Current Pharmaceutical Design - Volume 11, Issue 9, 2005
Volume 11, Issue 9, 2005
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Lipid Nucleoside Conjugates for the Treatment of Cancer
Authors: Richard L. Alexander and Gregory L. KuceraPhospholipid nucleoside conjugates and nucleosides with chemical additions to the hydroxyl and amino moieties have been used since the 1970s in order to increase the biological activity of the parent compound. Previous investigators have found that adding lipid moieties to ara-C or chemically linking ara-C to a phospholipid creates a prodrug that exhibits superior cytotoxic activity compared to ara-C alone when used in animal tumor models. The novel ara-C molecules reveal different pharmacological profiles from the parent compound such as decreased catabolism by cytidine deaminase, increased plasma half-life, and release of nucleoside monophosphate, a reaction that bypasses the rate limiting initial nucleoside phosphorylation. Additionally, these compounds were able to penetrate the blood-brain barrier and were active against tumor cells implanted i.c. The purpose of this review is to briefly cover the history and successes of previous investigators who have synthesized and tested these phospholipid ara-C conjugates, to discuss recent phospholipid ara-C and fludarabine conjugates, and to discuss the synthetic design and synthesis of a novel phospholipid gemcitabine conjugate. These phospholipid nucleoside conjugates possess the potential to have superior anti-neoplastic cytotoxicity profiles with fewer side effects than the parent nucleoside and merit further investigation.
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A Mechanistic Approach to Anticancer Therapy: Targeting the Cell Cycle with Histone Deacetylase Inhibitors
Authors: C. N. Mork, D. V. Faller and R. A. SpanjaardThe activity of genes encoded by the highly-condensed DNA in cellular nuclei must be precisely regulated. Regulation of the accessibility of gene promoters to transcription complexes is one level of gene regulation and is influenced by histone tail modifications such as acetylation, methylation, and phosphorylation. Acetylation is a reversible modification catalyzed by histone acetyl transferase (HAT) and histone deacetyltransferase (HDAC) enzymes. Histone deacetylation is associated with transcriptional repression of genes, as the removal of acetyl groups from lysine residues allows for tighter electrostatic interactions between DNA and histones, limiting accessibility of the DNA for transcription. Inhibition of HDAC activity permits histones to remain in an acetylated state, and through the resulting alterations in gene regulation, inhibits cell cycle progression, inhibits differentiation, and in some cases induces apoptosis. Inhibition of proliferation by HDAC inhibitors is characterized by arrest at the G1 or G2/M phases of the cell cycle. Many types of tumor cells then undergo programmed cell death. Exposure to HDAC inhibitors may also allow reactivation of tumor suppressor genes which had been silenced by hypoacetylation during tumorigenesis. HDAC inhibitors from a number of chemical classes have shown promise as anti-cancer agents in animal studies and early clinical trials. The development of HDAC inhibitors which specifically target HDAC isozymes, and more detailed understanding of their anti-neoplastic actions, heralds a new epigenetic antitumor therapeutic strategy.
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Targeting Telomerase by Antisense-Based Approaches: Perspectives for New Anti-Cancer Therapies
Authors: M. Folini and N. ZaffaroniOligonucleotide-based therapies have been under investigation for many years, and different antisense oligomers are being tested in clinical trials on patients with cancer and other diseases. Since telomerase reactivation has been defined as one of the six hallmarks of cancer because of the enzyme's ability to provide tumor cells with unlimited proliferative potential, antisense-based approaches, aimed to inhibit the core enzyme components, could represent innovative anticancer therapies. Overall, available information indicates antisense-based strategies as powerful tools to inhibit telomerase and interfere with tumor cell proliferative potential. Specifically, cancer cell growth arrest was observed in several tumor models as a consequence of telomere shortening in the presence of prolonged telomerase inhibition. However, in other studies, antisense-based treatments caused rapid loss of tumor cell viability and induced apoptosis independently of telomere attrition. The results would suggest that telomerase inhibition affects tumor cell growth by mechanisms that are dependent as well as independent of the enzyme telomere elongating activity. However, the role of telomerase in tumorigenesis and tumor progression, beyond the classical mechanism of telomere lengthening, needs to be further investigated to provide a better rationale for the design and development of antitelomerase-based therapies in clinical oncology.
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Novel Insights Into c-Src
Authors: O. Alper and E. T. BowdenSince identifying a transmissible agent responsible for tumorigenesis in chickens, the v-Src oncogene, significant progress has been made in determining the functions of its cellular homologue. c-Src is the product of the SRC gene and has been found both over-expressed and highly activated in a number of human cancers. In fact the relationship between c-Src activation and cancer progression is significant. Furthermore c-Src may play a role in the acquisition of the invasive and metastatic phenotype. In this review we will summarize some of the latest evidence for the role of c-Src in tumorigenesis and particularly in human tumor progression. In this review, specifically, we will address growth signals, adhesion, migration, invasion, angiogenesis and functional genomics.
