Key points are not available for this paper at this time.
Successful virotherapy requires efficient virus spread within tumors. We tested whether the expression of hyaluronidase, an enzyme which dissociates the extracellular matrix (ECM), could enhance the intratumoral distribution of an oncolytic adenovirus and improve its therapeutic activity. As a proof of concept, we demonstrated that intratumoral coadministration of hyaluronidase in mice-bearing tumor xenografts improves the antitumor activity of an oncolytic adenovirus. Next, we constructed a replication-competent adenovirus expressing a soluble form of the human sperm hyaluronidase (PH20) under the control of the major late promoter (MLP) (AdwtRGD-PH20). Intratumoral treatment of human melanoma xenografts with AdwtRGD-PH20 resulted in degradation of hyaluronan (HA), enhanced viral distribution, and induced tumor regression in all treated tumors. Finally, the PH20 cDNA was inserted in an oncolytic adenovirus that selectively kills pRb pathway-defective tumor cells. The antitumoral activity of the novel oncolytic adenovirus expressing PH20 (ICOVIR17) was compared to that of the parental virus ICOVIR15. ICOVIR17 showed more antitumor efficacy following intratumoral and systemic administration in mice with prestablished tumors, along with an improved spread of the virus within the tumor. Importantly, a single intravenous dose of ICOVIR17 induced tumor regression in 60% of treated tumors. These results indicate that ICOVIR17 is a promising candidate for clinical testing. Successful virotherapy requires efficient virus spread within tumors. We tested whether the expression of hyaluronidase, an enzyme which dissociates the extracellular matrix (ECM), could enhance the intratumoral distribution of an oncolytic adenovirus and improve its therapeutic activity. As a proof of concept, we demonstrated that intratumoral coadministration of hyaluronidase in mice-bearing tumor xenografts improves the antitumor activity of an oncolytic adenovirus. Next, we constructed a replication-competent adenovirus expressing a soluble form of the human sperm hyaluronidase (PH20) under the control of the major late promoter (MLP) (AdwtRGD-PH20). Intratumoral treatment of human melanoma xenografts with AdwtRGD-PH20 resulted in degradation of hyaluronan (HA), enhanced viral distribution, and induced tumor regression in all treated tumors. Finally, the PH20 cDNA was inserted in an oncolytic adenovirus that selectively kills pRb pathway-defective tumor cells. The antitumoral activity of the novel oncolytic adenovirus expressing PH20 (ICOVIR17) was compared to that of the parental virus ICOVIR15. ICOVIR17 showed more antitumor efficacy following intratumoral and systemic administration in mice with prestablished tumors, along with an improved spread of the virus within the tumor. Importantly, a single intravenous dose of ICOVIR17 induced tumor regression in 60% of treated tumors. These results indicate that ICOVIR17 is a promising candidate for clinical testing. IntroductionOncolytic adenoviruses are promising agents for the treatment of cancer. These viruses are designed to selectively target, replicate in and kill cancer cells, while sparing normal cells. The release of virus progeny from lysed tumor cells results in an exponential increase of the virus inoculum, which can spread laterally throughout the tumor mass and potentially induce tumor regression. Early clinical trials with oncolytic adenoviruses established the safety of this therapy,1Kirn 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 (301) Google Scholar even after i.v. administration.2Nemunaitis 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,3Reid T Warren R Kirn D Intravascular adenoviral agents in cancer patients: lessons from clinical trials.Cancer Gene Ther. 2002; 9: 979-986Crossref PubMed Scopus (210) Google Scholar However, only limited responses were noted, and treatment with first generation of oncolytic adenoviruses did not significantly alter the course of the disease.One of the main limitations that contributes to these suboptimal results is the inability of oncolytic adenoviruses to effectively spread in the solid tumors. Oncolytic adenoviruses, along with most novel targeted therapeutics, face tremendous transport barriers in the tumor interstitium, due in part to their relatively large size (90 nm), much larger than chemotherapeutic drugs. Also, solid tumor presents unique characteristics that hinder the transport of macromolecules.4Jang SH Wientjes MG Lu D Au JL Drug delivery and transport to solid tumors.Pharm Res. 2003; 20: 1337-1350Crossref PubMed Scopus (408) Google Scholar Among them, the presence of high amounts of extracellular matrix (ECM) and high interstitial fluid pressure in tumor interstitium are the main source of physical resistance to drug transport.One attractive method for improving viral spread through the