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• W2201036716 abstract "Spread of oncolytic viruses through tumor tissue is essential to effective virotherapy. Interstitial matrix is thought to be a significant barrier to virus particle convection between “islands” of tumor cells. One way to address this is to encode matrix-degrading enzymes within oncolytic viruses, for secretion from infected cells. To test the hypothesis that extracellular DNA provides an important barrier, we assessed the ability of DNase to promote virus spread. Nonreplicating Ad5 vectors expressing actin-resistant DNase (aDNAse I), proteinase K (PK), hyaluronidase (rhPH20), and chondroitinase ABC (CABC) were injected into established DLD human colorectal adenocarcinoma xenografts, transcomplemented with a replicating Ad5 virus. Each enzyme improved oncolysis by the replicating adenovirus, with no evidence of tumor cells being shed into the bloodstream. aDNAse I and rhPH20 hyaluronidase were then cloned into conditionally-replicating group B adenovirus, Enadenotucirev (EnAd). EnAd encoding each enzyme showed significantly better antitumor efficacy than the parental virus, with the aDNAse I-expressing virus showing improved spread. Both DNase and hyaluronidase activity was still measurable 32 days postinfection. This is the first time that extracellular DNA has been implicated as a barrier for interstitial virus spread, and suggests that oncolytic viruses expressing aDNAse I may be promising candidates for clinical translation. Spread of oncolytic viruses through tumor tissue is essential to effective virotherapy. Interstitial matrix is thought to be a significant barrier to virus particle convection between “islands” of tumor cells. One way to address this is to encode matrix-degrading enzymes within oncolytic viruses, for secretion from infected cells. To test the hypothesis that extracellular DNA provides an important barrier, we assessed the ability of DNase to promote virus spread. Nonreplicating Ad5 vectors expressing actin-resistant DNase (aDNAse I), proteinase K (PK), hyaluronidase (rhPH20), and chondroitinase ABC (CABC) were injected into established DLD human colorectal adenocarcinoma xenografts, transcomplemented with a replicating Ad5 virus. Each enzyme improved oncolysis by the replicating adenovirus, with no evidence of tumor cells being shed into the bloodstream. aDNAse I and rhPH20 hyaluronidase were then cloned into conditionally-replicating group B adenovirus, Enadenotucirev (EnAd). EnAd encoding each enzyme showed significantly better antitumor efficacy than the parental virus, with the aDNAse I-expressing virus showing improved spread. Both DNase and hyaluronidase activity was still measurable 32 days postinfection. This is the first time that extracellular DNA has been implicated as a barrier for interstitial virus spread, and suggests that oncolytic viruses expressing aDNAse I may be promising candidates for clinical translation. Oncolytic viruses have been engineered for tumor-selective replication, leaving normal cells virtually unharmed while specifically lysing cancer cells.1Russell SJ Peng KW Bell JC Oncolytic virotherapy.Nat Biotechnol. 2012; 30: 658-670Crossref PubMed Scopus (973) Google Scholar The ability to replicate within tumor cells before spreading to infect adjacent cells provides a renewable supply of virus within the tumor and should endow a high therapeutic index. Adenoviruses have been widely developed as oncolytic agents, however while clinical trials show little toxicity, anticancer efficacy is also usually limited, particularly after intravenous administration.2Kirn D Clinical research results with dl1520 (Onyx-015), a replication-selective adenovirus for the treatment of cancer: what have we learned?.Gene Ther. 2001; 8: 89-98Crossref PubMed Scopus (304) Google Scholar,3Liu TC Galanis E Kirn D Clinical trial results with oncolytic virotherapy: a century of promise, a decade of progress.Nat Clin Pract Oncol. 