Genetically engineered hypoxia-responsive promoters.
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 179 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 252 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
\n'}],latestNews:[{slug:"stanford-university-identifies-top-2-scientists-over-1-000-are-intechopen-authors-and-editors-20210122",title:"Stanford University Identifies Top 2% Scientists, Over 1,000 are IntechOpen Authors and Editors"},{slug:"intechopen-authors-included-in-the-highly-cited-researchers-list-for-2020-20210121",title:"IntechOpen Authors Included in the Highly Cited Researchers List for 2020"},{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"},{slug:"all-intechopen-books-available-on-perlego-20201215",title:"All IntechOpen Books Available on Perlego"},{slug:"oiv-awards-recognizes-intechopen-s-editors-20201127",title:"OIV Awards Recognizes IntechOpen's Editors"},{slug:"intechopen-joins-crossref-s-initiative-for-open-abstracts-i4oa-to-boost-the-discovery-of-research-20201005",title:"IntechOpen joins Crossref's Initiative for Open Abstracts (I4OA) to Boost the Discovery of Research"},{slug:"intechopen-hits-milestone-5-000-open-access-books-published-20200908",title:"IntechOpen hits milestone: 5,000 Open Access books published!"},{slug:"intechopen-books-hosted-on-the-mathworks-book-program-20200819",title:"IntechOpen Books Hosted on the MathWorks Book Program"}]},book:{item:{type:"book",id:"1867",leadTitle:null,fullTitle:"Numerical Modelling",title:"Numerical Modelling",subtitle:null,reviewType:"peer-reviewed",abstract:"This book demonstrates applications and case studies performed by experts for professionals and students in the field of technology, engineering, materials, decision making management and other industries in which mathematical modelling plays a role. 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Their principal characteristic is to feature a high surface area capable of storing energy or convert it from one form to another. This property could be used to enhance the performance of foams in terms of life existence, robustness and reliability. For these reasons, this book aim is to offer to readers a broad state-of-the-art situation of the current applications of foams, including thermal and acoustic issues and focusing on their new functions, usages and future trends.
",isbn:"978-1-83969-585-8",printIsbn:"978-1-83969-584-1",pdfIsbn:"978-1-83969-586-5",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,hash:"9495e848f41431e0ffb3be12b4d80544",bookSignature:"Dr. Marco Caniato",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10699.jpg",keywords:"Foaming, Vacuum, Molten Metal, Formability, Lightweight, Insulation, Vibration Reduction, Absorption, Resistance, Shock, Environmental Protection, Recycling",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 24th 2021",dateEndSecondStepPublish:"March 24th 2021",dateEndThirdStepPublish:"May 23rd 2021",dateEndFourthStepPublish:"August 11th 2021",dateEndFifthStepPublish:"October 10th 2021",remainingDaysToSecondStep:"23 days",secondStepPassed:!1,currentStepOfPublishingProcess:2,editedByType:null,kuFlag:!1,biosketch:'Dr. Marco Caniato is an internationally-oriented scientist with 10 years of experience in the Italian Universities of Trieste and of Ferrara. He is the inventor of 6 registered patents among which are "Acoustic panel for noise barriers and noise barrier provided with such a panel" and “Multilayer panel for building use".',coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"312499",title:"Dr.",name:"Marco",middleName:null,surname:"Caniato",slug:"marco-caniato",fullName:"Marco Caniato",profilePictureURL:"https://mts.intechopen.com/storage/users/312499/images/system/312499.jpg",biography:"Dr. Marco Caniato is an internationally-oriented scientist with 10 years of experience in well-known Italian universities. His research is focused on the effects of materials thermal and acoustic insulation and behavior. Specifically, his interests are addressed to their influence on human beings' comfort. Dr. Caniato published more than 80 papers, including conference proceedings, journal papers, and book chapters. He is also the inventor of 6 registered patents and often he is appointed organizer in several international congresses.",institutionString:"Free University of Bozen-Bolzano",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Free University of Bozen-Bolzano",institutionURL:null,country:{name:"Italy"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"8",title:"Chemistry",slug:"chemistry"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"347258",firstName:"Marica",lastName:"Novakovic",middleName:null,title:"Dr.",imageUrl:"//cdnintech.com/web/frontend/www/assets/author.svg",email:"marica@intechopen.com",biography:null}},relatedBooks:[{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophanides",surname:"Theophile",slug:"theophanides-theophile",fullName:"Theophanides Theophile"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4816",title:"Face Recognition",subtitle:null,isOpenForSubmission:!1,hash:"146063b5359146b7718ea86bad47c8eb",slug:"face_recognition",bookSignature:"Kresimir Delac and Mislav Grgic",coverURL:"https://cdn.intechopen.com/books/images_new/4816.jpg",editedByType:"Edited by",editors:[{id:"528",title:"Dr.",name:"Kresimir",surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3621",title:"Silver Nanoparticles",subtitle:null,isOpenForSubmission:!1,hash:null,slug:"silver-nanoparticles",bookSignature:"David Pozo Perez",coverURL:"https://cdn.intechopen.com/books/images_new/3621.jpg",editedByType:"Edited by",editors:[{id:"6667",title:"Dr.",name:"David",surname:"Pozo",slug:"david-pozo",fullName:"David Pozo"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"17924",title:"Gene Therapy Strategy for Tumour Hypoxia",doi:"10.5772/17645",slug:"gene-therapy-strategy-for-tumour-hypoxia",body:'\n\t\tA characteristic feature of solid tumours is the presence of cells under very low oxygen tensions, hypoxia. These cells, so called hypoxic tumour cells, express a transcription factor, hypoxia-inducible factor 1 (HIF-1), which induces the expression of more than one hundred genes related to angiogenesis, invasion, metastasis, and resistance to conventional treatments such as chemotherapy and radiotherapy. However, because hypoxia is unique to locally advanced malignant tumours, it provides the opportunity to develop tumour-specific targeting strategies. Such an approach has been applied to gene therapy; for example, hypoxia-activated gene therapy using HIF-1-dependent promoters resulted in the selective expression of therapeutic genes and anti-tumour effects with minimum side effects in normal tissues. Here, I review recent advances in the development of cancer gene therapy strategies targeting hypoxic/HIF-1-active tumour cells.
\n\t\tMost human tumours are highly heterogeneous and involve diverse microenvironments. A typical microenvironment seen in solid tumours is hypoxia, low-oxygen conditions under physiological level (Thomlinson & Gray, 1955; Vaupel, Kallinowski, & Okunieff, 1989). Tumour hypoxia is a concern in cancer therapy because it increases the metastatic and angiogenic potential of cancer cells (Erler et al., 2006; Forsythe et al., 1996; Yang et al., 2008) and can render cancer cells resistant to radiation and chemotherapy (Brown & Wilson, 2004; Teicher, 1994; Thomlinson & Gray, 1955).
\n\t\t\tA typical feature of cancer cells is an extraordinarily accelerated proliferation caused by the activation of oncogenes and/or disruption of tumour suppressor genes (Hanahan & Weinberg, 2000). It leads to an imbalance in the supply and consumption of O2 in a solid tumour. This disequilibrium along with the inadequate diffusion of molecular oxygen can cause a dynamic gradient of O2 content in a solid tumour (Thomlinson & Gray, 1955; Vaupel et al., 1989). Tumour cells proliferate and grow actively only if supplied with enough oxygen and nutrients from tumour blood vessels; therefore, malignant solid tumours grow as a conglomerate of so-called “tumour cords” in each of which a blood vessel is sequentially surrounded with well-oxygenated viable cells (normoxic cells), dormant cells under low oxygen conditions (hypoxic cells), and dead cells (necrotic cells) Fig. 1(Hall, 1994). Because of the distance that O2 can diffuse, hypoxic cells exist 70-100 μm from a tumour blood vessel in a tumour cord (Hall, 1994). Hypoxic conditions are usually defined as < 2% O2, and anoxic conditions (severe hypoxia) as < 0.02% O2.
\n\t\t\t\tSpatial relationship between blood vessels and hypoxia in a malignant solid tumour. Chronic hypoxic regions (red) exist 70-100 μm from tumour blood vessels. Acute/cycling hypoxia caused by fluctuations in tumour blood flow occurs proximal to tumour blood vessels.