tumor mass is to degrade ECM with proteolytic enzymes. In this regard, pretreatment of tumors with trypsin or collagenase has been shown to enhance distribution of viral vectors after intratumoral administration.5Kuriyama N Kuriyama H Julin CM Lamborn KR Israel MA Protease pretreatment increases the efficacy of adenovirus-mediated gene therapy for the treatment of an experimental glioblastoma model.Cancer Res. 2001; 61: 1805-1809PubMed Google Scholar,6Kuriyama N Kuriyama H Julin CM Lamborn K Israel MA Pretreatment with protease is a useful experimental strategy for adenovirus-mediated cancer gene Gene Ther. PubMed Scopus Google Scholar Also, replication-competent adenoviruses expressing a that have been and results showed that ECM degradation can enhance viral spread and the of S N et oncolytic adenovirus of Res. 2007; PubMed Scopus Google H expression from adenoviruses and its intratumoral and PubMed Scopus Google is an of the is a high of of are in and with and from extracellular to PubMed Scopus Google Scholar of with hyaluronidase has been shown to enhance the of chemotherapeutic agents in The of extracellular matrix the of solid and clinical results of hyaluronidase to PubMed Scopus Google B J a for clinical PubMed Scopus Google Scholar is to and to interstitial fluid fluid pressure in human of and the to intratumoral of Res. 20: Google Scholar agents to cells. has been that hyaluronidase have S B R human cancer xenografts in J 2002; PubMed Scopus Google a that intratumoral coadministration of hyaluronidase and replication-competent adenoviruses can enhance viral distribution and improve virus in S D K Intratumoral coadministration of hyaluronidase enzyme and oncolytic adenoviruses virus in tumor Res. 14: PubMed Scopus Google Scholar In the we these results a single dose of hyaluronidase and an oncolytic adenovirus in a melanoma that high of results were this strategy is limited to intratumoral As have intravenous administration improve the of an oncolytic for cancer. we to whether expression of hyaluronidase an oncolytic of could enhance viral spread throughout the tumor after systemic an we constructed a replication-competent adenovirus expressing PH20 hyaluronidase under the control of the major late promoter PH20 is a hyaluronidase in The of hyaluronidase and 2001; 20: PubMed Scopus Google Scholar PH20 hyaluronidase was for its to degrade in to human and that are only In to a soluble hyaluronidase, we the of of a soluble PH20 enhanced virus spread and improved therapeutic compared to the parental in tumor regression in all treated tumors. We constructed an oncolytic adenovirus expressing PH20 hyaluronidase The of and in the promoter ICOVIR17 for in pRb pathway-defective tumor cells. degradation enhanced the intratumoral spread of ICOVIR17 and improved its antitumor efficacy its expression in tumor to a for in we first expression in of tumor an As shown in melanoma cells and cells the amounts of Next, we in human tumors of the of that and tumors high amounts of and tumor cells. tumors than cells and this was within the tumor melanoma cells, which high amounts of in and in were for in administration of hyaluronidase the efficacy of an oncolytic adenovirus in whether the degradation of the in the ECM of solid tumors can enhance virus we an oncolytic J R of a and oncolytic adenovirus the Ther. 2007; PubMed Scopus Google Scholar in which is to cancer cells with a melanoma tumor xenografts size of were treated with a single intratumoral of hyaluronidase viral or a of hyaluronidase and of tumor was in tumors treated with the of virus and hyaluronidase compared with tumors treated with or hyaluronidase Importantly, hyaluronidase administration the antitumor efficacy of compared with the virus in in tumor these not of tumor is and after of hyaluronidase spread and antitumor activity of tumor xenografts were treated with hyaluronidase or a of PH20 hyaluronidase and is compared with tumors treated with compared with tumors treated with PH20 of extracellular matrix and adenovirus distribution in melanoma tumors treated with or and hyaluronidase after tumor were for the and with adenovirus was in with an and with adenovirus was in tumor with an and with whether the enhanced efficacy in treated with the was to a in in the tumor an improved distribution of was tumors after virus treatment tumors treated with and hyaluronidase showed of expression of and more adenoviral expression of virus compared with tumors treated with tumors with high of adenovirus cells not of PH20 hyaluronidase the efficacy of a replication-competent adenovirus in we constructed AdwtRGD-PH20 a replication-competent adenovirus that a soluble form of the human hyaluronidase (PH20) the hyaluronidase expression to the of the viral PH20 cDNA was inserted in the of the under the control of the that AdwtRGD-PH20 a soluble hyaluronidase, cells were with and were and for hyaluronidase