Abstract:
:This paper gives an overview of the available pharmacological and clinical data of a new class of anticancer drugs which act by binding DNA in the minor groove, comprising cyclopropylpyrrolo-indole (CC-1065) derivatives and Distamycin derivatives. The emphasis of this review is placed on the distinctive mode of action of these drugs. Molecular pharmacology studies indicate that CC-1065 and its derivatives, and the benzoyl mustard derivative of Distamycin, Tallimustine, possess the most striking DNA sequence specificity of alkylation observed to date for an alkylating agent of relatively small molecular weight. The effects on the regulation of gene transcription, the perturbation of the cell cycle, and the mechanism involved in the repair of the DNA lesions induced by these drugs all strongly support the view that minor groove ligands act by a mechanism different from those previously described for other anticancer drugs. The CC-1065 derivatives, Adozelesin and its prodrug, Carzelesin, and Tallimustine were found to be very effective against several murine tumours and human xenografts, and were shown to be active against experimental tumours that were resistant to other antineoplastic agents, including conventional alkylating agents. The clinical studies performed so far do not confirm in humans the remarkable antitumour activity observed in mice. The major reason appears to be a very high susceptibility of human bone marrow to both CC-1065 derivatives and Tallimustine as compared to mouse bone marrow, which makes it impossible to administer these drugs at sufficiently high doses to exert antitumour effects. The search for new minor groove binders, which possess a different DNA sequence specificity of alkylation and which are less cytotoxic for human bone marrow cells, is still in progress. It will be several years before it is possible to draw firm conclusions on the clinical effectiveness of this class of drugs.
journal_name
Expert Opin Investig Drugsjournal_title
Expert opinion on investigational drugsauthors
D'Incalci M,Sessa Cdoi
10.1517/13543784.6.7.875subject
Has Abstractpub_date
1997-07-01 00:00:00pages
875-84issue
7eissn
1354-3784issn
1744-7658journal_volume
6pub_type
杂志文章abstract:BACKGROUND:Age-related macular degeneration (AMD) affects > 14 million individuals worldwide. Although 90% of patients with AMD have the dry form, neovascular AMD accounts for the vast majority of patients who develop legal blindness. Until recently, few treatment options existed for treatment of neovascular AMD. The a...
journal_title:Expert opinion on investigational drugs
pub_type: 杂志文章,评审
doi:10.1517/13543780903201684
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abstract:INTRODUCTION:Minimal change disease (MCD) and Focal and segmental glomerulosclerosis (FSGS) are two of the major causes of nephrotic syndrome (NS) in children and adults. According to KDIGO (Kidney Disease: Improving Global Outcomes) guidelines, the treatment of adult primary MCD and FSGS should be based on immunosuppr...
journal_title:Expert opinion on investigational drugs
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journal_title:Expert opinion on investigational drugs
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abstract::Interstitial cystitis (IC) is a painful, sterile, disorder of the urinary bladder characterised by urgency, frequency, nocturia and pain. IC occurs primarily in women but also in men with recent findings indicating that chronic, abacterial prostatitis may be a variant of this condition. The prevalence of IC has ranged...
journal_title:Expert opinion on investigational drugs
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abstract:INTRODUCTION:The N-methyl-d-aspartate receptor-ionophore complex plays a key role in learning and memory and has efficacy in animals and humans with affective disorders. GLYX-13 is an N-methyl-d-aspartate receptor (NMDAR) glycine-site functional partial agonist and cognitive enhancer that also shows rapid antidepressan...
journal_title:Expert opinion on investigational drugs
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abstract:IMPORTANCE OF THE FIELD:Hepatitis C virus (HCV) is the main agent of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma in the western world. It affects more than 170 million people worldwide. HCV treatment, based on the combination of Peg-interferon and ribavirin, is effective in about 50% of treated pati...
journal_title:Expert opinion on investigational drugs
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journal_title:Expert opinion on investigational drugs
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journal_title:Expert opinion on investigational drugs
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journal_title:Expert opinion on investigational drugs
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abstract::Oxcarbazepine (OXC) was introduced in 1990 and is now registered in 54 countries worldwide as monotherapy, as add-on treatment for partial seizures, with or without secondarily generalised seizures, and primary generalised tonic-clonic seizures. OXC and its active metabolite, monohydroxy derivative (MHD), block voltag...
journal_title:Expert opinion on investigational drugs
pub_type: 杂志文章
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abstract:INTRODUCTION:Inhibitors against the PD-1/PD-L1 pathway are revolutionizing the treatment and management of malignancies. AREAS COVERED:We summarize our current understanding of the function of PD-1, its role in immune evasion, the clinical data available that support the use of PD-1 antagonist in Hodgkin and non-Hodgk...
journal_title:Expert opinion on investigational drugs
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abstract:INTRODUCTION:Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder caused by mutations in the dystrophin (DMD) gene. Most patients die from respiratory failure or cardiomyopathy. There are significant unmet needs for treatments for DMD as the standard of care is principally limited to symptom relief throu...