In addition to areas of chronic hypoxia, malignant tumours contain cancer cells which are temporally exposed to low oxygen conditions for minutes to hours and then reoxygenated (Brown, 1979). This phenomenon, called “acute hypoxia”, frequently reoccurs during tumour growth, leading to “cycling hypoxia”. The occurrence of acute and cycling hypoxia is attributed to the fact that tumour blood vessels are quite immature and tortuous; and therefore, tumour blood flow fluctuates dramatically during tumour growth (Brown & Wilson, 2004).
\n\t\t\tCancer cells are known to become chemo-resistant in hypoxic regions of locally advanced solid tumours through multiple mechanisms (Kizaka-Kondoh, Inoue, Harada, & Hiraoka, 2003; Teicher, 1994). First, because hypoxic regions occur far from functional vasculatures, the diffusion and delivery of most anticancer drugs are not extensive enough to have a cytotoxic effect (Durand, 1994; Hicks et al., 2006; Tannock, 1998). Second, the cytotoxicity of some anticancer drugs is known to depend on molecular oxygen. For example, bleomycin is reported to chelate metal ions, produce a pseudoenzyme that reacts with oxygen and generates superoxide and hydroxide free radicals, and then cleave DNA. Therefore, the cytotoxic effect of the drug dramatically decreases in the absence of O2 (Batchelder, Wilson, Hay, & Denny, 1996; Teicher, Lazo, & Sartorelli, 1981). Third, alkylating agents and antimetabolites are also less effective under hypoxic conditions. These kinds of drugs are the most effective against highly proliferating cancer cells, and therefore, hypoxic tumour cells, which are known to be dormant/less proliferating, can tolerate them (Tannock, 1968). Fourth, hypoxia upregulates the expression of genes involved in drug resistance, including the gene for p-glycoprotein (Comerford et al., 2002; Wartenberg et al., 2003). Finally, there is evidence that hypoxia can enhance genetic instability in tumour cells (N. Chan et al., 2008), thus allowing a more rapid development of drug resistance.
\n\t\t\tIonizing radiation produces DNA damage, such as DNA double/single strand breaks, DNA base damage, and DNA-DNA and DNA-protein crosslinks (Hall, 1994). The presence or absence of molecular oxygen influences the damage and death of cancer cells (Brown & Wilson, 2004; Thomlinson & Gray, 1955). This phenomenon, the so-called oxygen effect, was first identified in 1912 with the observation that the skin reaction to a radium applicator dramatically decreased when the applicator was pushed tightly onto the skin and consequently decreased blood flow there. The breakthrough linking the effect of oxygen with radioresistance of cancer cells was made by Thomlinson and Gray in 1955 (Thomlinson & Gray, 1955). They proposed that oxygen levels decreased in a solid tumour through successive layers of cancer cells distal to blood vessels, and cancer cells a distance of about 10 cell diameters from vessels are viable but radioresistant. Actually, cancer cells become 2-3 times more radioresistant under hypoxic conditions than normoxic conditions (Brown & Wilson, 2004).
\n\t\t\t\tThe hypoxia-mediated radioresistance is attributed to both chemical and biological mechanisms. Ionizing radiation induces ionization in or close to the genomic DNA of target cells and produces radicals (Brown & Wilson, 2004). The DNA radicals are subjected to oxidation in the presence of oxygen, leading to fixation of the damage. In the absence of oxygen, however, the DNA radicals are reduced by compounds containing sulfhydryl groups (SH groups), which restore the DNA to its original form. Therefore, DNA damage, especially irreparable double stranded breaks, is significantly less severe in the absence of molecular oxygen. Biological mechanisms are also important. It has been elucidated that hypoxic stimuli trigger changes in both the “DNA damage repair pathway” (Bindra, Crosby, & Glazer, 2007) and the “cell death/survival signaling pathway”. Moreover, recent advances in molecular and cellular biology revealed an important role for a transcription factor, hypoxia-inducible factor 1 (HIF-1), in tumour radioresistance (see Section 3 for details) (Harada & Hiraoka, 2010).
\n\t\t\tIn addition to mediating resistance to conventional treatments, hypoxia is known to increase the metastatic and angiogenic potential of tumour cells. Cancer patients with relatively more hypoxic regions have a tendency to suffer from distant metastasis as well as local recurrence regardless of whether the initial treatment is surgery or radiation therapy (Brizel et al., 1996). Recent molecular biological analyses have revealed that hypoxia stimulates the expression of a number of genes involved in metastatic cascades, such as lysyl oxidase and the chemokine receptor, CXCR4, osteopoetin (D. A. Chan & Giaccia, 2007; Erler et al., 2006; Rofstad, 2000). Also, cancer cells under hypoxic conditions trigger angiogenesis in order to improve surrounding conditions and obtain enough oxygen and nutrients for their survival (Folkman, 1971). HIF-1 is known to play a pivotal role in the hypoxia-mediated increase in both the metastatic and angiogenic potential of cancer cells.
\n\t\t\tMolecular and cellular biological research has identified HIF-1 as an important transcription factor in hypoxia-mediated angiogenesis, metastasis, and resistance to chemo/radiotherapy.
\n\t\t\tHIF-1 is a heterodimeric transcription factor composed of alpha (HIF-1α) and beta (HIF-1β/ARNT) subunits (Wang, Jiang, Rue, & Semenza, 1995). Its hypoxia-dependent activity is mainly regulated through the stabilization and modification of the HIF-1α subunit (Fig. 2).
\n\t\t\t\tMolecular mechanism behind the activation of HIF-1 under Hypoxic conditions.
The best-characterized regulatory mechanism is that modulating HIF-1α’s stability. Under well-oxygenated normoxic conditions, prolyl hydroxylation (by prolyl hydroxylases [PHDs]) and subsequent ubiquitination (by von-Hippel Lindau (VHL)-containing E3 ubiquitin-protein ligase) of the oxygen-dependent degradation (ODD) domain of HIF-1α leads to rapid degradation of HIF-1α with a half life of 5-8 min. Consequently, HIF-1 is inactive under normoxic conditions (Berra, Roux, Richard, & Pouyssegur, 2001; Hirota & Semenza, 2005; Jaakkola et al., 2001\n\t\t\t\t\t; Maxwell et al., 1999; Semenza, 2001). On the other hand, under oxygen-deprived hypoxic conditions, HIF-1α becomes stable because oxygen-depletion directly decreases the PHDs’ activity (Jaakkola et al., 2001). Then, HIF-1α interacts with HIF-1β, forms a heterodimer, HIF-1 (Wang et al., 1995), binds to its cognate DNA sequence, the hypoxic-responsive element (HRE), and finally induces the expression of various genes related to angiogenesis, metastasis, glycolysis and so on (D. A. Chan & Giaccia, 2007; Erler et al., 2006; Forsythe et al., 1996; Kim, Gao, & Dang, 2007; Rofstad, 2000).
\n\t\t\t\tIn addition to the regulation of HIF-1α’s stability, another post-translational modification of HIF-1α is known to function in the regulation of the transactivational activity of HIF-1. Under normoxic conditions, factor inhibiting HIF-1 (FIH-1) becomes active and hydroxylates an asparagine residue (N803) of HIF-1α (Hirota & Semenza, 2005; Mahon, Hirota, & Semenza, 2001; Semenza, 2001). The asparaginyl hydroxylation blocks the interaction of HIF-1α with the transcriptional co-factor p300 and CBP, resulting in the suppression of HIF-1’s transactivational activity. Because oxygen is a substrate of FIH-1 as well as PHDs, HIF-1’s transactivational activity is restored under oxygen-deprived hypoxic conditions.