activity. hyaluronidase activity was in of cells with of AdwtRGD-PH20 cells were to high to of not In of AdwtRGD-PH20 in a of tumor showed of viral and compared with the control not whether expression of the human PH20 hyaluronidase a replication-competent adenovirus the antitumor in mice-bearing tumors were with a single dose of or AdwtRGD-PH20 In this tumors treated with showed a of tumor to that of tumors In treatment with AdwtRGD-PH20 showed a in tumor compared with and after of tumors treated with AdwtRGD-PH20 showed of tumor tumor were in mice treated with or The enhanced antitumor activity the hyaluronidase expressing with a in tumor and of virus compared with tumors treated with shown of human hyaluronidase spread and antitumor activity of a replication-competent adenovirus. tumor xenografts were treated with or is compared with tumors treated with from to compared with tumors treated with from to of melanoma tumors treated with or tumor from tumors after administration were for the adenovirus was in from tumors after administration with an and with and of an oncolytic adenovirus expressing PH20 the of the we constructed an oncolytic adenovirus expressing PH20 of the PH20 cDNA in the of in a increase in of the size of this we a oncolytic which and to that of and with a In was the of and in the promoter of the PH20 expression from AdwtRGD-PH20 in of the resulted in the ICOVIR17 The of ICOVIR17 is larger than of hyaluronidase activity in the of tumor cells with and ICOVIR17 that ICOVIR17 a soluble hyaluronidase that is of high As hyaluronidase activity was in of tumor cells with of of with of cells after with and that ICOVIR17 a soluble that the of cells were with or ICOVIR17 high of the were and is the of the PH20 cDNA viral we compared the of and ICOVIR17 in cells. As shown in viruses the viral all viral Next, we the of ICOVIR17 to kill tumor cells compared with ICOVIR15. in and were and for and and for These results indicate that in virus spread is not expression of PH20 hyaluronidase not increase of a antitumor activity after intratumoral administration in the antitumor activity of ICOVIR17 in established melanoma tumors after intratumoral tumors size of were treated with a single intratumoral of or ICOVIR17 with viruses resulted in of tumor compared with tumors. These were throughout the of the after and ICOVIR17 induced a of tumor of 60% and compared to the control this were and the of the tumors was and tumors an of and treated with the were significantly compared with tumors treated with or with the control that PH20 expression can significantly enhance the antitumor activity of an oncolytic adenovirus after intratumoral of human PH20 the antitumor activity of an oncolytic adenovirus. tumor xenografts were treated with or is compared with tumors from to compared with tumors from to tumor xenografts were treated i.v. with a single dose of or is compared with tumors treated with from to compared with tumors treated with from to tumor xenografts were treated i.v. with a single dose of or is compared with tumors from to compared with tumors from to compared with tumors from to and tumors treated with or ICOVIR17 were the of and were in was in with an and with of and tumors are are of virus in for tumor were of of was compared with tumors. antitumor activity after systemic administration in efficacy of ICOVIR17 intratumoral administration to the of ICOVIR17 to control tumor i.v. melanoma tumor xenografts size of were treated with a single dose of or ICOVIR17 the In this tumor which high of tumors treated with showed therapeutic and all tumors to in a to treated with In a single intravenous of ICOVIR17 an tumor that throughout the of virus the tumors treated with ICOVIR17 showed a significantly tumor compared with and treated the of the after the a significantly antitumor than with 60% of tumors regression and of their pretreatment that the antitumor activity shown the adenoviruses was not to a single we an in human tumor tumors size of were treated with a single i.v. dose of or ICOVIR17 after were due to the large size of tumors. In these tumors, which of compared with tumors induced a tumor compared with Importantly, ICOVIR17 showed a in tumor that was compared with and from after the of the treatment through the of the of virus was in and tumors the of the and of was tumors treated with and ICOVIR17 showed of virus that were not in tumors. tumors showed of cells that of the Importantly, tumors treated with the showed a more of adenovirus of was for virus which was compared to tumors in tumor to after systemic administration in in showed that hyaluronidase expression enhanced the intratumoral spread of ICOVIR17 and improved its antitumor was whether this resulted in mice are for human adenoviruses, we this safety in which are and for were with or with a dose of of or ICOVIR17 the and were after viral and ICOVIR17 viruses