Enzyme Prodrug Strategies For Cancer Therapy
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Enzyme Prodrug Strategies For Cancer Therapy
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Author : Roger G. Melton
language : en
Publisher: Springer Science & Business Media
Release Date : 2012-12-06
Enzyme Prodrug Strategies For Cancer Therapy written by Roger G. Melton and has been published by Springer Science & Business Media this book supported file pdf, txt, epub, kindle and other format this book has been release on 2012-12-06 with Medical categories.
Antibody-directed enzyme prodrug therapy (ADEPT) directly addresses the major problem in cancer chemotherapy-its lack of selectivity. Antibody delivery combined with the amplification provided by the enzymatic activation of prodrugs enables selection to be made between tumour and normal tissue. ADEPT offers a novel field of opportunities in the therapy of systemic cancer and may be a major advance for the treatment of solid tumours. This book is the first to describe ADEPT in detail. Each chapter reviews an aspect of the immunology, enzymology, biochemistry, chemistry, and cancer chemotherapy which have been integrated into the ADEPT concept. An additional chapter describes the related approach of gene-directed enzyme prodrug therapy (GDEPT). This latter approach is still in its infancy but ADEPT has entered the clinic. The initial clinical studies with ADEPT are included and discussed in detail.
Development Of A Novel Enzyme Prodrug Strategy For Gene Therapy Of Breast Cancer
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Author :
language : en
Publisher:
Release Date : 2000
Development Of A Novel Enzyme Prodrug Strategy For Gene Therapy Of Breast Cancer written by and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2000 with categories.
We developed and tested a novel enzyme/prodrug strategy for cancer gene therapy using Carboxypeptidase A (CPA) to enzymatically convert the prodrug methotrexate-Alpha-phenylalanine (MTX-Phe) to methotrexate (MTX). CPA is normally synthesized as a zymogen that requires proteolytic removal of its pro-peptide by trypsin in order to gain catalytic activity. In Specific Aim I in order to use CPA as a therapeutic gene we engineered a battery of mutant forms of CPA which were designed to be activated by normal cellular secretory processes. We found that the best mutant, termed CPA(sub ST3), was secreted from tumor cells in an active form and biochemical analysis revealed that it had similar activity and substrate specificity to the wild-type enzyme. In Specific Aim II we produced recombinant retroviruses coding for this mutant form of CPA and demonstrated that tumor cells infected with these viruses were potently sensitized to MTX-Phe and that there was a significant 'bystander effect' even when less than 10% of the tumor cells were expressing CPA. We were unable to carry-out in vivo analysis of the MTX-Phe based system due to the unexpected instability of MTX-Phe in vivo. However, we did synthesize an active-site mutant of CPA(sub ST3) to convert the stable prodrug MTX-3-cyclopentyl-tyrosine.
Identification And Testing Of Enzymes And Prodrugs For Use In Directed Enzyme Prodrug Therapy Strategies For The Treatment Of Cancer
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Author : Patrick Ball
language : en
Publisher:
Release Date : 2019
Identification And Testing Of Enzymes And Prodrugs For Use In Directed Enzyme Prodrug Therapy Strategies For The Treatment Of Cancer written by Patrick Ball and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2019 with categories.
Development Of A Novel Erizyme Prodrug Strategy For Gene Therapy Of Breast Cancer
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Author : Daniel Hamstra
language : en
Publisher:
Release Date : 1998
Development Of A Novel Erizyme Prodrug Strategy For Gene Therapy Of Breast Cancer written by Daniel Hamstra and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 1998 with categories.
Treatment of advanced breast cancer with standard chemotherapy is often hampered by both local an systemic toxicities. We, therefore, propose to develop an enzyme / prodrug strategy for cancer gene therapy based upon methotrexate prodrugs and the enzyme carboxypeptidase A. To that end we have developed and characterized in vitro mutant forms of carboxypeptidase A which are activated in a trypsin independent manner. Enzymatic analysis of this mutant revealed that it had identical kinetic parameters and substrate specificity as the wild-type enzyme. In addition, expression of either a soluble or cell-surface form of this mutant resulted in potent sensitization of cells in culture to methotrexate-alpha-peptide prodrugs.
Optimizing The Enzyme Prodrug Axis Of Suicide Gene Therapy Using Protein Engineering Strategies
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Author : Adam James Johnson
language : en
Publisher:
Release Date : 2011
Optimizing The Enzyme Prodrug Axis Of Suicide Gene Therapy Using Protein Engineering Strategies written by Adam James Johnson and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2011 with categories.
The unifying goal of cancer therapy is to selectively eradicate cancer cells while sparing normal tissue from damage. As many current anticancer therapies lack specificity and cause unwanted side effects there is an unmet medical need for the development of clinical strategies able to overcome these obstacles. Suicide gene therapy (SGT) is an anticancer strategy with promise to reach this goal. Nevertheless, limitations such as poor prodrug activation and suicide enzyme immunogenicity hinder its applicability in a clinical setting. The work herein describes efforts to overcome these limitations.