\n\t\t\tIn cancer cells, HIF-1 plays pivotal roles in the adaptation to (metabolic reprograming), evasion from (invasion and metastasis), and improvement of (angiogenesis) severe hypoxic conditions (D. A. Chan & Giaccia, 2007; Erler et al., 2006; Forsythe et al., 1996; Semenza, 2007, 2008). Concerning angiogenesis in locally advanced malignant tumours, an up-regulation of HIF-1 activity caused by intratumoural hypoxia is associated with the overexpression of vascular endothelial growth factor (VEGF), a glycoprotein responsible for angiogenesis and vasculogenesis (Forsythe et al., 1996). Concerning the metabolic reprogramming of cancer cells, HIF-1 induces the expression of genes encoding glucose transporters and glycolytic enzymes to facilitate glycolysis (Semenza, 2009; Wood et al., 1998). At the same time, HIF-1-dependent genes decrease both mitochondrial metabolism (Fukuda et al., 2007; Semenza, 2007) and mitochondrial mass (Semenza, 2008; H. Zhang et al., 2008). These functions of HIF-1 are responsible for both the efficient production of ATP even under oxygen-deprived conditions and the decrease in the cytotoxic reactive oxygen species (ROS) produced through incomplete oxidative phosphorylation under hypoxic conditions (Fukuda et al., 2007; Semenza, 2007, 2009). Concerning invasion and metastasis, HIF-1 is known to trigger various pathways including epithelial-mesenchymal transition (EMT) and expression of the Met protooncogene and lysyl oxidase, which function in tumour metastasis (Erler et al., 2006; Pennacchietti et al., 2003).
\n\t\t\tPreclinical studies have found that inhibition of intratumour HIF-1 activity by a pharmacological HIF-1 inhibitor, YC-1, or by a dominant negative mutant of HIF-1α and the knockdown of HIF-1α expression by short hairpin RNA or short interfering RNA significantly delayed tumour growth after radiation (Harada et al., 2009; Moeller, Cao, Li, & Dewhirst, 2004; Moeller et al., 2005; X. Zhang et al., 2004). It was also confirmed through clinical studies that HIF-1α expression correlates with a poor prognosis after radiation therapy (Aebersold et al., 2001; Irie, Matsuo, & Nagata, 2004; Ishikawa et al., 2004). These results imply that HIF-1 has a certain biological function to increase tumour radioresistance. Actually, HIF-1-mediated radioresistance has been recently revealed: 1) radiation activates HIF-1 in a solid tumour, 2) HIF-1 induces the expression of VEGF, 3) VEGF protects endothelial cells from the cytotoxic effects of radiation, and 4) the radio-protected tumour blood vessels assure the supply of oxygen and nutrients to tumour cells and promote tumour growth (Harada et al., 2009; Moeller et al., 2004; Zeng et al., 2008).
\n\t\t\tBecause hypoxic/HIF-1-active cells are known to mediate tumour malignancy and resistance to conventional treatments, and because hypoxia has been recognized as a tumour-specific microenvironment, recent studies have tried to exploit hypoxic cells as targets for cancer therapy (Brown & Wilson, 2004; Harris, 2002; Semenza, 2003). Dachs et al. were the first to apply this concept to gene therapy (\n\t\t\t\t\tDachs, Patterson, et al., 1997\n\t\t\t\t). Since they demonstrated the effectiveness of hypoxia-specific gene therapy strategy using the HIF-1/HRE system, extensive efforts have been devoted to developing genetically engineered hypoxia-responsive promoters.
\n\t\t\tVarious HREs, such as murin phosphoglycerate kinase-1 (PGK-1) HRE, human enolase (ENO) HRE, murin lactate dehydrogenase (mLDH-A) HRE, human erythropoietin (EPO) HRE, and human VEGF HRE, have been used to develop artificial hypoxia-responsive promoters (Table 1) (Binley, Iqball, Kingsman, Kingsman, & Naylor, 1999; Boast et al., 1999; \n\t\t\t\t\t\tDachs, Patterson, et al., 1997\n\t\t\t\t\t; Harada et al., 2007; Rinsch et al., 1997; Shibata, Akiyama, Noda, Sasai, & Hiraoka, 1998; Shibata, Giaccia, & Brown, 2000). The number of HREs and combination with the basal promoter influence the hypoxia/HIF-1-responsiveness of each HRE-containing promoter (Table 1).
\n\t\t\t\tAbove all, the combination of five repeats of a HRE derived from the human VEGF promoter and the human cytomegarovirus (CMV) minimal promoter (mp), the so-called “the 5HRE promoter“, showed intense hypoxia-responsiveness and exhibited a more than 500-fold increase in luciferase activity in response to hypoxic stimuli (Shibata et al., 2000). Moreover, the absolute level of luciferase activity from the 5HRE promoter under hypoxic conditions reached the same level as that from the constitutively active CMV-driven promoter under normoxic conditions (Shibata et al., 2000).
\n\t\t\t\tHowever, the 5HRE promoter still has problems relating to the development of gene therapy. It shows a certain level of unwanted gene expression even when oxygen is available under normoxic conditions (Harada et al., 2007), which would cause high basal expression of therapeutic genes and result in side effects in well-oxygenated normal tissues. In order to decrease leakage under normoxic conditions, I and my colleagues came up with the idea of utilizing the ODD domain of HIF-1α. We fused the coding sequence of the ODD domain to that of luciferase, and inserted the fusion gene downstream of the 5HRE promoter. The resultant 5HREp-ODD-luc gene showed little leakage under normoxic conditions. Leakage from the conventional 5HREp-luc gene was 1.4 × 103 (arbitary units), on the other hand, that from the novel 5HREp-ODD-luc gene was just 1.5 × 101 (arbitary units), almost the same as the background level. Moreover, the oxygen-dependent destabilizing effect of the ODD domain contributed to an increase in the hypoxia-responsiveness to about 4.7 × 104.
\n\t\t\t\tThe potential of hypoxia/HIF-1-dependent promoters in vivo has been proved through immunohistochemical analyses and optical imaging experiments. The human melanoma cell line, Be11, was stably transfected with a plasmid expressing a derivative of EGFP, d2EGFP, under the control of the 5HRE promoter, and transplanted into immunodeficient nude mice