2007; 4: 101-117Crossref PubMed Scopus (386) Google Scholar,4Nemunaitis J Senzer N Sarmiento S Zhang YA Arzaga R Sands B et al.A phase I trial of intravenous infusion of ONYX-015 and enbrel in solid tumor patients.Cancer Gene Ther. 2007; 14: 885-893Crossref PubMed Scopus (61) Google Scholar This is thought largely to reflect the difficulties of delivery, both in the bloodstream and within the tumor itself. Recently clinical studies using the group B oncolytic adenovirus Enadenotucirev (EnAd) have shown good progress with successful systemic delivery5Boni V De La Portilla F Cubillo A Gil-Martin M Calvo E Salazar R et al.A phase 1 mechanism of action study of intra-tumoural (IT) or intravenous (IV) administration of enadenotucirev, an oncolytic Ad11/Ad3 chimeric group B adenovirus.Ann Oncol. 2014; 25: iv361-iv372Google Scholar,6Calvo E Gil-Martin M Machiels JP Rottey S Cubillo A Salazar R et al.A first-in-class, first-in-human phase I study of enadenotucirev, an oncolytic Ad11/Ad3 chimeric group B adenovirus, administered intravenously in patients with metastatic epithelial tumors.J Clinical Oncol. 2014; 32 (5s: Abstract 3103)Google Scholar and here, we will focus on strategies to improve virus delivery within tumor deposits. One of the major barriers for oncolytic viruses is the challenge of particulate spread through solid tumors. Possible contributory factors include the high interstitial fluid pressure (IFP) that restricts convection, coupled with phagocytosis of virus particles by immune cells. However, the dominant inhibitory effect is thought to be the dense extracellular matrix (ECM) that physically interferes with the movement of macromolecules and particles.7Netti PA Berk DA Swartz MA Grodzinsky AJ Jain RK Role of extracellular matrix assembly in interstitial transport in solid tumors.Cancer Res. 2000; 60: 2497-2503PubMed Google Scholar,8Sauthoff H Hu J Maca C Goldman M Heitner S Yee H et al.Intratumoral spread of wild-type adenovirus is limited after local injection of human xenograft tumors: virus persists and spreads systemically at late time points.Hum Gene Ther. 2003; 14: 425-433Crossref PubMed Scopus (107) Google Scholar,9Swiderek MS Mannuzza FJ Effects of ECM Proteins on Barrier Formation in Caco-2 Cells.Becton Dickinson Technical Bulletin. 1997; 421: 1-4Google Scholar,10Mok W Stylianopoulos T Boucher Y Jain RK Mathematical modeling of herpes simplex virus distribution in solid tumors: implications for cancer gene therapy.Clin Cancer Res. 2009; 15: 2352-2360Crossref PubMed Scopus (64) Google Scholar Tumor ECM is a complex, multicomponent structure and several components may interfere with spread of virus particles. Previous studies have shown that pretreatment of tumors with free enzymes to degrade the ECM could improve tumor interstitial convection. These included proteases11Cheng J Sauthoff H Huang Y Kutler DI Bajwa S Rom WN et al.Human matrix metalloproteinase-8 gene delivery increases the oncolytic activity of a replicating adenovirus.Mol Ther. 2007; 15: 1982-1990Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar,12Kuriyama N Kuriyama H Julin CM Lamborn K Israel MA Pretreatment with protease is a useful experimental strategy for enhancing adenovirus-mediated cancer gene therapy.Hum Gene Ther. 2000; 11: 2219-2230Crossref PubMed Scopus (69) Google Scholar to degrade extracellular proteins and hyaluronidase13Brekken C Bruland ØS de Lange Davies C Interstitial fluid pressure in human osteosarcoma xenografts: significance of implantation site and the response to intratumoral injection of hyaluronidase.Anticancer Res. 2000; 20 (5B): 3503-3512PubMed Google Scholar,14Shuster S Frost GI Csoka AB Formby B Stern R Hyaluronidase reduces human breast cancer xenografts in SCID mice.Int J Cancer. 2002; 102: 192-197Crossref PubMed Scopus (89) Google Scholar (e.g., rhPH20) to degrade hyaluronan, a viscous glycosaminoglycan. In exploiting these findings to improve the performance of therapeutic viruses, oncolytic adenoviruses have been “armed” to express ECM-degrading enzymes including relaxin, a peptide hormone that reduces expression of collagen and increases matrix-metalloproteinases, showing ECM degradation, improved virus spread and better antitumor efficacy.15Ganesh S Gonzalez Edick M Idamakanti N Abramova M Vanroey M Robinson M et al.Relaxin-expressing, fiber chimeric oncolytic adenovirus prolongs survival of tumor-bearing mice.Cancer Res. 2007; 67: 4399-4407Crossref PubMed Scopus (86) Google Scholar,16Kim JH Lee YS Kim H Huang JH Yoon AR Yun CO Relaxin expression from tumor-targeting adenoviruses and its intratumoral spread, apoptosis induction, and