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Choontaek Lee - One of the best experts on this subject based on the ideXlab platform.

  • combination therapy of Conditionally Replicating Adenovirus and histone deacetylase inhibitors
    International Journal of Molecular Medicine, 2011
    Co-Authors: Dal Rae Kim, Miyoung Park, Hyojeong Lim, Jongsun Park, Young Jae Cho, Seiwon Lee, Hoil Yoon, Jaeho Lee, Yeon Soo Kim, Choontaek Lee
    Abstract:

    Combination therapy of adenoviral gene therapy and a histone deacetylase (HDAC) inhibitor is important due to the enhancing effect of HDAC inhibitors on adenoviral transduction and transcription. However, contradictory results have been reported on the effect of combination of CRAd (Conditionally Replicating Adenovirus) and HDAC inhibitors. This study was designed to investigate the interaction of CRAd and HDAC inhibitors and determine the ideal way to combine the two agents. Combination of HDAC inhibitors (SK7041, SBHA and vorinostat) at pre- and post-transductional periods with CRAd enhanced the transduction of CRAd and expression of luciferase expression from Δ24-luc in vitro. However, suppression of luciferase expression from Δ24-luc injected tumor mass was observed by in vivo tumor bioluminescence imaging and drug interaction analysis also showed an antagonistic interaction that was probably related with the inhibitory effect of the HDAC inhibitor on adenoviral replication. Suppression of p21 induction by p21 siRNA reversed the suppressive effect of vorinostat on the replication of CRAd, but still failed to reverse the antagonistic interaction. Addition of vorinostat at the pre-transductional period revealed an improvement in the transduction efficiency of CRAd and also induced a synergistic interaction between CRAd and vorinostat, which was possibly related with prevention of the suppressive effect of vorinostat on adenoviral replication. In conclusion, the addition of HDAC inhibitor before CRAd injection showed synergistic antitumor effects, which warrants further investigation on the sequence of HDAC inhibitor and CRAd treatment in an animal tumor model.

  • genetic immunotherapy of lung cancer using Conditionally Replicating Adenovirus and Adenovirus interferon beta
    Cancer Gene Therapy, 2010
    Co-Authors: M Y Park, Dal Rae Kim, Hoil Yoon, Choontaek Lee, Heewon Jung, Jin Hak Lee
    Abstract:

    Genetic immunotherapy is considered an ideal treatment modality for cancer because of its systemic nature. This study was designed to develop a potent novel genetic immunotherapy by combining Conditionally Replicating Adenovirus (CRAd) and replication-defective Adenovirus expressing interferon-beta (ad-IFN-beta). We investigated the efficacy of this therapy in an immunocompetent mouse tumor model. Transduction with CRAd (Delta24RGD) induced cytolysis in a mouse lung cancer cell line (Lewis lung carcinoma (LLC)). Combined transduction of ad-IFN-beta and Delta24RGD in the LLC cells induced a greater and more prolonged production of IFN-beta. Media transfer from the LLC-Delta24RGD-ad-IFN-beta to untransduced LLC cells induced the production of IFN-beta; these results confirmed the replication and release of ad-IFN-beta. LLC cells transduced with ad-IFN-beta and Delta24RGD had decreased tumorigenicity in syngeneic mice. Tumor vaccination with irradiated LLC-ad-IFN-beta-Delta24RGD showed a significant increase in the survival of tumor-bearing syngeneic mice compared with mice with a single transduced LLC vaccination; this was mediated by an enhanced cytotoxic T-lymphocyte response against the LLC cells. The results of this study showed that cotransduced Delta24RGD to ad-IFN-beta aided the replication of ad-IFN-beta in the LLC cells. A high local concentration of IFN-beta and local release of tumor antigen by CRAd induced strong antitumor immunity. This combination strategy might provide a powerful means by which ad-cytokines and CRAd can be combined and other Adenoviruses expressing different cytokines might also be used.