and a increase in and Also, viruses induced a in and a increase in and compared with the Importantly, in of or were mice treated with or that PH20 expression did not significantly increase an oncolytic after systemic administration of ICOVIR17 in were with or with viral of or of virus were and and and were of The for and in after virus of are compared with of treated with or ICOVIR17 were after virus of the were and was with and was after systemic of from treated with and ICOVIR17 showed of with in the more of the were treated with or major to the of oncolytic adenovirus in cancer therapy is their inability to effectively spread in the solid tumors. In the we to enhance the intratumoral distribution of an oncolytic adenovirus with a soluble form of the human sperm hyaluronidase, this we have demonstrated that PH20 expression an oncolytic adenovirus the improves viral spread through the tumor mass and the antitumor efficacy its We have for the first that an oncolytic adenovirus with hyaluronidase antitumor efficacy after systemic a proof of we demonstrated that a single dose of hyaluronidase in with an oncolytic adenovirus is to improve adenovirus distribution within the tumor mass and enhance its antitumor activity. results that ECM degradation viral spread and is for the virotherapy for S N et oncolytic adenovirus of Res. 2007; PubMed Scopus Google H expression from adenoviruses and its intratumoral and PubMed Scopus Google S D K Intratumoral coadministration of hyaluronidase enzyme and oncolytic adenoviruses virus in tumor Res. 14: PubMed Scopus Google Scholar However, this presents The first the that the of hyaluronidase the ECM is and within the of the antitumoral activity with the therapy is due to an in the spread of viruses after the of the that of the ECM enhance adenoviral spread through the tumor. which has been et is to hyaluronidase this et demonstrated that treatment of an oncolytic adenovirus and human PH20 significantly increases the antitumor activity and of in However, these the of hyaluronidase is limited to intratumoral administration in this was to an oncolytic adenovirus with improved spread for the treatment of We that hyaluronidase expression replication-competent adenoviruses ECM degradation of viral virus spread within the tumor. this viruses were expressing a soluble of PH20 hyaluronidase under the control of the a replication-competent and a replication-selective adenovirus. In of the viruses showed that expression of a soluble hyaluronidase the was and did not virus In viruses antitumor efficacy compared with their in the tumor Importantly, PH20 expression oncolytic activity of ICOVIR17 after i.v. administration in tumor compared to its ICOVIR15. In all the this enhanced oncolytic activity was after a single administration of the and the tumor the of treatment or after tumor was is to that 60% of tumors showed and all tumors showed ICOVIR17 tumor responses were to the of tumor is that tumor of a intratumoral cells are not for human adenovirus However, not an for viral spread in the clinical results indicate that in of human not have to improve adenovirus spread matrix constructed oncolytic adenoviruses with a that expression of and expression of matrix with ECM degradation oncolytic viruses virus spread and improved antitumor S N et oncolytic adenovirus of Res. 2007; PubMed Scopus Google H expression from adenoviruses and its intratumoral and PubMed Scopus Google Scholar the that ECM viral spread following administration of that is whether expression of these proteolytic can increase the of the oncolytic In this regard, et demonstrated that of tumors with a virus increase in their in results showed that expression could increase which safety H expression from adenoviruses and its intratumoral and PubMed Scopus Google Scholar In we to expression of hyaluronidase in normal cells expressing PH20 late in the adenoviral under the control of the PH20 expression an oncolytic adenovirus to tumor cells, the safety of the virus in normal cells. In the in we have not in of or following i.v. of ICOVIR17 compared to that PH20 expression not to the safety of a oncolytic adenovirus. Importantly, the safety and of hyaluronidase has been in clinical that hyaluronidase has normal or The of extracellular matrix the of solid and clinical results of hyaluronidase to PubMed Scopus Google CM K J trial of of hyaluronidase in cancer PubMed Scopus Google J H therapy with hyaluronidase to of PubMed Scopus Google Scholar In hyaluronidase administration in and clinical trials has not been to an increase of S B R human cancer xenografts in J 2002; PubMed Scopus Google S D K Intratumoral coadministration of hyaluronidase enzyme and oncolytic adenoviruses virus in tumor Res. 14: PubMed Scopus Google T H significantly the efficacy of of PubMed Scopus Google the therapeutic of in treatment of for the of PubMed Scopus Google J H S J of hyaluronidase