\n\t\t\t\tHRE | \n\t\t\t\t\t\t\tBasal Promoter | \n\t\t\t\t\t\t\tReporter Gene | \n\t\t\t\t\t\t\tInduction Ratio | \n\t\t\t\t\t\t\tReferences | \n\t\t\t\t\t\t
3 × mPGK-1 | \n\t\t\t\t\t\t\tmPGK-1 | \n\t\t\t\t\t\t\tCD2 | \n\t\t\t\t\t\t\t1.4-1.9 | \n\t\t\t\t\t\t\tDachs, 1997 | \n\t\t\t\t\t\t
3 × mPGK-1 | \n\t\t\t\t\t\t\tminHSV TK | \n\t\t\t\t\t\t\tCD2 | \n\t\t\t\t\t\t\t2.2-2.33 | \n\t\t\t\t\t\t|
3 × mPGK-1 | \n\t\t\t\t\t\t\t9-27 gene | \n\t\t\t\t\t\t\tCD2 | \n\t\t\t\t\t\t\t2.2-4.1 | \n\t\t\t\t\t\t|
mPGK-1 | \n\t\t\t\t\t\t\tmPGK-1 | \n\t\t\t\t\t\t\thEPO | \n\t\t\t\t\t\t\t2.7 | \n\t\t\t\t\t\t\tRinsch, 1997 | \n\t\t\t\t\t\t
hVEGF | \n\t\t\t\t\t\t\thVEGF | \n\t\t\t\t\t\t\tluciferase | \n\t\t\t\t\t\t\t3.3-8.5 | \n\t\t\t\t\t\t\tShibata, 1998 | \n\t\t\t\t\t\t
hEPO | \n\t\t\t\t\t\t\tSV40 | \n\t\t\t\t\t\t\tluciferase | \n\t\t\t\t\t\t\t2-5 | \n\t\t\t\t\t\t|
5 × hVEGF | \n\t\t\t\t\t\t\thVEGF | \n\t\t\t\t\t\t\tluciferase | \n\t\t\t\t\t\t\t20 | \n\t\t\t\t\t\t|
5 × hVEGF | \n\t\t\t\t\t\t\thVEGF+ minE1b | \n\t\t\t\t\t\t\tluciferase | \n\t\t\t\t\t\t\t44 | \n\t\t\t\t\t\t|
3 × hENO | \n\t\t\t\t\t\t\tSV40 | \n\t\t\t\t\t\t\tluciferase | \n\t\t\t\t\t\t\t120 | \n\t\t\t\t\t\t\tBoast, 1999 | \n\t\t\t\t\t\t
3 × hENO | \n\t\t\t\t\t\t\tSV40 | \n\t\t\t\t\t\t\tluciferase | \n\t\t\t\t\t\t\t63 | \n\t\t\t\t\t\t|
2 × mLDHA | \n\t\t\t\t\t\t\tSV40 | \n\t\t\t\t\t\t\tluciferase | \n\t\t\t\t\t\t\t81 | \n\t\t\t\t\t\t|
4 × mLDHA | \n\t\t\t\t\t\t\tSV40 | \n\t\t\t\t\t\t\tluciferase | \n\t\t\t\t\t\t\t65 | \n\t\t\t\t\t\t|
4 × hEPO | \n\t\t\t\t\t\t\tSV40 | \n\t\t\t\t\t\t\tluciferase | \n\t\t\t\t\t\t\t255 | \n\t\t\t\t\t\t|
3 × hENO | \n\t\t\t\t\t\t\tSV40 | \n\t\t\t\t\t\t\tluciferase | \n\t\t\t\t\t\t\t146 | \n\t\t\t\t\t\t|
3 × mPGK-1+ VEGF 3\' UTR | \n\t\t\t\t\t\t\tSV40 | \n\t\t\t\t\t\t\tluciferase | \n\t\t\t\t\t\t\t300 | \n\t\t\t\t\t\t|
mPGK-1 | \n\t\t\t\t\t\t\tSV40 | \n\t\t\t\t\t\t\tβ-gal | \n\t\t\t\t\t\t\t8.5-50 | \n\t\t\t\t\t\t\tBinley, 1999 | \n\t\t\t\t\t\t
5 or 10 × hVEGF | \n\t\t\t\t\t\t\tSV40 | \n\t\t\t\t\t\t\tluciferase | \n\t\t\t\t\t\t\t54-57 | \n\t\t\t\t\t\t\tShibata, 2000 | \n\t\t\t\t\t\t
5 or 10 × hVEGF+ 5\' VEGF UTR | \n\t\t\t\t\t\t\tSV40 | \n\t\t\t\t\t\t\tluciferase | \n\t\t\t\t\t\t\t23-27 | \n\t\t\t\t\t\t|
5-10 × hVEGF+ 5\' VEGF UTR | \n\t\t\t\t\t\t\tE1b | \n\t\t\t\t\t\t\tluciferase | \n\t\t\t\t\t\t\t56-60 | \n\t\t\t\t\t\t|
5 × hVEGF+ 5\' VEGF UTR | \n\t\t\t\t\t\t\tE1b | \n\t\t\t\t\t\t\tluciferase | \n\t\t\t\t\t\t\t131 | \n\t\t\t\t\t\t|
5 × hVEGF+ 5\' VEGF UTR+ 3\' VEGF UTR | \n\t\t\t\t\t\t\tE1b | \n\t\t\t\t\t\t\tluciferase | \n\t\t\t\t\t\t\t193 | \n\t\t\t\t\t\t|
5 × hVEGF | \n\t\t\t\t\t\t\thCMV-mp | \n\t\t\t\t\t\t\tluciferase | \n\t\t\t\t\t\t\t524 | \n\t\t\t\t\t\t|
5 × hVEGF | \n\t\t\t\t\t\t\thCMV-mp | \n\t\t\t\t\t\t\tluciferase | \n\t\t\t\t\t\t\t47,000 | \n\t\t\t\t\t\t\tHarada, 2007 | \n\t\t\t\t\t\t
Genetically engineered hypoxia-responsive promoters.
(Liu et al., 2005). Resultant tumour xenografts showed heterogeneous, partition-dependent and weak green fluorescence. Immunohistochemical analyses confirmed that d2EGFP-positive cells were located at the boundary between well-oxygenated viable regions and necrotic regions, which were stained with a hypoxia marker, pimonidazole (Raleigh et al., 1998). When human cervical cancer cells, HeLa cells, transfected with the 5HREp-luc or 5HREp-ODD-luc gene were transplanted into nude mice, the resultant xenografts showed intense bioluminescence after the tumour-bearing leg was ligated and the blood flow to the xenograft decreased (Harada, Kizaka-Kondoh, & Hiraoka, 2005; Harada et al., 2007).
\n\t\t\tTo exploit tumour hypoxia/HIF-1 active cells as a tumour-specific therapeutic target, several approaches have been examined including (1) hypoxia-targeting using hypoxia/HIF-1-responsive promoters combined with Gene-Directed Enzyme Prodrug Therapies (GDEPT) (Greco, Marples, Joiner, & Scott, 2003; Liu, Harada, Ogura, Shibata, & Hiraoka, 2007; Ogura et al., 2005; Patterson et al., 2002; Shibata, Giaccia, & Brown, 2002), and (2) hypoxia-specific replication of adenovirus (Hernandez-Alcoceba, Pihalja, Qian, & Clarke, 2002; Post & Van Meir, 2003) (Table 2).
\n\t\t\t\tDelivery System | \n\t\t\t\t\t\t\tHypoxia-specific Strategy | \n\t\t\t\t\t\t\tResult | \n\t\t\t\t\t\t\tReference | \n\t\t\t\t\t\t
NA (Transfected cancer cell line) | \n\t\t\t\t\t\t\tGDEPT: 5 x VEGF-HRE-containing promoter driven NTR gene expression in HT1080 cells and i.p. injection of the anticancer prodrug CB1954. | \n\t\t\t\t\t\t\tSignificant tumour growth delay | \n\t\t\t\t\t\t\tShibata, 2002 | \n\t\t\t\t\t\t
NA (Transfected cancer cell line) | \n\t\t\t\t\t\t\tGDEPT: 5 x VEGF-HRE-containing promoter-driven HSV-TK gene expression and i.p. injection of GCV | \n\t\t\t\t\t\t\tTumour growth suppression | \n\t\t\t\t\t\t\tOgura, 2005 | \n\t\t\t\t\t\t
NA (Transfected cancer cell line) | \n\t\t\t\t\t\t\tGDEPT: PGK-1 HRE/SV40 chimeric promoter-driven P450R gene expression and i.p. injection of the 2-nitroimidazole bioreductive prodrug, RB6145 | \n\t\t\t\t\t\t\tEnhanced Radiotherapy | \n\t\t\t\t\t\t\tPatterson, 2002 | \n\t\t\t\t\t\t
Adenovirus | \n\t\t\t\t\t\t\tGDEPT: optimized hypoxia response promoter using PGK-1 HRE-driven human cytochrome P450 (CYP2B6) gene expression and i.p. injection of cyclophosphamide | \n\t\t\t\t\t\t\tDelay in tumour growth | \n\t\t\t\t\t\t\tBinley, 2003 | \n\t\t\t\t\t\t
Adenovirus | \n\t\t\t\t\t\t\t3XHRE/5XERE-regulated E1A expression and hTERT (AdEHT2) or E2F-1 (AdEHE2F) promoter-regulated E4 expression. | \n\t\t\t\t\t\t\tTumour growth suppression and regression | \n\t\t\t\t\t\t\tHernandez-Alcoceba, 2002 | \n\t\t\t\t\t\t
Adenovirus (intratumoural injection) | \n\t\t\t\t\t\t\tGDEPT: 5 x VEGF-HRE-containing promoter-driven bacterial cytosine deaminase (BCD) gene expression and i.p. injection of 5-FC. | \n\t\t\t\t\t\t\tTumour growth suppression and enhanced radiotherpy | \n\t\t\t\t\t\t\tLiu, 2007 | \n\t\t\t\t\t\t
Adenovirus | \n\t\t\t\t\t\t\thuman VEGF promoter-driven BAX gene expression | \n\t\t\t\t\t\t\tinduction of apoptosis and suppression of cell growth in vitro | \n\t\t\t\t\t\t\tKaliberov, 2002 | \n\t\t\t\t\t\t
Gene therapy strategies for tumour hypoxia examined so far.