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Hsp90 Inhibitor Geldanamycin and Its Derivatives as Novel Cancer Chemotherapeutic Agents
By Y. MiyataGeldanamycin, an ansamycin-derivative benzoquinone compound, was originally isolated as a natural product with anti-fungal activity. Later, geldanamycin was found to have anti-proliferative activity on tumor cells transformed by oncogene kinases such as v-Src. Geldanamycin neither bind nor inhibit oncogene kinases directly, but specifically binds and inhibits a major molecular chaperone, Hsp90. Hsp90 is a highly abundant and essential cytosolic protein and the expression level of Hsp90 increases by environmental stress. Hsp90 functions as a molecular chaperone by binding to various cellular proteins and supporting the proper folding, stability, and function of target proteins. The Hsp90 client proteins include a wide variety of signal-transducing proteins that regulate cell growth and differentiation, such as protein kinases and steroid hormone receptors. Hsp90 functions in an ATP-dependent manner in cooperation with other molecular chaperones such as Cdc37 and FKBP52. Geldanamycin specifically inhibits the essential ATPase activity of Hsp90. Thus, treatment of cells with geldanamycin results in inactivation, destabilization, and degradation of Hsp90 client proteins. Because Hsp90 client proteins play important roles in the regulation of the cell cycle, cell growth, cell survival, apoptosis, and oncogenesis, geldanamycin obstructs the proliferation of cancer cells and shows anti-cancer activity in experimental animals. Although difficulties with solubility and toxicity should be overcome, Hsp90 inhibitors will be potential and effective cancer chemotherapeutic drugs with a unique profile. In fact, a modified geldanamycin with lower toxicity, 17-allylaminogeldanamycin (17-AAG), has been examined in phase I clinical trials with encouraging results.
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Receptor Tyrosine Kinases and Anticancer Therapy
Authors: Michael Medinger and Joachim DrevsReceptor and non-receptor protein tyrosine kinases (PTKs) are essential enzymes in cellular signaling processes and signal transduction pathways that regulate cell growth, differentiation, migration and metabolism by catalyzing protein phosphorylation and dephosphorylation. In recent years, different tyrosine kinase receptors were identified as regulators of tumor or tumor vessel growth. Their inhibition by specific tyrosine kinase inhibitors and antibodies targeting growth factors and their receptors were recently shown to constitute a new modality for treating cancers. The pathognomonic role of the inhibited tyrosine kinase defines the way of action, whereas the amount of expression in tumor tissue is thought to define the indication for the tumor entity. Various compounds targeting PTKs are under clinical investigation in phase I - III trials or are already approved. This review describes new drugs targeting BCR-Abl, c-kit, EGFR (epidermal growth factor receptor), tumor angiogenesis via VEGF (vascular endothelial growth factor), HER2/neu and “multitarget” tyrosine kinase inhibitors.
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Apoptosis Following Photodynamic Tumor Therapy: Induction, Mechanisms and Detection
Authors: Kristjan Plaetzer, Tobias Kiesslich, Christian B. Oberdanner and Barbara KrammerAs a treatment modality for malign and certain non-malignant diseases, photodynamic therapy (PDT) involves a two step protocol which consists of the (selective) uptake and accumulation of a photosensitizing agent in target cells and the subsequent irradiation with light in the visible range. Reactive oxygen species (ROS) produced during this process cause cellular damage and, depending on the treatment dose / severity of damage, lead to either cellular repair / survival, apoptotic cell death or necrosis. PDT-induced apoptosis has been focused on during the last years due to the intimate connection between ROS generation, mitochondria and apoptosis; by this PDT employs mechanisms different to those in the action of radio- and chemotherapeutics, giving rise to the chance of apoptosis induction by PDT even in cells resistant to conventional treatments. In this review, the (experimental) variables determining the cellular response after PDT and the known mechanistic details of PDT-triggered induction and execution of apoptosis are discussed. This is accompanied by a critical evaluation of wide-spread methods employed in apoptosis detection with special respect to in vitro / cellbased methodology.