efficacy.J Natl Cancer Inst. 2006; 98: 1482-1493Crossref PubMed Scopus (172) Google Scholar Oncolytic adenoviruses expressing hyaluronidase have also shown improved interstitial spread and are now undergoing clinical evaluation.17Guedan S Rojas JJ Gros A Mercade E Cascallo M Alemany R Hyaluronidase expression by an oncolytic adenovirus enhances its intratumoral spread and suppresses tumor growth.Mol Ther. 2010; 18: 1275-1283Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar Similarly chondroitin sulfate, usually found as a proteoglycan, interacts with multiple constituents in the tumor tissue reducing fluid convection and drug permeation.18Rhodes KE Fawcett JW Chondroitin sulphate proteoglycans: preventing plasticity or protecting the CNS?.J Anat. 2004; 204: 33-48Crossref PubMed Scopus (249) Google Scholar Chondroitinase ABC (CABC)19Crespo D Asher RA Lin R Rhodes KE Fawcett JW How does chondroitinase promote functional recovery in the damaged CNS?.Exp Neurol. 2007; 206: 159-171Crossref PubMed Scopus (121) Google Scholar,20Prabhakar V Capila I Bosques CJ Pojasek K Sasisekharan R Chondroitinase ABC I from Proteus vulgaris: cloning, recombinant expression and active site identification.Biochem J. 2005; 386 (Pt 1): 103-112Crossref PubMed Scopus (83) Google Scholar can degrade proteoglycans by removing glycosaminoglycan side chains from the protein core. This has been exploited in an oncolytic herpes virus expressing CABC which also leads to both better intratumoral spread and improved anticancer efficacy.21Dmitrieva N Yu L Viapiano M Cripe TP Chiocca EA Glorioso JC et al.Chondroitinase ABC I-mediated enhancement of oncolytic virus spread and antitumor efficacy.Clin Cancer Res. 2011; 17: 1362-1372Crossref PubMed Scopus (56) Google Scholar Cell death within tumors is likely to include nonapoptosis mechanisms such as ischemic death (oncosis),22Kroemer G Galluzzi L Kepp O Zitvogel L Immunogenic cell death in cancer therapy.Annu Rev Immunol. 2013; 31: 51-72Crossref PubMed Scopus (1973) Google Scholar and this may release large fragments of genomic DNA into the extracellular space.23Weerasinghe P Buja LM Oncosis: an important non-apoptotic mode of cell death.Exp Mol Pathol. 2012; 93: 302-308Crossref PubMed Scopus (145) Google Scholar,24Escobar ML Vazquez-Nin G. Echeverria O. Oncosis.in: Vazquez-Nin G Cell Death in Mammalian Ovary. Springer Science and Business Media, Berlin, Germany2011: pp. 103-110Crossref Google Scholar Since DNA is very hydrophilic and viscous, we postulated it might also inhibit interstitial spread of oncolytic virus particles. DNAse I25Shak S Capon DJ Hellmiss R Marsters SA Baker CL Recombinant human DNase I reduces the viscosity of cystic fibrosis sputum.Proc Natl Acad Sci USA. 1990; 87: 9188-9192Crossref PubMed Scopus (594) Google Scholar,26Ulmer JS Herzka A Toy KJ Baker DL Dodge AH Sinicropi D et al.Engineering actin-resistant human DNase I for treatment of cystic fibrosis.Proc Natl Acad Sci USA. 1996; 93: 8225-8229Crossref PubMed Scopus (74) Google Scholar is an endonuclease that cleaves both double-stranded and single-stranded DNA producing a mixture of 5'-phosphate mononucleotides and oligonucleotides. DNAse I is an important treatment for cystic fibrosis where the enzyme greatly reduces the viscosity of cystic fibrosis sputum. In this study, we therefore explored the use of actin-resistant recombinant human DNAse I (aDNAse I) as a means to improve interstitial virus convection. To provide context, we included the use of hyaluronidase (PH20), CABC and proteinase K in parallel experiments. Proteinase K (PK) is a serine protease with broad substrate specificity.27Gunkel FA Gassen HG Proteinase K from Tritirachium album Limber. Characterization of the chromosomal gene and expression of the cDNA in Escherichia coli.Eur J Biochem. 1989; 179: 185-194Crossref PubMed Scopus (77) Google Scholar We engineered it to carry a human signal peptide and introduced a furin cleavage site between the propeptide and mature protein to allow activation by proteolytic cleavage at the cell surface. We constructed E1,E3-deleted type 5 adenovirus vectors expressing aDNAse I, rhPH20, CABC and PK, under the control of a CMV promoter, using the AdZ system developed by Prof G. Wilkinson.28Stanton RJ McSharry BP Armstrong M Tomasec P Wilkinson GW Re-engineering adenovirus vector systems to enable high-throughput analyses of gene function.Biotechniques. 