NA, not applicable; HSV-TK, the herpes simplex virus thymidine kinase; GCV, ganciclovir; GDEPT, Gene-Directed Enzyme Pordrug Therapy; NTR, nitroreductase; CRAD, conditionally replicative adenoviruses; ER, estrogen receptor; ERE, estrogen response element; hTERT, human telomerase reverse transcriptase; CD, cytosine deaminase; VEGF, Vascular Endthelial Growth Factor, 5-FU, 5-fluorouracil; 5-FC, 5-flucytosine;
\n\t\t\t\tGDEPT involves the delivery to target cells of a foreign gene, which is non-toxic but activates prodrugs to toxic agents and induces anti-tumour effects (Fig. 3\n\t\t\t\t\t\tDachs, Dougherty, Stratford, & Chaplin, 1997; Greco et al., 2003). HIF-1 activity is detected at high levels in hypoxic tumour cells but generally not in normal tissues as mentioned above; therefore, HIF-1-dependent promoters provide a chance to accomplish tumour-specific GDEPT. The target-specificity and therapeutic effects of GDEPT with HIF-1-dpendent promoters have been examined in experimental tumour systems either by administering viral vectors (Binley et al., 2003; Liu et al., 2007) or by using unique tumour xenografts prepared by transplanting cancer cells which express a prodrug-activating enzyme under the control of a HIF-1-dependent promoter (Ogura et al., 2005; Patterson et al., 2002; Shibata et al., 2002). Examples of enzyme/prodrug combinations in GDEPT are the bacterial nitroreductase (NTR)/anticancer prodrug CB1954, the cytochrome P450 reductase (P450R)/RSU1069, the herpes simplex virus thymidine kinase (HSV-TK)/ganciclovir (GCV), and the bacterial cytosine deaminase (BCD)/anti-herpes viral agent 5- fluorocytosine (5-FC).
\n\t\t\t\t\tConcept of GDEPT targeting tumour hypoxia.
Using HREs derived from the VEGF promoter, Shibata et al. generated vectors expressing a bacterial NTR gene in a HIF-1-dependent manner, and established stable transfectants of a human fibrosarcoma cell line, HT1080 (Shibata et al., 2002). Hypoxia-induced expression of the NTR protein correlated with increased sensitivity of HT1080 cells to the prodrug CB1954 (Shibata et al., 2002). Growth delay assays with established tumour xenografts derived from the same cells showed that significant antitumour effects were achieved with intraperitoneal injections of CB1954 (Shibata et al., 2002). In addition, respiration of 10% O2 increased the hypoxic fraction in the tumour xenograft in vivo and enhanced the antitumour effects (Shibata et al., 2002).
\n\t\t\t\t\tA one-electron reductase, such as P450R, can be used for prodrug-activation. Patterson et al. reported that selective hypoxia-targeting could be accomplished by using an optimized PGK-1 HRE/SV40 chimeric promoter to regulate the expression of P450R. HT1080 cells stably transfected with the gene produced a 3.4-fold increase in P450R activity as a result of anoxic incubation, leading to a 30-fold enhancement of the cytotoxicity of the 2-nitroimidazole bioreductive prodrug, RSU1069 (Patterson et al., 2002).
\n\t\t\t\t\tAs for HSV-TK/GCV gene therapy, Ogura et al. demonstrated that promoters containing 5 copies of the VEGF HRE assured the expression of the HSV-TK gene in a HIF-active renal cell carcinoma, resulting in GCV-dependent tumour growth suppression (Ogura et al., 2005). An important point of their study is that HIF-dependent HSV-TK/GCV gene therapy can target not only hypoxic but also normoxic renal cell carcinoma (RCC) cells because the VHL gene, which triggers the destruction of HIF-1α and HIF-2α during normoxia, is inactive in 33–57% of sporadic clear-cell RCCs, which accounts for 75% of RCCs.
\n\t\t\t\t\tBinley et al. used an optimized hypoxia-responsive promoter (OBHRE) with the PGK-1 HRE and investigated hypoxia-targeted gene expression in vivo in the context of an adenoviral vector (Binley et al., 2003). The OBHRE promoter showed limited activity in the liver or spleen such that expression was 1000-fold lower than that driven by the strong CMV/IE promoter (Binley et al., 2003). However, in the context of the tumour microenvironment, the OBHRE promoter achieved expression levels comparable to that of the CMV/IE promoter. Moreover, they showed that an adenovirus expressing the human cytochrome P450 (CYP2B6) regulated by the OBHRE promoter delays tumour growth in response to the prodrug cyclophosphamide (CPA) (Binley et al., 2003).
\n\t\t\t\t\tAs for CD/5-FC gene therapy, Liu et al. constructed an adenoviral vector in which the 5HRE promoter was responsible for the HIF-1-dependent expression of CD (Liu et al., 2007). Administration of the adenovirus resulted in the expression of CD in hypoxic regions of solid tumours, leading to 5- FC-dependent tumour growth suppression and enhancement of the therapeutic effect of radiation therapy (See Section 4.4 for details about the radio-enhancing effect).
\n\t\t\t\t\tIn general, GDEPT is thought to have two advantages: amplification of its therapeutic effect and a bystander therapeutic effect. The former is due to the ability of each prodrug-activating enzyme to activate a number of prodrug molecules. The latter advantage results from an extension of the killing effects of the activated/converted drug to surrounding cancer cells, which don’t express the therapeutic gene and don’t convert the prodrug to the active anticancer drug. Therefore, even if systemic delivery of the therapeutic genes is not effective Fig. 3, tumour eradication may still be achieved.
\n\t\t\t\tAn alternative GDEPT uses cytotoxic proteins instead of prodrug-activating enzymes expressed in a HIF-1-dependent manner (Table 2). Kaliberov et al. prepared an adenovirus, AdVEGFBAX, which expressed an inducer of apoptosis, BAX, under the control of a VEGF promoter (Kaliberov et al., 2002). They confirmed the potential therapeutic application of VEGF promoter–driven cancer-specific expression of the pro-apoptotic Bax gene.
\n\t\t\t\t\tThe lytic cycle of adenoviruses is known to result in the death of infected cells, and thus this property has been exploited as a therapeutic strategy against cancer. Post and Van Meir have developed a hypoxia/HIF-dependent replicative adenovirus (HYPR-Ad) that exhibits HIF-1-dependent E1A expression and conditional cytolysis of hypoxic cells but not normoxic cells (Post & Van Meir, 2003). This is the first evidence that an attenuated oncolytic adenovirus that selectively lyses hypoxic tumour cells can be generated.
\n\t\t\t\t\tTo measure the damage to normal tissue after gene therapy targeting tumour hypoxia, Binley et al. evaluated the activity of lactate dehydrogenase (LDH) as an indicator of liver dysfunction after their hypoxia-responsive thymidine kinase/ganciclovir (TK/GCV) suicide gene therapy (Binley et al., 2003). Hypoxia-dependent TK expression and subsequent GCV treatment caused no irregularity in LDH levels. On the other hand, constitutive TK expression from a CMV promoter and GCV treatment significantly elevated LDH levels in mice. These results suggest that a hypoxia-responsive promoter would facilitate target specificity and so reduce the side effects on well-oxygenated normal tissues, meaning an increased therapeutic window for cytotoxic cancer gene therapies.
\n\t\t\t\tLiu et al observed no obvious side effects after hypoxia-targeting gene therapy with a 5HRE promoter-mediated BCD/5-FC strategy (Liu et al., 2007). On the other hand, after the Ad/EFp-BCD/5-FC treatment, which constitutively expresses BCD regardless of surrounding oxygen conditions, they observed significant weight loss and severe diarrhea (Liu et al., 2007). These results strengthen the argument that we can exploit tumour hypoxia as a tumour-specific target of cancer gene therapy, and that hypoxia/HIF-1-dependent therapeutic gene expression helps to avoid side effects in normal tissues.
\n\t\t\tAs tumour hypoxia and HIF-1 activity are responsible for tumour radioresistance (Aebersold et al., 2001; Harada et al., 2009; Irie et al., 2004; Ishikawa et al., 2004; Moeller et al., 2004; Moeller et al., 2005; X. Zhang et al., 2004), the specific targeting of tumour hypoxia and/or HIF-1 activity by gene therapy strategies may improve the efficacy of radiotherapy. Actually, Patterson et al. demonstrated that the therapeutic effect of radiation can be enhanced by a hypoxia-targeting gene therapy strategy (Patterson et al., 2002). They transfected HT1080 cells with a hypoxia-regulated expression vector encoding the human P450 reductase (HRE-P450R). Xenografts of HRE-P450R and empty vector transfectants had comparable hypoxic fractions and were refractive to a single dose of radiotherapy of up to 15 Gy. However, combining a prodrug RSU1069 with a reduced dose of radiotherapy (10 Gy) cured 50% of mice bearing HRE-P450R xenografts by 100 days after the treatment. On the other hand, one hundred percent mortality was observed by day 44 in the empty vector control xenografts treated using the same protocol.