Recent Advancement In Prodrugs
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Author : Kamal Shah
language : en
Publisher: CRC Press
Release Date : 2020-05-13
Recent Advancement In Prodrugs written by Kamal Shah and has been published by CRC Press this book supported file pdf, txt, epub, kindle and other format this book has been release on 2020-05-13 with Science categories.
Recent Advancement in Prodrugs Drugs used as medicines have many limitations like low chemical stability, aqueous solubility, or oral absorption/bioavailability, rapid presystemic metabolism, toxicity, inadequate site specificity, or poor patient acceptance/compliance (unwanted adverse effects, unacceptable taste or odor, irritation or pain). Prodrugs design is an approach to overcome these limitations. Key features Covers recent advancements in development of prodrugs Presents balanced synthesis and applications of prodrug chemistry Discusses broad spectrum of prodrug categories and outlines industrial applications Reviews prodrugs in cancer nanomedicine, its therapy and treatment Elucidates mathematical models to study the kinetics of prodrugs This book covers recent advances in the design of prodrugs. It contains all the significant recent examples of prodrug chemistry developments and will aid academics and researchers seeking to generate new projects in the field.
Gene Dependant Enzyme Prodrug Therapy For Head And Neck Cancer
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Author : Daniel Allan Hamstra
language : en
Publisher:
Release Date : 2001
Gene Dependant Enzyme Prodrug Therapy For Head And Neck Cancer written by Daniel Allan Hamstra and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2001 with categories.
Macromolecular Anticancer Therapeutics
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Author : L. Harivardhan Reddy
language : en
Publisher: Springer Science & Business Media
Release Date : 2010-03-20
Macromolecular Anticancer Therapeutics written by L. Harivardhan Reddy and has been published by Springer Science & Business Media this book supported file pdf, txt, epub, kindle and other format this book has been release on 2010-03-20 with Medical categories.
In spite of the development of various anticancer drugs, the therapy of cancer has remained challenging for decades. The current therapy of cancer is overwhelmed because of the inability to deliver therapeutics to all regions of a tumor in effective therapeutic concentrations, intrinsic or acquired resistance to the treatment with currently available agents via genetic and epigenetic mechanisms, and toxicity. As a result, cancer therapy using conventional therapeutics and different types of treatment regimens using this therapeutics has not led to a convincing survival benefit of the patients. In this context, Macromolecular therapeutics offer several advantages over conventional low molecular therapeutics by various ways such as, enable the use of larger doses of these agents by limiting the toxicity, by enhanced permeability and retention into tumors, by tumor targeting using tumor-specific antibodies, by specific inhibition of oncogenes using anticancer oligonucleotides etc. Cancer treatment using this macromolecular therapeutics has considerably improved the survival benefit for patients. As a result, various macromolecular therapeutics are already commercialized or are under clinical development. Although we are far from a real magic bullet today, looking at the pace of research and current success in this field of macromolecular therapeutics, it appears that we are approaching a magic bullet for the efficient treatment of cancer. Thus, we believe that the subject of this book is very timely, and that the book will fill an unmet need in the market. This book is unique and assembles various types and aspects of macromolecular anticancer therapeutics for cancer therapy in one shell and conveys the importance of this interdisciplinary field to the broad audience. Thus, in a nutshell, this book details the basics of cancer, and various therapeutic strategies such as those based on macromolecular therapeutics hence can become an important reference for practitioners, oncologists, medical pharmacologists, medicinal chemists, biomedical scientists, experimental pharmacologists, pharmaceutical technologists, and particularly it can essentially become a handbook of macromolecular therapeutics for cancer therapy for graduates, post-graduates and Ph.D. students in these fields.
Drug Delivery Strategies Using Light Sensitive Molecules
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Author : Martin Dcona
language : en
Publisher:
Release Date : 2012
Drug Delivery Strategies Using Light Sensitive Molecules written by Martin Dcona and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2012 with Drug delivery systems categories.