2008; 45: 659-62, 664Crossref PubMed Scopus (90) Google Scholar Constructs were characterized for enzyme production in vitro and effects of the ECM-degrading enzymes on oncolytic activity was assessed in vivo. Expression of all of the enzymes, including aDNAse I, led to a strong reduction in tumor growth. We then compared conditionally-replicating group B chimeric adenovirus, EnAd, expressing aDNAse I and rhPH20. Both “armed” oncolytic viruses showed greater replication in vivo than parental EnAd, and both also showed significantly enhanced anticancer efficacy. We constructed four replication-incompetent E1,E3-deleted type 5 adenoviruses expressing either human aDNAse I, rhPH20, CABC, or PK under control of the CMV promoter, using the AdZ5 recombination system (Figure 1a).28Stanton RJ McSharry BP Armstrong M Tomasec P Wilkinson GW Re-engineering adenovirus vector systems to enable high-throughput analyses of gene function.Biotechniques. 2008; 45: 659-62, 664Crossref PubMed Scopus (90) Google Scholar In addition, an AdZ5 control virus was engineered which had the same backbone as the other constructs but lacked a transgene. Analysis of enzyme activity in the supernatants of HEK293 cells infected with each of the four viruses indicated each virus expressed a soluble enzyme that was capable of degrading its corresponding substrate (Figure 1b–e). As expected, no activity was detected with any of the substrates in the supernatants of HEK293 cells infected with the AdZ5 control virus. To analyze the impact of incorporating the transgenes on virus replication, HEK293 cells were infected separately with each virus. As shown in Figure 2a, all viruses produced very similar amounts of viral genomes over the period 24–96 hours. To ensure these genomes were packaged into viable infectious particles, viruses from the supernatants of infected HEK293 cells were harvested on day 4 and titrated on HEK293 Trex cells (to inhibit transgene expression by inhibiting tet operators in the CMV promoters) allowing direct measurement and comparison of infectivity (Figure 2b). There was no significant difference in viral titers between the adenoviruses encoding the enzymes and the control AdZ5 virus. Collectively, these results indicate a similar level of viral replication for all viruses and the secreted enzymes had no direct effect on virus infection or replication. Next, we assessed the impact of the transgenes on viability of infected cells. HEK293 cells were infected separately with each Ad5 virus and cell viability was measured every 24 hours using an MTS assay. The data were normalised to uninfected control cells. As shown in Figure 2c, all viruses showed slightly greater cytotoxicity compared to AdZ5, although AdPK showed significantly greater cytotoxicity than the other viruses (P ≤ 0.001), most likely reflecting nonspecific cytotoxicity of the secreted protease. Given that the enzyme-expressing Ad5 viruses are nonreplicating, assessment of their ability to potentiate virotherapy in vivo is easiest to address by transcomplementation with a conditionally-replicating or replication-competent virus. For this purpose, we used a modified wild-type Ad5 with luciferase fused to the 3' terminal of E1A (“E1A-AdLuc”), providing both transcomplementation and luminescence imaging potential.29Cawood R Chen HH Carroll F Bazan-Peregrino M van Rooijen N Seymour LW Use of tissue-specific microRNA to control pathology of wild-type adenovirus without attenuation of its ability to kill cancer cells.PLoS Pathog. 2009; 5: e1000440Crossref PubMed Scopus (113) Google Scholar To confirm suitability of E1A-AdLuc for transcomplementation, A549 cells were infected with AdZ5 alone or AdZ5 with E1A-AdLuc. Genomes of AdZ5 were measured by quantitative polymerase chain reaction (QPCR) using primers and probe designed to the CMV promoter. As shown in Figure 3a, over a 3-day period, increasing numbers of AdZ5 genomes were detected in cells coinfected with both viruses while there was no increase in genome number in cells infected with AdZ5 only. This suggests that there is sufficient E1A produced by the E1A-AdLuc to allow transcomplementation and replication of the engineered Ad5 viruses. Next, we analyzed