factors, including i) a potent inhibition of topoisomerase I, ii) a persistent stabilization of the cleavable complex, iii) an increased intracellular accumulation, and iv) a peculiar subcellular localization; 2) enhanced lactone stability and favorable pharmacokinetics; 3) remarkable antitumor efficacy in a large panel of human tumor xenografts (including tumor models relatively resistant to topotecan and irinotecan), particularly on squamous cell carcinomas. The clinical development of namitecan is currently ongoing. Namitecan exhibited an acceptable toxicity profile, with neutropenia being the dose-limiting toxic effect, and clinical benefit was appreciable in patients with different tumor types, particularly bladder and endometrium carcinomas. In this article, we review the relevant features of namitecan, with particular reference to its advantages compared with the two analogues (topotecan and irinotecan) approved for clinical use.
Export Options
About this article
Cite this article as:
L. Beretta G., Zuco V., De Cesare M., Perego P. and Zaffaroni N., Namitecan: a Hydrophilic Camptothecin with a Promising Preclinical Profile, Current Medicinal Chemistry 2012; 19 (21) . https://dx.doi.org/10.2174/092986712801323252
DOI https://dx.doi.org/10.2174/092986712801323252 |
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
Approaches to the treatment of chronic inflammation
Chronic inflammation is a hallmark of numerous diseases, significantly impacting global health. Although chronic inflammation is a hot topic, not much has been written about approaches to its treatment. This thematic issue aims to showcase the latest advancements in chronic inflammation treatment and foster discussion on future directions in this ...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
- 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
-
Surface Markers of Cancer Stem Cells in Solid Tumors
Current Stem Cell Research & Therapy Synthesis and Antiproliferative Evaluation of Hybrids of Indolin-2-one and Quinazoline-4(3H)-one Linked via Imine Bond
Letters in Drug Design & Discovery Toll-Like Receptors in Alzheimer's Disease: A Therapeutic Perspective
CNS & Neurological Disorders - Drug Targets Protein-Protein Interactions: Recent Progress in the Development of Selective PDZ Inhibitors
Current Chemical Biology Can Diabetes Heal?- From Observations to Perspectives
Current Diabetes Reviews Malignancy Risk in Systemic Lupus: Recent Research and Ongoing Challenges
Current Rheumatology Reviews Prevalence of HIV in Patients with Malignancy and of Malignancy in HIV Patients in a Tertiary Care Center from North India
Current HIV Research Effect of Oxidative Stress on the Pharmacokinetics of Clomipramine in Rats Treated with Ferric-Nitrilotriacetate
Drug Metabolism Letters Translational Molecular Imaging in Drug Development: Current Status and Challenges
Current Medical Imaging Radioprotective Effects of Plants from the Lamiaceae Family
Anti-Cancer Agents in Medicinal Chemistry Drug-Loaded Nanocarriers in Tumor Targeted Drug Delivery
Current Biotechnology Life and Death of Nerve Cells: Therapeutic Cytokine Signaling Pathways
Current Signal Transduction Therapy Natural Products Targeting Autophagy via the PI3K/Akt/mTOR Pathway as Anticancer Agents
Anti-Cancer Agents in Medicinal Chemistry A Comparative Study of Glucose and Fructose in the Development of Sarcoma 180 in Mice
Letters in Organic Chemistry Recent Advances of Chitosan and its Derivatives in Biomedical Applications
Current Medicinal Chemistry Gold Nanoparticles as Carrier(s) for Drug Targeting and Imaging
Pharmaceutical Nanotechnology Characterization of Cepharanthin Nanosuspensions and Evaluation of Their In Vitro Activity for the HepG2 Hepatocellular Carcinoma Cell Line
Anti-Cancer Agents in Medicinal Chemistry Cancer Control by Phytochemicals
Current Pharmaceutical Design Bone Regeneration: Microparticulate and Biomimetic Strategies
Current Tissue Engineering (Discontinued) Current Developments of Coumarin Compounds in Medicinal Chemistry
Current Pharmaceutical Design