\n\t\t\t\tLiu et al. treated HeLa tumour xenografts with adenovirus-mediated hypoxia-targeting cytosine deaminase gene therapy (Ad/5HREp-BCD/5-FC) and/or radiotherapy (IR), and carried out growth delay assays (Liu et al., 2007). They intentionally chose a low dose of Ad/5HREp-BCD/5-FC, which had minimal effects on the tumour growth rate compared to that after sham-treatment. Combined with IR, the gene therapy strikingly suppressed tumour growth as compared to radiotherapy alone. The period taken for tumour growth to increase two-fold from the initial volume (tumour growth doubling time: TGDT) was 13.2 ± 5.6 days after gene therapy alone, which is not significantly longer than that after sham-treatment (8.2 ± 3.1 days). On the other hand, the combination of gene therapy with radiotherapy prolonged the TGDT to 47.2 ± 16.8 days, which was about 2.4-fold longer than that after radiotherapy alone (19.4 ± 4.8 days). Similar results were observed after fractionated irradiation (3 Gy × 5 fractions). The TGDT after gene therapy alone was 13.0 ± 4.4 days, which is not significantly longer than that after sham treatment (9.8 ± 5.8 days). On the other hand, the TGDT after the fractionated radiotherapy was 17.0 ± 3.7 days, which was significantly delayed by the combination with the gene therapy to 43.3 ± 23.8 days. These results also lead to a conclusion that hypoxia-targeting gene therapy combined with radiotherapy is a promising approach to cancer treatment.
\n\t\t\tCancer cells under hypoxic conditions/HIF-1-active cancer cells have been recognized as crucial and excellent targets for cancer therapy not only because they mediate tumour malignancy and resistance to conventional treatments but also because they are only seen in malignant tumours, not in normal tissues. Several approaches have been used to target these cell populations; hypoxia-targeting using hypoxia-responsive promoters combined with GDEPT, and hypoxia-specific replication of adenovirus as well as hypoxic cytotoxins and HIF-1 inhibitors. Hypoxia/HIF-1-targeting gene therapy is a promising tumour-specific approach with few side effects in normal tissues, and has the potential to enhance the effect of radiation therapy. Some approaches are now in clinical trials and are expected to lead to breakthroughs in cancer therapy.
\n\t\tThis study was supported by the “Funding Program for Next Generation World-Leading Researchers” from the Japan Society for the Promotion of Science (JSPS), by the “Program for the Promotion of Fundamental Studies in Health Science” from the National Institute of Biomedical Innovation (NIBIO), Japan, by Grants-in-aid for Scientific Research for Young Scientists (B) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan, and by the Sagawa Foundation for the Promotion of Cancer Research.
\n\t\tA 2015 research report stated that 90% of the global burden of disease lies in Low- and Mid- Income Countries [1]. A different report in the same year stated that over 24% of global disease burden lies in Africa, has access to only 3% health workers and less than 1% of the world’s financial resources [2, 3, 4]. Healthcare system in Africa has estimated medical personnel (physician) to patient ratio of 2.7:10,000 compared to 5.9 South East Asia, 12.7 Eastern Mediterranean, 15.5 Western Pacific, 21.5 Americas, and 32.1 European region [3]. Generally, Africa is heavily burdened by non-infectious diseases and health conditions (e.g., diabetes, cancer, cardiovascular disease, pregnancy and childbirth related problems, musculoskeletal diseases, road accidents, etc.) and these are also the major causes of mortality and disability in the African population [3, 5, 6, 7]. Arthritis belongs to this category and is a major reason for adult disability in the continent. Rheumatoid arthritis was reported to have worldwide prevalence of 1%, while between 1990 and 2010 prevalence in Africa seem to have increased from 0.36 to 0.42% [8]. In a more recent review, the prevalence of Rheumatoid arthritis was recorded as follows: 0.40% in South Asia, 0.37% in Eastern Mediterranean, 0.62% in Europe, 1.25% in America and 0.42% in Western Pacific, no information was provided on the African burden of Rheumatoid arthritis [7]. However, a study reported a 0.13% prevalence of Rheumatoid Arthritis in urban Barika Algeria, North Africa in 2013 with an estimated 0.15% prevalence for the general population [9].
Major challenges to arthritis management in Africa include the fact that its’ economic/health import is downplayed in favor of communicable or infectious diseases. Consequently, research in this area is minimal with small sample population & clinic-based studies that are not representative of the true situation of arthritis disease (prevalence, treatment burden and resulting disability) in the African population. Also, little is known about causes and types of arthritis disease; and the psychosocial challenges patients face especially with regards to gender, ethnic or tribal dichotomies in the continent. However, these issues are beyond the scope of this chapter. This paper is focused on providing information about the state of psychological interventions in the management of arthritis pain in Africa and what can be done to improve the situation so as to offer more effective pain management protocols to arthritis patients. This review covers the use of psychological interventions in arthritis treatment in general drawing from clinical practices and studies conducted across gender and outside Africa.
Arthritis is widely recognized as a leading cause of pain and disability among the aged (adults 50 years and above) across the globe. Its burden is well noted in developed nations like the United States and measures are taken to care for sufferers. The case is different in African countries, starting with under-diagnosis due to little or no presentation of cases at orthodox hospitals, misconceptions about the disease, poverty, expensive (unaffordable) medical care, inadequate medical facility and distractions by heavy burden of infectious diseases in the health sectors, as such little attention is given to arthritis disease in these countries. South Africa with on 85 rheumatologists is reported to have the largest number of rheumatologists in Africa [3].
Arthritic disease has been described as a chronic inflammatory disorder that affects joints of the body [10]. It has painful, debilitating and detrimental [5, 11] effects on the health and well-being of those affected. While it is assumed to be more common among the elderly (65+ years), it afflicts people of all age brackets including children, male and female alike. Over a hundred type of arthritis have been recorded [11, 12] overtime and across the globe. Studies in Africa have noted the existence of seven types of arthritis- 1) Rheumatoid arthritis 2) Osteoarthritis (Mseleni Joint Disease) 3) Ankylosing Spondylitis 4) juvenile idiopathic arthritis 5) juvenile chronic arthritis 6) psoriatic arthritis 7) Gout 8) Osteoarthritis. Literature showed that most studies on arthritis were conducted with non-African populations. Majority of the studies conducted in African Nations were centered on Rheumatoid Arthritis (RA) a few on osteo arthritis. Some meta-analytic reviews were on the prevalence of various types of arthritis in Africa. Both genetic and environment have been reported to contribute to the onset or arthritic conditions (e.g. aging, obesity, injury). The arthritis conditions identified among Africans will be briefly discussed.
Rheumatoid Arthritis (RA): RA is described as an autoimmune disease in which the immune system attacks the lining of joints and connected tissues [8, 7] causing inflammation of small joints of the hand, wrist, knee and feet. It is a chronic condition that if left untreated leads to extensive erosion on cartilage causing deformity and disability [13]. Its symptoms include daily pain, morning stiffness, fatigue, swelling of joints, generalized weakness, loss of weight, and low-grade fever. This is the most studied arthritic condition in Africa [6]. Generally, RA is reported to have 1–2% prevalence in western world and 1% worldwide [14]. Another report showed an increasing incidence of RA across African Nations including Uganda, Kenya, Nigeria and South Africa [6]. Report reveals a prevalence rate range of 0.1% to 2.5% in various urban and rural settings of Democratic Republic of the Congo (DRC), Lesotho and South Africa [10]. RA is most prevalent in South Africa with a prevalence ratio of 2:3 for men to women [8]. The report on Nigeria and Liberia with the next highest occurrences of RA showed greater incidence in men with a prevalence range of 3:1 for men to women. However, two studies that used the American College of Rheumatology (ACR) 1987 rheumatic arthritis criteria for diagnosis found no incidence of RA in Botswana and Nigeria.
Osteoarthritis (OA): Osteoarthritis occurs among older people of 65+ years. It is described as a
Degenerative joint disease that can affect any bodily joint but typically affects the hands, hips, kneel and spine. OA causes degradation of articular cartilage overtime resulting in bones rubbing up against one another leading to pain, joint swelling, tenderness and limited mobility ([12], p. 5-6).