the antitumor activity of all the enzyme-expressing Ad5 viruses (coadministered with E1A-AdLuc) in subcutaneous colon carcinoma tumors. SCID mice bearing DLD tumor xenografts were treated with a single intratumoral injection of PBS, or E1A-AdLuc (5 × 108 vp/tumor) plus AdZ5, AdDNAse, AdCABC, or AdPK (5 × 108 vp/tumor) (Figure 3b). Tumors were allowed to develop to 100 mm3 prior to injection, and sizes were subsequently measured every 3 days. There was no significant difference in tumor growth observed between the two control groups of PBS-treated and E1A-AdLuc/AdZ5-treated mice. Treatment with AdPH20, AdCABC, and AdPK (combined with E1A-AdLuc) all inhibited tumor growth, for example, at day 24, tumors were significantly smaller compared to the control groups in each case (P ≤ 0.05). Interestingly, treatment with AdDNAse (combined with E1A-AdLuc) inhibited tumor growth with tumor sizes significantly smaller than PBS alone (P ≤ 0.05) or AdZ5 (P ≤ 0.05) from day 9 onwards. Expression of exogenous enzymes within tumors often raises questions about possible enhancement of metastasis. To investigate whether these treatments would promote spontaneous metastasis, we assessed the level of human DNA present within the bloodstream using human-specific QPCR. This would allow detection of circulating tumor cells that have been shed from the primary tumor after oncolytic treatment, with a sensitivity of less than 80 pg DNA/sample (approximately 14 cells). QPCR was performed using human-specific primers and probe, targeting the PTGER2 gene, against a mouse background.30Alcoser SY Kimmel DJ Borgel SD Carter JP Dougherty KM Hollingshead MG Real-time PCR-based assay to quantify the relative amount of human and mouse tissue present in tumor xenografts.BMC Biotechnol. 2011; 11: 124Crossref PubMed Scopus (48) Google Scholar There was no detection of human-specific DNA in blood samples from any mice treated with oncolytic adenovirus expressing aDNAse I, rhPH20, CABC, or PK, suggesting none of the treatments mobilized appreciable numbers of tumor cells (Supplementary Figure S1). The ability of DNase to improve oncolytic virus activity has not been previously reported. Coupled with published reports of the antimetastatic activity of this enzyme, we prioritized oncolytic viruses expressing aDNAse I for further development. Hyaluronidase (rhPH20) was also selected given that a hyaluronidase-expressing adenovirus is already in clinical study. EnAd is an oncolytic group B adenovirus (previously known as ColoAd1), currently undergoing several early phase clinical trials for treatment of cancer. The virus combines good systemic kinetics and promising clinical activity31Calvo E Machiels J-PH Rottey S Cubillo A Salazar R et al.A first-in-class, first-in-human phase I study of enadenotucirev, an oncolytic Ad11/Ad3 chimeric group B adenovirus, administered intravenously in patients with metastatic epithelial tumors.J Clin Oncol. 2014; 32 (15, suppl.) abstract 3103Google Scholar,32Calvo E Martín MG Cubillo A Machiels J Rottey S Mardjuadi F et al.A phase 1 study of enadenotucirev, an oncolytic ad11/ad3 chimeric group b adenovirus, administered intravenously-analysis of dose expansion and repeat cycle cohorts in patients with metastatic colorectal cancer (mCRC).Ann Oncol. 2014; 25: iv367Google Scholar with the possibility to encode and express transgenes. Accordingly, we constructed EnAd expressing aDNAse I and rhPH20 hyaluronidase. These enzymes, under the control of a CMV promoter, were inserted into the EnAd backbone, downstream of the fiber gene (Figure 1a). Analysis of aDNAse I and rhPH20 activity in the supernatant of A549 cells infected with “armed” EnAd confirmed the enzymes were secreted and capable of digesting exogenous DNA and hyaluronic acid respectively (data not shown). To analyze the effect of transgene expression on virus replication, the viruses were tested for their replication kinetics by measuring effects on cell viability, virus quantification, and genome production. While there were slightly more virus genomes produced in EnAdPH20-infected cells compared to EnAdDNAse and EnAd (measured by QPCR), there was no significant difference in the number of infectious particles produced, nor in cell kill (Figure 4). Next, we analyzed the antitumor activity of the