and for treatment of of the and J PubMed Scopus Google Scholar In this regard, et demonstrated that the size of in the interstitial matrix after of PH20 hyaluronidase the of to in et al.A human enzyme for enhanced interstitial transport of PubMed Scopus Google Scholar adenovirus not tumor cells, to through these has shown an in and systemic cancer The which hyaluronidase therapeutic of is not degradation of the ECM is to improve the of the drug the tumor However, has been that hyaluronidase have activity. In this regard, et that hyaluronidase administration in mice-bearing human tumors in tumor and that hyaluronidase treatment of tumor cells to have induced an in S B R human cancer xenografts in J 2002; PubMed Scopus Google Scholar et cancer to and hyaluronidase T hyaluronidase in cancer: a tumor promoter and Res. PubMed Scopus Google Scholar demonstrated that hyaluronidase is high can a tumor In this we that hyaluronidase coadministration or hyaluronidase expression an oncolytic adenovirus virus distribution within the in a viral and improved therapeutic In viruses were in viral spread is not all viruses showed in all results that the main which hyaluronidase increases oncolytic in is to the ECM degradation and interstitial fluid pressure However, we the that in cancer cells, could to the enhanced of results that ECM hyaluronidase the distribution of oncolytic adenovirus within the tumor which results in a more antitumor in all tumor Also, we that an oncolytic adenovirus expressing has antitumor activity after intratumoral and systemic in tumor regression. that oncolytic adenoviruses have shown promising results in with of oncolytic adenoviruses in therapy for Res. PubMed Scopus Google Scholar and that hyaluronidase administration improves antitumor of we that of ICOVIR17 with We that ICOVIR17 is promising for clinical for the treatment of and with and cells, melanoma cells, cells, tumor cells, and cancer cells were from the cells were from normal cells and were from the and tumor cells were established in et of the in human cancer PubMed Scopus Google Scholar were tested presence and and were in with the in the of were to 60% in was and cells were in was and with of in was an expression of in PubMed Scopus Google the of the viruses in this is shown in and have been J R of a and oncolytic adenovirus the Ther. 2007; PubMed Scopus Google Scholar is a adenovirus in which expression of the adenovirus gene is a which and adenoviruses, a was constructed PH20 and were the The to was designed that the for the was The to and were and with to the PH20 The the of the virus and the and the a for The the PH20 was with and to the D R the efficacy of a adenovirus expressing the a late gene in a Ther. 2007; 14: PubMed Scopus Google Scholar to The of and the a from I et adenovirus with of a and adenovirus PubMed Google the and a to the in were in resulted in generation of the was a was with and with the of AdwtRGD-PH20 and ICOVIR17 were in and in cells. viruses were in cells and to and cells were with of virus to for was cells were with and with the cells and were and to of of were in to an method in N T R of and in the of oncolytic Gene Ther. PubMed Scopus Google for hyaluronidase activity. cells were with of virus to for was and cells were with was and The hyaluronidase activity of was T of hyaluronan and its to of hyaluronidase 2002; PubMed Scopus Google Scholar soluble hyaluronidase were with a in and and were after with were and a and was and cells in in with were with with after or after were with and for and was The to was from regression an efficacy were the and the for in coadministration melanoma tumors were established of cells the of tumors mice were and tumors were treated with a single intratumoral of of hyaluronidase or a of and PH20 hyaluronidase the intratumoral efficacy of viruses expressing the PH20 hyaluronidase, mice-bearing established tumors a single intratumoral of or of systemic melanoma or tumors were established of cells the of tumors the tumor for tumors and for mice were treatment tumors and treated with a single intravenous of or of or ICOVIR17 all tumor and were and the of tumor were J R of a and oncolytic adenovirus the Ther. 2007; PubMed Scopus Google Scholar The was to the in tumor and tumor in mice in the from were and tumors were and was in and the was in for and in were single dose of of and ICOVIR17 was the in a of of The control was with an of were and after these were for clinical of were and and were through Clinical of and were the Clinical and of the the of were and were in for or in late was tumor J R of a and oncolytic adenovirus the Ther. 2007; PubMed Scopus Google N T R of and in the of oncolytic Gene Ther. PubMed Scopus Google Scholar of were an adenovirus in for tumor were of of was of tumors were treated with an was with to the of were were and activity was for in in were for with normal in the were