journal_title:Expert opinion on investigational drugs
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abstract:INTRODUCTION:Signal transducer and activator of transcription 3 (STAT3) controls a key signaling pathway in the development of many malignant diseases. Several genetic studies have proven its central role in the regulation of apoptosis, proliferation, angiogenesis and immune responses making it an attractive target for...
journal_title:Expert opinion on investigational drugs
pub_type: 杂志文章,评审
doi:10.1517/13543784.2011.601739
更新日期:2011-09-01 00:00:00
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journal_title:Expert opinion on investigational drugs
pub_type: 杂志文章
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abstract::IBC's 5(th) Annual Conference on Blood Substitutes was held on November 20-21, 1997. Approximately 100 medical researchers, academic scientists, blood substitute company speakers and representatives from major pharmaceutical companies with an interest or partner in the field attended. The papers presented focused on t...
journal_title:Expert opinion on investigational drugs
pub_type: 杂志文章
doi:10.1517/13543784.7.2.283
更新日期:1998-02-01 00:00:00
abstract::BCR-ABL, a constitutively active tyrosine kinase, causes chronic myeloid leukaemia (CML). Rational development of drugs targeting BCR-ABL has significantly improved the treatment of CML. Imatinib (a BCR-ABL tyrosine kinase inhibitor) produces haematological and cytogenetic remissions across all phases of CML and is th...
journal_title:Expert opinion on investigational drugs
pub_type: 杂志文章,评审
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更新日期:2007-05-01 00:00:00
abstract::Gaucher disease (GD) is an inborn error of glycosphingolipid metabolism, associated with multisystemic manifestations resulting from the lysosomal accumulation of an incompletely degraded material (glucosylceramide) within cells of monocyte/macrophage lineage. In the majority of GD patients with non-neurological invol...
journal_title:Expert opinion on investigational drugs
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abstract::All of the glucose-lowering agents available today for the treatment of diabetes resulted from the in vivo antidiabetic drug discovery approach. This is not surprising given the limited understanding of the biochemical basis of diabetes. With new developments in the elucidation of the biochemistry and physiology of di...
journal_title:Expert opinion on investigational drugs
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doi:10.1517/13543784.7.6.987
更新日期:1998-06-01 00:00:00
abstract::Binding of microbial cell surface adhesins to host receptor molecules is a critical early step in microbial infection and pathogenesis. Anti-adhesive strategies aimed at blocking this interaction offer an attractive means of preventing infection at an early stage. The strategy should reduce the likelihood of resistant...
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abstract::Two classes of luteinising hormone-releasing hormone (LHRH) analogues have been developed so far to be used for oncological therapies: LHRH agonists and antagonists. LHRH agonists are widely and successfully used for the management of steroid-dependent malignancies. Chronic administrations of these compounds result in...
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abstract:INTRODUCTION:Soft tissue sarcomas (STS) are a rare and difficult to treat malignancy. Efforts to utilize targeted therapy have been ongoing for the last decade and have resulted in the approval of pazopanib for treatment of advanced disease. Although several other agents have been investigated, the inability to predict...
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abstract::Poly (ADP-ribose) polymerase (PARP) plays a key role in DNA repair mechanisms by detecting and initiating repair after DNA strand breaks. Inhibition of PARP in DNA repair-defective tumors (like those with BRCA1 or BRCA2 mutations) can lead to gross genomic instability and cell death. Likewise, combining PARP inhibitio...
journal_title:Expert opinion on investigational drugs
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abstract:INTRODUCTION:Multiple myeloma (MM) remains an incurable malignancy indicating a need for continued investigation of novel therapies. Recent studies have highlighted the role of cyclin-dependent kinases (CDK) in the pathogenesis of MM. PD0332991 (Palbociclib) is an orally bioavailable, highly selective inhibitor of the ...
journal_title:Expert opinion on investigational drugs
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abstract::Complement is part of the innate immune system, acting to protect the host from microorganisms such as bacteria, and other foreign and abnormal cells. Although primarily protective, complement activation can also cause damage to the host. In a number of inflammatory diseases, including rheumatoid arthritis and dermati...
journal_title:Expert opinion on investigational drugs
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abstract::Introduction: Plasma kallikrein is a mediator of vascular leakage and inflammation. Activation of plasma kallikrein can induce features of diabetic macular edema (DME) in preclinical models. Human vitreous shows elevated plasma kallikrein levels in patients with DME. Because of the incomplete response of some patient...
journal_title:Expert opinion on investigational drugs
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abstract::Leukotriene B(4) (LTB(4)) is a lipid inflammatory mediator derived from membrane phospholipids by the sequential actions of cytosolic phospholipase A2 (PLA2), 5-lipoxygenase (5-LO) and leukotriene A(4) (LTA(4)) hydrolase. Several inflammatory diseases, including asthma, chronic obstructive pulmonary disease, arthritis...
journal_title:Expert opinion on investigational drugs
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abstract::Hepatitis C virus is the most common chronic, blood-bourne infection, affecting 170 million people worldwide, approximately 3% of the global population. Of those infected with hepatitis C virus, 50 - 85% will develop chronic hepatitis C. Although hepatitis C is primarily a disease of the liver, a diagnosis is currentl...
journal_title:Expert opinion on investigational drugs
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