enzyme-expressing EnAd viruses after a single intratumoral injection of a relatively low virus dose (1 × 109 vp/tumor) into pre-established DLD human colon carcinoma xenografts. This low dose and protocol was adopted to mimic a poor delivery scenario, and to maximize the potential for improved spread to enhance oncolytic activity. Both engineered viruses mediated considerable inhibition of tumor growth in comparison mice treated with PBS and unmodified EnAd (Figure 5a). At 32 days, animals were killed and the tumors removed for measurement of virus genomes by QPCR (Figure 5b) and immunohistochemical analysis. Tumors treated with EnAdDNAse showed significantly higher numbers of virus genomes present compared to both EnAd and EnAdPH20 treated tumors (12.9- and 6.5-fold respectively). To assess whether enhanced efficacy observed in mice treated with either EnAdDNAse or EnAdPH20 was as a result of improved distribution of virus, immunohistochemical analysis was performed on tumors 32 days postinfection (Figure 5c–e). All of the DLD tumors treated with either EnAdDNAse or EnAdPH20 showed evidence of active virus infection (5/5 tumors for each enzyme), with many cells showing strong intranuclear hexon stain, indicative of virus packaging. It was noticeable that large patches of infection were spread throughout the tumor mass in each case. In the case of EnAdDNAse, the patches of hexon expression were coincident with strong expression of DNAse activity (Figure 5e). In contrast, only two out of five tumors in the group treated with unmodified EnAd showed signs of ongoing virus infection at day 32 (one of these is shown in Figure 5c), and no expression of DNAse (Figure 5e). Tumors treated with PBS showed no adenoviral staining (data not shown). Intriguingly, tumors treated with EnAdDNAse showed particularly wide-spread staining pattern, with many individual cells staining strongly for hexon even in regions spatially separated from the main areas of infection. This effect was not observed for the other viruses, except very close to areas of strong infection, and suggests that the DNAse-expressing virus is capable of better intratumoral spread (Figure 5c-2). This was further supported by quantifying the percentage of stained areas. EnAdDNAse-treated tumors showed significantly more positive staining compared to tumors treated with EnAd alone (Figure 5d). To determine whether enzymes encoded within viruses remained active 32 days after intratumoral administration, tumor xenografts were resected and homogenates were assayed for substrate-specific degradation. Homogenates of tumors injected with unmodified EnAd showed a significant ability to degrade calf thymus DNA, reflecting endogenous cell-associated DNAse activity, although EnAdDNAse injected tumors showed much stronger DNA degradation due to the encoded aDNAse I activity (Figure 5f). Similarly, EnAdPH20-injected tumors showed powerful ability to digest high molecular weight hyaluronic acid, and in this case there was no evidence of any endogenous hyaluronic acid-degrading activity in the control groups. These data support the possibility that the increased intratumoral spread of EnAdDNAse, and the improved anticancer activity of both EnAdDNAse and EnAdPH20 (compared to the unmodified parental virus) is associated with persistent expression and activity of the encoded enzymes. Limited spread of adenovirus particles through solid tumor tissue is thought to have played a significant role in limiting the success of early clinical trials.2Kirn D Clinical research results with dl1520 (Onyx-015), a replication-selective adenovirus for the treatment of cancer: what have we learned?.Gene Ther. 2001; 8: 89-98Crossref PubMed Scopus (304) Google Scholar,3Liu TC Galanis E Kirn D Clinical trial results with oncolytic virotherapy: a century of promise, a decade of progress.Nat Clin Pract Oncol. 2007; 4: 101-117Crossref PubMed Scopus (386) Google Scholar,9Swiderek MS Mannuzza FJ Effects of ECM Proteins on Barrier Formation in Caco-2 Cells.Becton Dickinson Technical Bulletin. 1997; 421: 1-4Google Scholar,33Parato KA Senger D Forsyth PA Bell JC Recent progress in the battle between oncolytic viruses and tumours.Nat Rev Cancer. 