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Targeting Cytotoxic Conjugates of Somatostatin, Luteinizing Hormone- Releasing Hormone and Bombesin to Cancers Expressing Their Receptors: A “Smarter” Chemotherapy
Authors: A. Nagy and A. V. SchallyChemotherapy is one of the main modalities in the therapy of cancer. However, an improvement in the efficacy and a reduction in the toxicity of chemotherapeutic agents remains a great challenge to oncologists. A specific delivery of cytotoxic drugs to cancerous cells may help improving both aspects. Peptide hormones, for which receptors have been found in various human cancers, can serve as carriers for a local delivery of cytotoxic agents or radiopharmaceuticals to the tumors, as demonstrated by the successful clinical use of radiolabeled somatostatin analog Octreoscan for the detection and treatment of some somatostatin receptor-positive tumors. Thus, in recent years we developed a series of cytotoxic peptide hormone conjugates based on derivatives of hypothalamic hormones such as somatostatin and luteinizing hormone-releasing hormone (LHRH), and the brain-gut hormone bombesin. To create targeted conjugates with high cytotoxic activity, a derivative of doxorubicin (DOX), 2-pyrrolino-DOX (AN-201), which is 500-1, 000 times more active than its parent compound, was developed. This agent was coupled to somatostatin octapeptide RC-121 to form cytotoxic conjugate AN-238, and to [D-Lys6]LHRH carrier to produce analog AN-207. Cytotoxic bombesin hybrid AN- 215 also contains AN-201. DOX was likewise linked to [D-Lys6]LHRH to form AN-152. A comprehensive testing of these cytotoxic conjugates in experimental models of various human and rodent cancers led to their selection as candidates for clinical trials.
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Autologous Formalin-Fixed Tumor Vaccine
By T. OhnoA novel tumor vaccine consisting of autologous formalin-fixed tumor fragments, cytokine-encapsulated microparticles, and an adjuvant was developed. Although mice experiments revealed mild efficacy, vaccination in a Phase I/IIa clinical trial of patients after resection of hepatocellular carcinoma resulted in significantly longer time before the first recurrence with no problematic adverse effect, than compared to historical control patients operated in the same department. In the followed academic Phase IIb randomized clinical trial, the vaccination significantly improved the recurrence-free survival and overall survival rates in a median follow-up of 15 months. The vaccine will be promising against recurrence of many types of human cancers after resection.
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New Methodologies for Ligand-Based Virtual Screening
Authors: Florence L. Stahura and Jürgen BajorathComputational screening of compound databases has become increasingly popular in pharmaceutical research. Virtual screening approaches can roughly be divided into target structure-based screening (often referred to as docking) and screening using active compounds as templates (ligand-based virtual screening). Ligand-based screening techniques essentially focus on comparative molecular similarity analysis of compounds with known and unknown activity, regardless of the methods or algorithms used. In this review, we first provide an overview of widely used ligand-based virtual screening approaches including various database filters and then discuss recent trends in this field and new methodological developments.
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Cell Therapy for Inner Ear Diseases
Authors: T. Nakagawa and J. ItoDegeneration of inner ear cells, especially sensory hair cells and associated neurons, results in hearing impairment and balance disorders. These disabilities are incurable because loss of hair cells and associated neurons is currently irreversible. Protection or regeneration of hair cells and associated neurons is an important area of research for developing an effective treatment for inner ear diseases. Cell therapy is a rapidly growing area of research and has potential applications in the treatment of inner ear disorders. The first attempts to examine the feasibility of cell therapy in the treatment of inner ear disorders have been performed using neural stem cells (NSCs). Grafted NSCs can survive in the inner ear and differentiate into neural, glial and/or hair cell-phenotypes, making NSC transplantation for the restoration of inner ear cells a potentially viable treatment. Further studies have suggested embryonic stem cells (ESCs), dorsal ganglion cells and cell lines derived from fetal inner ear cells could be used to restore damaged inner ear cells. Cell transplantation has also been suggested as a strategy for drug delivery into the inner ear, and the ability of NSC-derived cells to produce neurotrophins in the inner ear has been demonstrated. Results from studies using autologous bone marrow stromal cells (MSCs) indicate a high survival and migration potential suggesting that MSCs can be used as a drug delivery vehicle to the inner ear. These cell transplantation findings provide a sound foundation for the development of therapies to treat inner ear disorders.
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Volumes & issues
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Volume 31 (2025)
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Volume (2025)
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Volume 30 (2024)
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Volume 29 (2023)
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Volume 28 (2022)
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Volume 27 (2021)
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Volume 26 (2020)
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Volume 25 (2019)
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Volume 24 (2018)
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Volume 23 (2017)
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Volume 22 (2016)
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Volume 21 (2015)
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Volume 20 (2014)
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Volume 19 (2013)
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Volume 18 (2012)
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Volume 17 (2011)
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Volume 16 (2010)
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Volume 15 (2009)
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Volume 14 (2008)
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Volume 13 (2007)
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Volume 12 (2006)
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Volume 11 (2005)
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Volume 10 (2004)
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Volume 9 (2003)
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Volume 8 (2002)
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Volume 7 (2001)
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Volume 6 (2000)
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