with of a The of was tested with of hyaluronidase for to the of the with the were in and treated with were with and with in for tumor were of of was IntroductionOncolytic adenoviruses are promising agents for the treatment of cancer. These viruses are designed to selectively target, replicate in and kill cancer cells, while sparing normal cells. The release of virus progeny from lysed tumor cells results in an exponential increase of the virus inoculum, which can spread laterally throughout the tumor mass and potentially induce tumor regression. Early clinical trials with oncolytic adenoviruses established the safety of this therapy,1Kirn 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 (301) Google Scholar even after i.v. administration.2Nemunaitis 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,3Reid T Warren R Kirn D Intravascular adenoviral agents in cancer patients: lessons from clinical trials.Cancer Gene Ther. 2002; 9: 979-986Crossref PubMed Scopus (210) Google Scholar However, only limited responses were noted, and treatment with first generation of oncolytic adenoviruses did not significantly alter the course of the disease.One of the main limitations that contributes to these suboptimal results is the inability of oncolytic adenoviruses to effectively spread in the solid tumors. Oncolytic adenoviruses, along with most novel targeted therapeutics, face tremendous transport barriers in the tumor interstitium, due in part to their relatively large size (90 nm), much larger than chemotherapeutic drugs. Also, solid tumor presents unique characteristics that hinder the transport of macromolecules.4Jang SH Wientjes MG Lu D Au JL Drug delivery and transport to solid tumors.Pharm Res. 2003; 20: 1337-1350Crossref PubMed Scopus (408) Google Scholar Among them, the presence of high amounts of extracellular matrix (ECM) and high interstitial fluid pressure in tumor interstitium are the main source of physical resistance to drug transport.One attractive method for improving viral spread through the tumor mass is to degrade ECM with proteolytic enzymes. In this regard, pretreatment of tumors with trypsin or collagenase has been shown to enhance distribution of viral vectors after intratumoral administration.5Kuriyama N Kuriyama H Julin CM Lamborn KR Israel MA Protease pretreatment increases the efficacy of adenovirus-mediated gene therapy for the treatment of an experimental glioblastoma model.Cancer Res. 2001; 61: 1805-1809PubMed Google Scholar,6Kuriyama N Kuriyama H Julin CM Lamborn K Israel MA Pretreatment with protease is a useful experimental strategy for adenovirus-mediated cancer gene Gene Ther. PubMed Scopus Google Scholar Also, replication-competent adenoviruses expressing a that have been and results showed that ECM degradation can enhance viral spread and the of S N et oncolytic adenovirus of Res. 2007; PubMed Scopus Google H expression from adenoviruses and its intratumoral and PubMed Scopus Google is an of the is a high of of are in and with and from extracellular to PubMed Scopus Google Scholar of with hyaluronidase has been shown to enhance the of chemotherapeutic agents in The of extracellular matrix the of solid and clinical results of hyaluronidase to PubMed Scopus Google B J a for clinical PubMed Scopus Google Scholar is to and to interstitial fluid fluid pressure in human of and the to intratumoral of Res. 20: Google Scholar agents to cells. has been that hyaluronidase have S B R human cancer xenografts in J 2002; PubMed Scopus Google a that intratumoral coadministration of hyaluronidase and replication-competent adenoviruses can enhance viral distribution and improve virus in S D K Intratumoral coadministration of hyaluronidase enzyme and oncolytic adenoviruses virus in tumor Res. 14: PubMed Scopus Google Scholar In the we these results a single dose of hyaluronidase and an oncolytic adenovirus in a melanoma that high of results were this strategy is limited to intratumoral As have intravenous administration improve the of an oncolytic for cancer. we to whether expression of hyaluronidase an oncolytic of could enhance viral spread throughout the tumor after systemic an we constructed a replication-competent adenovirus expressing PH20 hyaluronidase under the control of the major late promoter PH20 is a hyaluronidase in The of hyaluronidase and 2001; 20: PubMed Scopus Google Scholar PH20 hyaluronidase was for its to degrade in to human and that are only In to a soluble hyaluronidase, we the of of a soluble PH20 enhanced virus spread and improved therapeutic compared to the parental in tumor regression in all treated tumors. We constructed an oncolytic adenovirus expressing PH20 hyaluronidase The of and in the promoter ICOVIR17 for in pRb pathway-defective tumor cells. degradation enhanced the intratumoral spread of ICOVIR17 and improved its antitumor efficacy its
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