2005; 5: 965-976Crossref PubMed Scopus (454) Google Scholar The dense ECM restricts the intercellular percolation of macromolecules and particles,10Mok W Stylianopoulos T Boucher Y Jain RK Mathematical modeling of herpes simplex virus distribution in solid tumors: implications for cancer gene therapy.Clin Cancer Res. 2009; 15: 2352-2360Crossref PubMed Scopus (64) Google Scholar,34Pipiya T Sauthoff H Huang YQ Chang B Cheng J Heitner S et al.Hypoxia reduces adenoviral replication in cancer cells by downregulation of viral protein expression.Gene Ther. 2005; 12: 911-917Crossref PubMed Scopus (73) Google Scholar,35Shen BH Hermiston TW Effect of hypoxia on Ad5 infection, transgene expression and replication.Gene Ther. 2005; 12: 902-910Crossref PubMed Scopus (67) Google Scholar,36Smith E Breznik J Lichty BD Strategies to enhance viral penetration of solid tumors.Hum Gene Ther. 2011; 22: 1053-1060Crossref PubMed Scopus (44) Google Scholar and degradation of the ECM by injection of enzymes has already been shown to enhance therapeutic activity of oncolytic viruses.12Kuriyama N Kuriyama H Julin CM Lamborn K Israel MA Pretreatment with protease is a useful experimental strategy for enhancing adenovirus-mediated cancer gene therapy.Hum Gene Ther. 2000; 11: 2219-2230Crossref PubMed Scopus (69) Google Scholar,17Guedan S Rojas JJ Gros A Mercade E Cascallo M Alemany R Hyaluronidase expression by an oncolytic adenovirus enhances its intratumoral spread and suppresses tumor growth.Mol Ther. 2010; 18: 1275-1283Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar However, the need for multiple reinjections of enzyme was found to limit the utility of this approach,37Ganesh S Gonzalez-Edick M Gibbons D Van Roey M Jooss K Intratumoral coadministration of hyaluronidase enzyme and oncolytic adenoviruses enhances virus potency in metastatic tumor models.Clin Cancer Res. 2008; 14: 3933-3941Crossref PubMed Scopus (76) Google Scholar paving the way for ECM-degrading enzymes to be encoded within the virus, with enzymes consequently produced and secreted from infected tumor cells throughout the duration of virus infection. Tumor ECM is a complex mixture including proteins, carbohydrates, nucleic acids and lipids, all of which components may impact on virus particle convection. Here, we have explored the use of several ECM-degrading enzymes, encoded within adenoviruses as a strategy to enhance oncolytic virus spread through tumors. Hyaluronidase has previously been shown to enhance anticancer activity when encoded in replicating adenovirus.17Guedan S Rojas JJ Gros A Mercade E Cascallo M Alemany R Hyaluronidase expression by an oncolytic adenovirus enhances its intratumoral spread and suppresses tumor growth.Mol Ther. 2010; 18: 1275-1283Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar Chondroitinase ABC21Dmitrieva N Yu L Viapiano M Cripe TP Chiocca EA Glorioso JC et al.Chondroitinase ABC I-mediated enhancement of oncolytic virus spread and antitumor efficacy.Clin Cancer Res. 2011; 17: 1362-1372Crossref PubMed Scopus (56) Google Scholar and proteases such as metalloproteinases11Cheng J Sauthoff H Huang Y Kutler DI Bajwa S Rom WN et al.Human matrix metalloproteinase-8 gene delivery increases the oncolytic activity of a replicating adenovirus.Mol Ther. 2007; 15: 1982-1990Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar and protease-inducers such as relaxin15Ganesh S Gonzalez Edick M Idamakanti N Abramova M Vanroey M Robinson M et al.Relaxin-expressing, fiber chimeric oncolytic adenovirus prolongs survival of tumor-bearing mice.Cancer Res. 2007; 67: 4399-4407Crossref PubMed Scopus (86) Google Scholar,16Kim JH Lee YS Kim H Huang JH Yoon AR Yun CO Relaxin expression from tumor-targeting adenoviruses and its intratumoral spread, apoptosis induction, and efficacy.J Natl Cancer Inst. 2006; 98: 1482-1493Crossref PubMed Scopus (172) Google Scholar have also shown promising activity, and the wide substrate specificity of proteinase K, coupled with its high activity at a broad pH and temperature range, makes it a promising candidate. We also explored the usefulness of DNAse, reasoning that the ongoing" @default.
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• W2201036716 title "Actin-resistant DNAse I Expression From Oncolytic Adenovirus Enadenotucirev Enhances Its Intratumoral Spread and Reduces Tumor Growth" @default.
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