It has also been affirmed that the degenerative nature of osteoarthritis affects cartilage and its surrounding tissues, remodels the subarticular bone, causes osteophyte formation, ligamentous laxity, weakening of particular muscles and at times synovial inflammation [13]. Mseleni Joint Disease is a type of osteoarthritis common among people in Northern Kwazulu Natal province of South Africa and locally known as unyonga, meaning a disease of the joints [15]. It affects large joints in mid childhood. Some symptoms include joint pain, morning stiffness and stiffness on resumption of activity, limited mobility, bone enlargement, joint instability and severe physical disability. OA disease progresses slowly, and knee OA is reported as the most prevalent compared to hand and hip OA. People who are above age 50, obese, inactive, who smoke and who have joint injury are at greater risk of developing OA. The incidence of OA increases with age and it is reported more in women than males aged over 50 years. Osteoarthritis is recorded as the most prevalent form of arthritis in Africa with a prevalence range of 55.1% to 82.7% in urban and rural South Africa respectively [10]. However, it is not as extensively studied as RA.
Juvenile Arthritis: This includes Juvenile Idiopathic Arthritis (JIA) and Juvenile Chronic Arthritis (JCA) among others that afflict children of 15 years and younger. Juvenile arthritis is a progressive inflammatory autoimmune disease that may affect multiple joints (e.g., knee, hand, elbow, ankle, wrists, etc.) in the body by the time the child becomes an adult resulting in restricted mobility [12]. The symptoms include swelling, joint pains and stiffness. JIA is reported as the most prevalent arthritis in this class [10]. Reported records of the prevalence of JIA among African children (10–15 years) are as follows: 0.003–0.33% prevalence in Egypt and 00.1% in Cameroun.
Psoriatic Arthritis: It is described as a chronic inflammatory join disease with negative test for rheumatoid factors and cutaneous psoriasis [16]. The symptoms include morning stiffness, joint pain, skin flaking, intermittent swelling, fatigue and itching. This type of arthritis has also been noted to be incident in Africa with a 4.4% prevalence rate in urban South Africa, 1% & 0.1% in Uganda and Cameroun respectively. In Africa records of its incidence is linked to HIV infection.
Gout: This particular type of arthritis is considered to have significant genetic underlining as it is found to run in families [12]. Its symptoms include acute joint pain, swelling in the knees, foot and big toe. It is more prevalent in males than females. The prevalence of gout is reported as 0.70% among white South African and 0.30% among HIV-infected population in Burkina Faso.
Ankylosing Spondylitis: It is a chronic, progressive arthritic condition that leads to severe disability. It occurs in early adulthood with symptoms like pain in the mid and lower back, heel, eyes, shoulder, ankle, and knee, reduced flexibility in the spine, sleep disorder, inflammatory bowel disease, and abnormal bone formation. Some occurrences of this type of arthritis are recorded in South Africa, Cameroun and Egypt [10, 17].
Pain often contributes to dramatic reduction in a patient’s quality of life. Like every other pain, arthritis pain is multidimensional [18]. It has physical, social, psychological and economic dimensions and how each person perceives these dimensions influences their treatment outcome. Despite the obvious, treatment of pain and arthritis pain in particular is usually and largely based on the biomedical procedures like medication, surgery and physical therapy. Traditionally, arthritis disease known as a musculoskeletal disorder is classified as a biological and physiological condition. As such, its epidemiology, pathogenesis as well as treatment efforts have been majorly focused on and drawn from the biomedical field. This has largely served to under-prioritize the potential contributions of other approaches especially psychological approaches to the treatment and care of arthritis patients. It has also indirectly suppressed the understanding of pain, in this context arthritic pain, as a psychological experience with cognitive, emotional and behavioral components.
Pain is described as an unpleasant experience signaled by behavioral expressions such as crying, screaming, withdrawal, change in posture, gait or facial expression [19] which limits, hinders or alters the bearer’s behavior. Pain was defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage [14]. The relationship between the incidence of pain and possible cell damage or existence of disease provides clear evidence or support for the biomedical understanding of pain. Nevertheless, this connection is not able to explain why two individuals with the same level of cell damage or disease activity would have varying degrees of pain. The biomedical perspective is considered as being weak due to its inability to explain the differentials in pain responses of patients with similar disease activity [20], neither is it able to address psychological factors in the experience of pain. Again, the biomedical drug treatment approach to the management of arthritis in Africa with recourse to non-pharmacological or surgical treatments may have increased the likelihood for self-medication among sufferers. This is most likely because of the problems of inaccessible, unavailable or expensive healthcare services in Africa (especially among rural women dwellers). A situation that may explain the seemingly low prevalence rates arthritis disease reported by studies originating from Africa. Therefore, the argument that pain sensation is not merely a biological process but mostly a psychological experience forms the basis for this call to fully adapt psychological techniques in the management of arthritis pain among Africans and all people in general. The importance of this call for the use of psychological techniques in the treatment of arthritis pain, relates to the bio-psychosocial model of [21] which postulated that no particular factor can account for health outcome. Rather, that health outcome depends on the synergistic and reciprocal interactions of various factors that relates to a patient’s disease experience. In this paper, it is argued that because the perception of pain depends on a lot of factors including but not limited to age, sex, wellbeing, cognition, belief, learning, emotional stability, culture, economic status, etc., The insistence or rigidity that sustains the biomedical model of pain management has to be revaluated in light of new knowledge and best practices across the globe. When adopted, psychological methods [21, 23, 24], would mostly enhance patients’ health outcome by:
Improving patients’ understanding of perceived illness
Improving patients’ adherence to treatment protocols and life style changes
Improving level of acceptance of the illness
Addressing ethno-cultural factors contributing to illness experience and illness sustenance
Addressing issues of interpersonal relationship, communication, and social support relating to patient care.
Addressing gendered issues that may be hindering positive health outcome or hinder access to health services.
Assessing and treating pre- or co-morbid psychological problems like drug misuse/abuse, depression, anxiety, sleep problems, etc.
Teaching patients effective selfcare and pain management protocols
There is a clear challenge of limited empirical studies on arthritis in Africa. A report [10] showed that between 1975 and 2014, about fifty studies relating to arthritis were published across Africa. However, none of those studies and none that was found in the course of writing this chapter were focused on African women or arthritis treatment. Instead, most were on prevalence and the remaining, either studied risk factors or are meta-analytic reviews of others. Meanwhile, information on women experience of arthritis pain and its treatment is lacking. Studies from other parts of the world including United States of America, United Kingdom and France point to the use of non-drug treatments in the management of arthritis pain. A meta-analytic study that assessed the efficacy of psychosocial interventions in the management of arthritic pain in the United States, reported that patients who received psychosocial interventions displayed significantly lower post-treatment anxiety, depression and psychological disability [24, 22]. Reported the use of non-pharmacological treatments as depending on disease progression, personality, environment and objectives of the patient [25]. Some identified non-pharmacological treatments include physiotherapy, balneotherapy, spa therapy, psychological interventions, therapeutic patient education, dietetics and acupuncture.
Attempts to explain pain and human experience of pain dates back to the time of Descartes in the 17th century, with pain described and understood as a sensory experience. Later theories like the pattern theory also derived from the biomedical models, till mid-20th century when Melzack and Wall in 1965 propounded the gate control theory of pain. Unlike the biomedical models before it, the gate control theory expanded the understanding of pain perception and experience to include psychological factors like stress, emotions, motivations, past experience, context and their impact on pain processing in the brain. This new understanding of pain opened doors for the use of psychological therapies in the control and management of pain. The understanding that not all kinds of pain can be explained by disease activity or tissue damage that are responded to by peripheral nerves gave room for a potentially better explanation of pain [26]. Consequently, the gate control theory proposed that higher neural mechanisms in the brain make meaning of a pain experience by incorporating other individualized factors including cognition, emotion, and motivation.
This theory contributed to a better understanding of pain so that it is scientifically understood and clinically practical that pain is dependent on a reciprocal relationship between ascending nociceptive input from peripheral nerves (pathophysiology) and feedback from higher brain activities (psychological factors) see Figure 1.
An illustration of how activities in the higher brain areas and inputs from nociceptive neurons influence gate opening or closing in the dorsal horn to elicit a pain experience. Pain is experienced when the combined activities results in the opening of the gate.