Cancer remains one of the most dreaded diseases due to inevitable suffering and possible fatality. Only cardiac disease has caused more deaths than cancer. Present day cancer treatment involves radiation, surgery or chemotherapy. In chemotherapy, an anti-tumoral drug is used to treat the tumor either by killing or stalling the growth of the tumor cells. In certain types of cancer, for e.g. metastatic breast cancer, the first line of therapy is often chemotherapy. But the inability of current clinically approved drugs to selectively target tumor cells, ultimately results in side effects. To reduce these side effects, prodrug therapies have been developed. A prodrug is defined as a drug molecule inactivated by a temporary cap or carrier, subsequently removed by an external intra or extracellular stimulus. Several prodrug strategies such as ADEPT (Antibody's Directed Enzyme Prodrug Therapy) have been tested in clinical trials but have thus far met with limited success. In the wake of these limitations, development of photo-activatable prodrugs may be particularly desirable for minimizing the adverse side effects associated with current cancer chemotherapeutics. Photodynamic therapy (PDT) is a light dependent tumor treatment modality that has existed for many years. PDT involves a photosensitizer which is administered to the patient and later activated using the light of wavelengths between 650-800 nm. The activated photosensitizer creates singlet oxygen, which acts as cytotoxic agent to the tumor cells. But this approach has several drawbacks including slow uptake of the photosensitizer by the tumor cells and the dependence on molecular oxygen that is not always present at even moderate levels in the tumor tissues. To address these limitations of PDT, we developed a new prodrug concept called "Photocaged Permeability" in our first project, and demonstrated drug delivery using this approach. The basis of this concept is that, by attaching a hydrophilic molecule to the drug via a photosensitive linker, the permeability of the drug could be restrained. But the drug could be released at the site of the tumor after irradiating with UV light. To achieve this goal, we designed and synthesized a photosensitive drug conjugate that was comprised of doxorubicin attached to a negatively charged, cell impermeable molecule, EDANS (5-((2-Aminoethyl) amino) naphthalein-1-sulfonic acid) via a photosensitive nitroveratryl linker. Later, we performed MTT (cell viability) assays using esophageal adenocarcinoma (JH-EsoAd1) cells to determine the efficiency of our drug conjugate to induce cell death. As expected our drug conjugate was able to induce cell death, but only in presence of light. But in the dark, the cells remained unaffected. Also, we did several control studies to substantiate the fact that the cell death was actually due to drug release but not due to light or other entities. Further, we performed FACS (Fluorescence Assisted Cell Sorting) and confocal assays to show that in dark, the drug conjugate did not permeate cells. But upon irradiation with UV light, the drug was released from the conjugate, permeated the cells and induced cell death. A weakness of the above mentioned approach is that the drug is "decaged" or photo-released from the conjugates only under UV light; which cannot be translated to physiological conditions. This is because the UV light cannot penetrate deeper than 5 mm into the human skin. As a result, tumor cells that are deeply embedded in the human body cannot be treated using these approaches. To address this problem, Near Infrared (NIR) light could be used as it penetrates deeper than UV. Recently, several groups have reported using Upconverting Nanoparticles (UCNP) for the purpose of drug activation. The basis of this phenomenon is that the incidence of NIR light on these particles initiates multi-photon processes, eventually emitting UV/VIS wavelengths. The advantage of the NIR is that it deeply penetrates into the human skin. In our latest project, we have designed a drug conjugate that would be attached to UCNPs. We envision that after grafting the drug conjugate onto the nanoparticles and irradiating it with NIR drug release will occur as a result of upconversion. The above two systems describes novel methodologies for controlled release of the drug. To further improve the efficacy of the drug action, we designed new photosensitive systems based on the concept of targeted drug delivery. Targeted drug delivery is a treatment methodology in which the modified chemotherapeutic drug with higher tumor affinity could be concentrated in the tumor tissues. In certain cases, the receptors of tumor cells are targeted for the purpose of therapy. Receptors are cell surface proteins that are expressed on their plasma membrane. A select few of them such as Folic Acid Receptor (FAR) and PSMA (Prostate Specific Membrane Antigen) are overexpressed in malignant cells. In our new designs, we attached folic acid and urea based (DUPA) ligand, which were previously reported to bind to FAR and PSMA receptors respectively. Cell studies are currently underway to determine the specificity of these drug conjugates in targeting tumor cells. Once we demonstrate the above drug delivery strategies in vitro and later in vivo, we will have established novel drug delivery systems that could potentially be applied towards chemotherapeutic treatment.
Organic Materials As Smart Nanocarriers For Drug Delivery
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Author : Alexandru Mihai Grumezescu
language : en
Publisher: William Andrew
Release Date : 2018-03-26
Organic Materials As Smart Nanocarriers For Drug Delivery written by Alexandru Mihai Grumezescu and has been published by William Andrew this book supported file pdf, txt, epub, kindle and other format this book has been release on 2018-03-26 with Science categories.
Organic Materials as Smart Nanocarriers for Drug Delivery presents the latest developments in the area of organic frameworks used in pharmaceutical nanotechnology. An up-to-date overview of organic smart nanocarriers is explored, along with the different types of nanocarriers, including polymeric micelles, cyclodextrins, hydrogels, lipid nanoparticles and nanoemlusions. Written by a diverse range of international academics, this book is a valuable reference for researchers in biomaterials, the pharmaceutical industry, and those who want to learn more about the current applications of organic smart nanocarriers. Explores the most recent molecular- and structure-based applications of organic smart nanocarriers in drug delivery Highlights different smart nanocarriers and assesses their intricate organic structural properties for improving drug delivery Assesses how molecular organic frameworks lead to more effective drug delivery systems
