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
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
-
Harnessing the Capacity of Cell-Penetrating Peptides for Drug Delivery to the Central Nervous System
Current Pharmaceutical Biotechnology MEK Inhibitors: A Therapeutic Approach to Targeting the Ras-MAP Kinase Pathway in Tumors
Current Pharmaceutical Design Competitive Fluorescence Polarization Assays for the Detection of Phosphoinositide Kinase and Phosphatase Activity
Combinatorial Chemistry & High Throughput Screening Conditionally Replicating Adenoviruses for Cancer Treatment
Current Cancer Drug Targets Advances in the Development of Virus-Like Particles as Tools in Medicine and Nanoscience
Current Chemical Biology Integrated Genomic and Pharmacological Approaches to Identify Synthetic Lethal Genes as Cancer Therapeutic Targets
Current Molecular Medicine Plumbagin Inhibits Breast Tumor Bone Metastasis and Osteolysis by Modulating the Tumor-Bone Microenvironment
Current Molecular Medicine Alphaviruses and their Derived Vectors as Anti-Tumor Agents
Current Cancer Drug Targets Cell Elimination as a Strategy for Repair in Acute Spinal Cord Injury
Current Pharmaceutical Design Circulating Biomarkers for Tumor Angiogenesis: Where Are We?
Current Medicinal Chemistry 3D-QSAR Studies of Natural Steroidal Saponins as Anticancer Agents in Human Nasopharyngeal Carcinoma Epithelial Cells
Letters in Drug Design & Discovery Cranberry as Promising Natural Source of Potential Anticancer Agents: Current Evidence and Future Perspectives
Anti-Cancer Agents in Medicinal Chemistry Direct Evidence on the Immune-Mediated Spontaneous Regression of Human Cancer: An Incentive for Pharmaceutical Companies to Develop a Novel Anti-Cancer Vaccine
Current Pharmaceutical Design P2X Receptors in the Cardiovascular System and their Potential as Therapeutic Targets in Disease
Current Medicinal Chemistry Molecular Targets for Nutritional Preemption of Cancer
Current Cancer Drug Targets Tryptamine Induces Axonopathy and Mitochondriopathy Mimicking Neurodegenerative Diseases via Tryptophanyl-tRNA Deficiency
Current Alzheimer Research Synthesis, Biological Activity of Thiazolidinones Bearing Indoline Moiety and Isatin Based Hybrids
Mini-Reviews in Organic Chemistry Selected Attributes of Polyphenols in Targeting Oxidative Stress in Cancer
Current Topics in Medicinal Chemistry Drug Design Targeting the CXCR4/CXCR7/CXCL12 Pathway
Current Topics in Medicinal Chemistry Secondary Metabolites from Cordyceps Species and Their Antitumor Activity Studies
Recent Patents on Biotechnology