Psychological theories that form the bases for pain management psychotherapies include the behavioral, cognitive and humanistic models and modern models like the psychological flexibility model. Behavioral theories like operant conditioning of BF Skinner and classical conditioning of IvanPavlov explain behavior as an outcome of learning and as such a learned behavior can also be unlearned [27]. Therapies that generate from these theories like behavior modification techniques (e.g., token economy) cause behavioral change, either by decreasing unwanted behavior or increasing wanted behavior [28]. In the instance of chronic pain, these patients are taught new coping skills that would help them reduce or eliminate aversive or problematic pain behaviors. On the other hand, cognitive theories of psychology like Albert Ellis rational emotive behavior and Beck’s cognitive theory would address a patient’s thoughts, feelings and actions in relation to their pain experience [28]. These theories and therapies generating from them would explain problems like depression, pain catastrophizing, pain avoidance behaviors, feelings of helplessness, etc., that commonly accompany chronic pain conditions. The humanistic theories of psychology would explain pain experience in its social, economic, cultural, etc., contexts. How these factors could be contributing to the experience and sustenance of pain or how they can help alleviate the problem. Therapies developed from this theoretical background would focus on providing emotional support while encouraging social support and selfcare strategies with a goal of reducing the psychological distress experienced by the patient. Finally, the psychological flexibility model for chronic pain management is a recently developed understanding that is attracting the attention of researchers and practitioners in recent times. The model refers to “the capacity to persist or to change behaviour in a way that (a) includes conscious and open contact with thoughts and feelings, (b) appreciates what the situation affords and (c) is guided by one’s goals and values”. This model integrates both cognitive and environmental influences in describing and understanding behavior [29]. It focuses on such processes like acceptance, cognitive defusion, flexible present-focused attention, self-as-observer, values, and committed action; of these, acceptance has risen in popularity among psychotherapist and in treatment of chronic conditions.
Effective pain management protocols are therefore expected to also cover the psychological (cognition, emotional, behavioral) aspect of pain experience. Pain management especially management of chronic pain (like arthritis pain) that is based on biomedical approach is apparently deficient of the psychological intervention protocol and would most likely result in poor health outcome. This is true and supports or explains the extensive acceptance and inclusion of psychological interventions in comprehensive wholistic pain management approaches used in developed nations like France.
Across the globe but especially in Africa, the use of psychological interventions in the management of pain is quite minimal. Psychological interventions are mostly present in the management of cancer patients, hence, the development of Psycho-Oncology; but lacking in the management of other chronic conditions particularly arthritis. This is despite the established knowledge that arthritis disease onset, progression, severity and treatment outcome affects and can be affected by a person’s life style, psychological and social circumstances [22]. It has therefore become imperative to reawaken psychologists and other health care professionals in Africa to the need to provide better healthcare service to arthritis patients by incorporating psychological interventions that could improve treatment outcome, quality of life, and adjustment skill for the patient. This can be done by referring arthritis patients presenting in the hospitals and clinics to psychologists for pain management psychological therapies. Such referral can be made when chronic arthritis pain results in or is as a result of the following:
Depression
Disability
Low self-efficacy for pain control
Pain catastrophizing
Inadequate social support (informational, behavioral and emotional)
Stress
Insomnia (Sleep disorder)
Emotional distress
Anxiety [22]
Assessment of chronic pain condition for which psychological intervention is required should be characterized by the following;
Circumstances surrounding the pain; where and when it occurs
Duration; how long does the pain last at each episode – chronic, intermittent or remitting.
Severity of the pain from the beginning
Which joint(s) of the body does the pain sensation occur and how often in a day, week, or month.
What triggers the pain sensation and what makes it better or brings relief
Use visual analogue scale to rate severity of pain experience at initial clinical assessment. An example is using a scale of 0–10, with zero as no pain and ten as severe pain
Client’s beliefs and thoughts about the pain; is pain seen as unacceptable, a punishment or beyond their control. This relates to pain catastrophizing.
Client’s feelings about and perception of the pain and the circumstances surrounding it. This relates to pain locus of control
Client’s lifestyle and coping strategies being used to cope with the pain; also assess client’s activity level
Client’s belief about their ability to control the pain experience. This relates to pain self-efficacy
Social context and stress level of patient suffering arthritis pain
Addiction to drugs (including misuse or abuse of prescription drugs for pain management)
Anxiety disorder
Sleep disorder
Depression
There are also evidence-based pain assessment instruments developed to measure various pain related concern like coping and self-efficacy. Some commonly used ones are pain self-efficacy questionnaire, coping strategies questionnaire, brief COPE inventory, and chronic pain coping inventory. The scale a therapist chooses to use depends on their interest. Generally, the scales are developed to measure behavioral and or cognitive aspects of pain experience or pain coping. A therapist can select a scale if they want to have a more objective assessment of how well a patient uses a particular coping skill when experiencing pain. The following are some coping skills assessed with the scales; diverting attention, reinterpreting pain sensation, guarding, resting, asking for assistance, coping self-statement, ignoring pain, praying and hoping, relaxation, task persistence, exercise, increasing behavioral activities, catastrophizing, stretching and seeking social support [30].
2.5.3. Treatment Planning: This will involve clinical decision about required or further investigation to help decide the nature of pain as well as the treatment protocol of choice. Assessment of personality variables, lifestyle, thinking pattern and social network are also important. And the results of biomedical investigations like laboratory, radiological and physical examinations should also be considered. Though arthritis pain is the general concern, psychotherapy should be tailored to suit the personal needs and circumstances of each arthritis patient. Patients, therefore, work with therapists in a collaborative manner during assessment and treatment planning stages, to design the best interventions possible to achieve their treatment goals in the shortest time possible or help them function better with minimal pain and psychological distress.
Cognitive restructuring aimed at changing existing beliefs about pain and creating new ways to think about it and resolve it.
Relaxation techniques to help deal with anxiety induced by the painful condition
Stress management, this is important as painful conditions can be stressful or worsened by other stressors (e.g., work related stress)
Psychoeducation about possible psychological symptoms
Assertiveness skills to help with pain communication between patients, their caregivers and other support network
Hypnosis and Distraction techniques
Treatment approach can be either group or individual or both as the case may be. Therapy can be as short as 8 sessions; however, the length of psychotherapy depends on the severity of the problem. Common therapies applied to arthritis patients include:
Cognitive-behavioral therapy: This is used especially when client is presenting with comorbid depression and or anxiety disorder. Techniques used here would address the affect, cognition and behavior of a patient in relation to pain experience. Some applicable techniques are relaxation, cognitive restructuring, problem solving, in vivo desensitization, sleep hygiene, etc., [28].
Behavioral therapy: This is aimed at changing existing unhelpful pain behaviors, lifestyle, diet and to get the client to adopt new, more adaptive and pain relieving behaviors that will encourage continuous participation in work and recreational activities (habit reversal techniques). Some applicable techniques include assertions, exercise, deep muscle relaxation, token economy, etc.
Psychosocial counseling: The goal here is to help the patient clarify, calibrate, differentiate and understand their various concerns. It is common that the practical problems like pain, reduced physical activity and low income would have accompanying emotional distress. Therapies using this model would help patients separate the two and address the practical problems and the emotional distress sequentially. It is supposed that once the emotional distress is resolved client would be more capable to perform tasks that could help resolve the practical problems. Some applicable techniques are supportive counseling, problem solving, psychoeducation for adaptive coping skills, etc.
Other psychotherapies that could address issues like depression, catastrophizing, anxiety, fear of pain and other accompanying psychological problems can also be applied. However, psychological interventions for chronic pain management are best when applied as a multicomponent therapy that would address the various psychosocial dimensions of pain experience.
Treatment of arthritis is largely done using drugs and surgery, however, the use of other non-pharmacological and psychosocial approaches have been widely noted in other parts of the world aside Africa. There is no clear and reliable evidence of the reality of arthritis disease burden in Africa. Hence, the seemingly misleading conclusion that arthritis is less prevalent in African nations compared to the developed and industrialized nations of the world. Rather, poverty, inadequate healthcare facility, expensive healthcare service as well as reliance on traditional remedies might explain the seeming lack of hospital presentations or low diagnosis of arthritis in Africa. Psychological interventions have been proven to be beneficial in other nations. The chapter highlighted various psychological interventions and their positive impacts on the existing arthritis treatment protocols.
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