  • combination gene therapy of lung cancer with Conditionally Replicating Adenovirus and Adenovirus herpes simplex virus thymidine kinase
    International Journal of Molecular Medicine, 2010
    Co-Authors: Miyoung Park, Dal Rae Kim, Hoil Yoon, Jaeho Lee, Yeon Soo Kim, Junghee Lee, Seonhui Shim, Jinhaeng Chung, Myungwhun Sung, Choontaek Lee
    Abstract:

    A major obstacle to the success of gene therapy strategies that directly target cancer cells is the low gene transfer rate. To address this problem, we had previously proposed a combination adenoviral gene therapy containing a Conditionally Replicating Adenovirus (CRAD) expressing mutant E1 (Δ24RGD), and a replication-defective E1-deleted Adenovirus to enhance the efficiency of gene transfer. Suicide/pro-drug gene therapy has an important additional benefit to the therapy of cancer. This relates to the transfer and expression of non-mammalian genes encoding enzymes that convert non-toxic pro-drugs into cellular toxins. We investigated the interaction between CRAD (Δ24RGD) and a replication-defective E1-deleted Adenovirus (ad-HSTK) containing a suicide gene (HSTK: herpes simplex virus thymidine kinase gene) with respect to therapeutic gene production and tumor cell killing efficacy. Combined transduction of CRAD and ad-HSTK increased the transduction efficiency of HSTK and increased its sensitivity to ganciclovir (GCV) more efficiently than ad-HSTK alone. Transfer of medium of CRAD and ad-HSTK co-transduced cells induced the transfer of HSTK (media transferable bystander effect), and enhanced its sensitivity to GCV. In an animal tumor model, combined intratumoral injection of CRAD and ad-HSTK followed by GCV administration induced prolonged expression of HSTK and stronger growth suppression of established lung cancer xenografts than single injections. These data demonstrate that the selective replication of ad-HSTK due to the presence of mutant E1, produced by a Δ24RGD and HSTK/GCV suicide gene system, resulted in a striking improvement in anti-tumor effects in vitro and in vivo.

  • Conditionally Replicating Adenovirus improves gene replication efficiency and anticancer effect of e1 deleted Adenovirus carrying trail in head and neck squamous cell carcinoma
    Cancer Science, 2010
    Co-Authors: Choontaek Lee, Seonhui Shim, Hun J Hah, Jaejung Lee, Seokwoo Park, Dae Seog Heo, Myungwhun Sung
    Abstract:

    To overcome the low efficiency of gene therapy, we combined a Conditionally Replicating Adenovirus (CRAd) and an adenoviral vector with a therapeutic gene. CRAd has an oncolytic activity in cancer cells with abnormal Rb activity and helps the replication of therapeutic genes incorporated in the E1-deleted Adenovirus. We investigated the anticancer effect of a combination of CRAd and Adenovirus carrying tumor necrosis factor-related apoptosis inducing ligand (ad-TRAIL). We expected to see increased gene expression in cancer cells as well as an antitumor effect. With the combined application of CRAd and ad-luciferase in head and neck cancer cell lines, we observed considerably increased luciferase activity that was 10- to 50-fold greater than with ad-luciferase alone. The combination of CRAd and ad-TRAIL showed significant suppression of growth in cell lines and increased the sub-G1 portion of cells 30-fold compared to any single treatment. The expression of TRAIL was highly amplified by the combined treatment and was accompanied by expression of molecules related to apoptosis. In a xenograft animal model, mice treated with CRAd and ad-TRAIL showed complete regression of established tumors, whereas mice treated with CRAd or ad-TRAIL alone did not. In conclusion, this combined strategy using CRAd and Adenovirus carrying a therapeutic gene increased the gene transfer rate and enhanced antitumor effects. We expect that this combination strategy could be extended to a multitarget cancer gene therapy by combining multiple Adenoviruses and CRAd. (Cancer Sci 2009)

  • histone deacetylase inhibitors improve the antitumor effect of Conditionally Replicating Adenovirus by increasing car expression
    Cancer Research, 2007
    Co-Authors: Miyoung Park, Hoil Yoon, Jaeho Lee, Yoon Jin Lee, Sungyoun Kwon, Yungjue Bang, Choontaek Lee
    Abstract:

    3300 The efficacy of adenoviral gene therapy was partly influenced by the infectivity of Adenovirus which was determined by CAR expression on cancer cells. The expression levels of CAR in cancer cells were extremely variable. In general, cancer cells in human tumor tissue showed lower level of CAR expression compared with corresponding cancer cell lines. We previously reported that sodium butyrate, histone deacetylase inhibitor(HDAC inhibitor), could increase the CAR expression in CAR deficient bladder cancer lines and made them vulnerable to Adenovirus-p16 (Lee CT et al. Clin Cancer Res 2001). In this study, we used new HDAC inhibitor (SK-7041, -7068) and Conditionally Replicating Adenovirus(CRAD: ad-Δ24) for the oncolytic adenoviral gene therapy in several CAR deficient cancer cell lines. Pretreatment of SK-7041 and SK-7068: Park JH et al. Clin Cancer Res 2004) increased the CAR expression in two human bladder cancer cell lines(J82, HT1376) and two human lung cancer cell lines (NCI H460 and NCI H2122). The luciferase expression from ad-Δ24-luc was markedly increased by pretreatment of SK-7041 and SK7068. Cell cytolysis due to ad-Δ24 was markedly increased by SK-7041 and SK-7068 in J82, HT1376, NCI H460 and NCI H2122. This finding suggests the value of combination therapy with HDAC inhibitor and CRAD. Further study will focus on the animal tumor models with different cell lines.

John C Morris - One of the best experts on this subject based on the ideXlab platform.

  • Viral Dose, Radioiodine Uptake, and Delayed Efflux in Adenovirus Mediated NIS Radiovirotherapy Correlates with Treatment Efficacy
    2016
    Co-Authors: Miguel A. Trujillo, Michael J. Oneal, Samantha Mcdonough, John C Morris
    Abstract:

    We have constructed a prostate tumor specific Conditionally Replicating Adenovirus (CRAd), named Ad5PB_RSV-NIS that expresses the human sodium iodine symporter gene (hNIS). LNCaP tumors were established in nude mice and infected with this CRAd to study tumor viral spread, NIS expression, and efficacy. Using quantitative polymerase chain reaction (QPCR) we found a linear correlation between the viral dose and viral genome copy numbers recovered after tumor infection. Confocal microscopy showed a linear correlation between Adenovirus density and NIS expression. Radioiodine uptake vs. virus dose-response curves revealed that the dose response curve was not linear and displayed a lower threshold of detection at 107 vp and an upper plateau of uptake at 1011 vp. The outcome of radiovirotherapy was highly dependent upon viral dose. At 1010 vp no significant differences were observed between virotherapy alone or radiovirotherapy. However, when radioiodine therapy was combined with virotherapy at a dose of 1011 vp, significant improvement in survival was observed, indicating a relationship between viral dose-response uptake and the efficacy of radiovirotherapy. The reasons behind the differences in radioiodine therapy efficacy can be ascribed to more efficient viral tumor spread and a decrease i

  • Viral Dose, Radioiodine Uptake, and Delayed Efflux in Adenovirus Mediated NIS Radiovirotherapy Correlates with Treatment Efficacy
    2016
    Co-Authors: Miguel A. Trujillo, Michael J. Oneal, Samantha Mcdonough, John C Morris
    Abstract:

    We have constructed a prostate tumor specific Conditionally Replicating Adenovirus (CRAd), named Ad5PB_RSV-NIS that expresses the human sodium iodine symporter gene (hNIS). LNCaP tumors were established in nude mice and infected with this CRAd to study tumor viral spread, NIS expression, and efficacy. Using quantitative polymerase chain reaction (QPCR) we found a linear correlation between the viral dose and viral genome copy numbers recovered after tumor infection. Confocal microscopy showed a linear correlation between Adenovirus density and NIS expression. Radioiodine uptake vs. virus dose-response curves revealed that the dose response curve was not linear and displayed a lower threshold of detection at 107 vp and an upper plateau of uptake at 1011 vp. The outcome of radiovirotherapy was highly dependent upon viral dose. At 1010 vp no significant differences were observed between virotherapy alone or radiovirotherapy. However, when radioiodine therapy was combined with virotherapy at a dose of 1011 vp, significant improvement in survival was observed, indicating a relationship between viral dose-response uptake and the efficacy of radiovirotherapy. The reasons behind the differences in radioiodine therapy efficacy can be ascribed to more efficient viral tumor spread and a decrease in the rate of radioisotope efflux. Our results have important implications regarding the desirables and undesirable characteristics of vectors for clinical translation of virus-mediated NIS transfer therap

  • A probasin promoter, Conditionally Replicating Adenovirus that expresses the sodium iodide symporter (NIS) for radiovirotherapy of prostate cancer
    Gene Therapy, 2010
    Co-Authors: Miguel A. Trujillo, Michael J. Oneal, Samantha Mcdonough, Rui Qin, John C Morris
    Abstract:

    The sodium iodide symporter (NIS) directs the uptake and concentration of iodide in thyroid cells. We have extended the use of NIS-mediated radioiodine therapy to other types of cancer, we transferred and expressed the NIS gene into prostate, colon and breast cancer cells using adenoviral vectors. To improve vector efficiency we have developed a Conditionally Replicating Adenovirus (CRAd) in which the E1a gene is driven by the prostate-specific promoter, Probasin and the cassette RSV promoter human NIScDNA-bGH polyA replaces the E3 region (CRAd Ad5PB_RSV-NIS). In vitro infection of the prostate cancer cell line LnCaP resulted in virus replication, cytolysis and release of infective viral particles. Conversely, the prostate cancer cell line PC-3 (androgen receptor negative) and the pancreatic cancer cell line Panc-1 were refractory to the viral cytopathic effect and did not support viral replication. Radioiodine uptake was readily measurable in LnCaP cells infected with Ad5PB_RSV-NIS 24 h post-infection, confirming NIS expression. In vivo , LnCaP tumor xenografts in nude-mice injected intratumorally with Ad5PB_RSV_NIS CRAd expressed NIS actively as evidenced by ^99Tc uptake and imaging. Administration of therapeutic ^131I after virus injection significantly increased survival probability in mice carrying xenografted LnCaP tumors compared with virotherapy alone. These data indicate that Ad5PB_RSV_NIS replication is stringently restricted to androgen-positive prostate cancer cells and results in effective NIS expression and uptake of radioiodine. This construct may allow multimodal therapy, combining cytolytic virotherapy with radioiodine treatment, to be developed as a novel treatment for prostate cancer.

  • construction of an muc 1 promoter driven Conditionally Replicating Adenovirus that expresses the sodium iodide symporter for gene therapy of breast cancer
    Breast Cancer Research, 2009
    Co-Authors: Miguel A. Trujillo, E R Bergert, Michael J. Oneal, Julia Davydova, Masato Yamamoto, John C Morris
    Abstract:

    Introduction The sodium iodide symporter (NIS) directs the uptake and concentration of iodide in thyroid cells. This in turn allows radioiodine imaging and therapy for thyroid cancer. To extend the use of NIS-mediated radioiodine therapy to other types of cancer, we successfully transferred and expressed the sodium-iodide symporter (NIS) gene in prostate, colon, and breast cancer cells both in vivo and in vitro by using nonReplicating adenoviral vectors. Methods To improve virotherapy efficiency, we developed a Conditionally Replicating Adenovirus (CRAd) in which the transcriptional cassette RSV promoter-human NIScDNA-bGH polyA was also inserted at the E3 region. The E1a gene is driven by the tumor-specific promoter MUC-1 in the CRAd Ad5AMUCH_RSV-NIS. Results In vitro infection of the MUC-1-positive breast cell line T47D resulted in virus replication, cytolysis, and release of infective viral particles. Conversely, the MUC-1-negative breast cancer cell line MDA-MB-231 was refractory to the viral cytopathic effect and did not support viral replication. The data indicate that Ad5AMUCH_RSV-NIS activity is stringently restricted to MUC-1-positive cancer cells. Radioiodine uptake was readily measurable in T47 cells infected with Ad5AMUCH_RSV-NIS 24 hours after infection, thus confirming NIS expression before viral-induced cell death. Conclusions This construct may allow multimodal therapy, combining virotherapy with radioiodine therapy to be developed as a novel treatment for breast and other MUC1-overexpressing cancers.

Miguel A. Trujillo - One of the best experts on this subject based on the ideXlab platform.

  • Viral Dose, Radioiodine Uptake, and Delayed Efflux in Adenovirus Mediated NIS Radiovirotherapy Correlates with Treatment Efficacy
    2016
    Co-Authors: Miguel A. Trujillo, Michael J. Oneal, Samantha Mcdonough, John C Morris
    Abstract:

    We have constructed a prostate tumor specific Conditionally Replicating Adenovirus (CRAd), named Ad5PB_RSV-NIS that expresses the human sodium iodine symporter gene (hNIS). LNCaP tumors were established in nude mice and infected with this CRAd to study tumor viral spread, NIS expression, and efficacy. Using quantitative polymerase chain reaction (QPCR) we found a linear correlation between the viral dose and viral genome copy numbers recovered after tumor infection. Confocal microscopy showed a linear correlation between Adenovirus density and NIS expression. Radioiodine uptake vs. virus dose-response curves revealed that the dose response curve was not linear and displayed a lower threshold of detection at 107 vp and an upper plateau of uptake at 1011 vp. The outcome of radiovirotherapy was highly dependent upon viral dose. At 1010 vp no significant differences were observed between virotherapy alone or radiovirotherapy. However, when radioiodine therapy was combined with virotherapy at a dose of 1011 vp, significant improvement in survival was observed, indicating a relationship between viral dose-response uptake and the efficacy of radiovirotherapy. The reasons behind the differences in radioiodine therapy efficacy can be ascribed to more efficient viral tumor spread and a decrease i

  • A Probasin Promoter, Conditionally Replicating Adenovirus that Expresses the Sodium Iodide Symporter (NIS) for Radiovirotherapy of Prostate Cancer
    2016
    Co-Authors: Miguel A. Trujillo, Michael J. Oneal, Samantha Mcdonough, Rui Qin, John C
    Abstract:

    The sodium iodide symporter (NIS) directs the uptake and concentration of iodide in thyroid cells. We have extended the use of NIS-mediated radioiodine therapy to other types of cancer, we transferred and expressed the sodium-iodide symporter (NIS) gene into prostate, colon, and breast cancer cells using adenoviral vectors. To improve vector efficiency we have developed a Conditionally Replicating Adenovirus (CRAd) in which the E1a gene is driven by the prostate specific promoter, Probasin and the cassette RSV promoter-human NIScDNA-bGH polyA replaces the E3 region (CRAd Ad5PB_RSV-NIS). In vitro infection of the prostate cancer cell line LnCaP resulted in virus replication, cytolysis, and release of infective viral particles. Conversely, the prostate cancer cell line PC-3 (androgen receptor negative) and the pancreatic cancer cell line Panc-1 were refractory to the viral cytopathic effect and did not support viral replication. Radioiodine uptake was readily measurable in LnCaP cells infected with Ad5PB_RSV-NIS 24 hours post-infection, confirming NIS expression. In vivo, LnCaP tumor xenografts in nude mice injected intratumorally with Ad5PB_RSV_NIS CRAd expressed NIS actively as evidenced by 99Tc uptake and imaging. Administration of therapeutic 131I after virus injection significantl

  • Viral Dose, Radioiodine Uptake, and Delayed Efflux in Adenovirus Mediated NIS Radiovirotherapy Correlates with Treatment Efficacy
    2016
    Co-Authors: Miguel A. Trujillo, Michael J. Oneal, Samantha Mcdonough, John C Morris
    Abstract:

    We have constructed a prostate tumor specific Conditionally Replicating Adenovirus (CRAd), named Ad5PB_RSV-NIS that expresses the human sodium iodine symporter gene (hNIS). LNCaP tumors were established in nude mice and infected with this CRAd to study tumor viral spread, NIS expression, and efficacy. Using quantitative polymerase chain reaction (QPCR) we found a linear correlation between the viral dose and viral genome copy numbers recovered after tumor infection. Confocal microscopy showed a linear correlation between Adenovirus density and NIS expression. Radioiodine uptake vs. virus dose-response curves revealed that the dose response curve was not linear and displayed a lower threshold of detection at 107 vp and an upper plateau of uptake at 1011 vp. The outcome of radiovirotherapy was highly dependent upon viral dose. At 1010 vp no significant differences were observed between virotherapy alone or radiovirotherapy. However, when radioiodine therapy was combined with virotherapy at a dose of 1011 vp, significant improvement in survival was observed, indicating a relationship between viral dose-response uptake and the efficacy of radiovirotherapy. The reasons behind the differences in radioiodine therapy efficacy can be ascribed to more efficient viral tumor spread and a decrease in the rate of radioisotope efflux. Our results have important implications regarding the desirables and undesirable characteristics of vectors for clinical translation of virus-mediated NIS transfer therap

  • A probasin promoter, Conditionally Replicating Adenovirus that expresses the sodium iodide symporter (NIS) for radiovirotherapy of prostate cancer
    Gene Therapy, 2010
    Co-Authors: Miguel A. Trujillo, Michael J. Oneal, Samantha Mcdonough, Rui Qin, John C Morris
    Abstract:

    The sodium iodide symporter (NIS) directs the uptake and concentration of iodide in thyroid cells. We have extended the use of NIS-mediated radioiodine therapy to other types of cancer, we transferred and expressed the NIS gene into prostate, colon and breast cancer cells using adenoviral vectors. To improve vector efficiency we have developed a Conditionally Replicating Adenovirus (CRAd) in which the E1a gene is driven by the prostate-specific promoter, Probasin and the cassette RSV promoter human NIScDNA-bGH polyA replaces the E3 region (CRAd Ad5PB_RSV-NIS). In vitro infection of the prostate cancer cell line LnCaP resulted in virus replication, cytolysis and release of infective viral particles. Conversely, the prostate cancer cell line PC-3 (androgen receptor negative) and the pancreatic cancer cell line Panc-1 were refractory to the viral cytopathic effect and did not support viral replication. Radioiodine uptake was readily measurable in LnCaP cells infected with Ad5PB_RSV-NIS 24 h post-infection, confirming NIS expression. In vivo , LnCaP tumor xenografts in nude-mice injected intratumorally with Ad5PB_RSV_NIS CRAd expressed NIS actively as evidenced by ^99Tc uptake and imaging. Administration of therapeutic ^131I after virus injection significantly increased survival probability in mice carrying xenografted LnCaP tumors compared with virotherapy alone. These data indicate that Ad5PB_RSV_NIS replication is stringently restricted to androgen-positive prostate cancer cells and results in effective NIS expression and uptake of radioiodine. This construct may allow multimodal therapy, combining cytolytic virotherapy with radioiodine treatment, to be developed as a novel treatment for prostate cancer.

  • construction of an muc 1 promoter driven Conditionally Replicating Adenovirus that expresses the sodium iodide symporter for gene therapy of breast cancer
    Breast Cancer Research, 2009
    Co-Authors: Miguel A. Trujillo, E R Bergert, Michael J. Oneal, Julia Davydova, Masato Yamamoto, John C Morris
    Abstract:

    Introduction The sodium iodide symporter (NIS) directs the uptake and concentration of iodide in thyroid cells. This in turn allows radioiodine imaging and therapy for thyroid cancer. To extend the use of NIS-mediated radioiodine therapy to other types of cancer, we successfully transferred and expressed the sodium-iodide symporter (NIS) gene in prostate, colon, and breast cancer cells both in vivo and in vitro by using nonReplicating adenoviral vectors. Methods To improve virotherapy efficiency, we developed a Conditionally Replicating Adenovirus (CRAd) in which the transcriptional cassette RSV promoter-human NIScDNA-bGH polyA was also inserted at the E3 region. The E1a gene is driven by the tumor-specific promoter MUC-1 in the CRAd Ad5AMUCH_RSV-NIS. Results In vitro infection of the MUC-1-positive breast cell line T47D resulted in virus replication, cytolysis, and release of infective viral particles. Conversely, the MUC-1-negative breast cancer cell line MDA-MB-231 was refractory to the viral cytopathic effect and did not support viral replication. The data indicate that Ad5AMUCH_RSV-NIS activity is stringently restricted to MUC-1-positive cancer cells. Radioiodine uptake was readily measurable in T47 cells infected with Ad5AMUCH_RSV-NIS 24 hours after infection, thus confirming NIS expression before viral-induced cell death. Conclusions This construct may allow multimodal therapy, combining virotherapy with radioiodine therapy to be developed as a novel treatment for breast and other MUC1-overexpressing cancers.

Hoil Yoon - One of the best experts on this subject based on the ideXlab platform.

  • combination therapy of Conditionally Replicating Adenovirus and histone deacetylase inhibitors
    International Journal of Molecular Medicine, 2011
    Co-Authors: Dal Rae Kim, Miyoung Park, Hyojeong Lim, Jongsun Park, Young Jae Cho, Seiwon Lee, Hoil Yoon, Jaeho Lee, Yeon Soo Kim, Choontaek Lee
    Abstract:

    Combination therapy of adenoviral gene therapy and a histone deacetylase (HDAC) inhibitor is important due to the enhancing effect of HDAC inhibitors on adenoviral transduction and transcription. However, contradictory results have been reported on the effect of combination of CRAd (Conditionally Replicating Adenovirus) and HDAC inhibitors. This study was designed to investigate the interaction of CRAd and HDAC inhibitors and determine the ideal way to combine the two agents. Combination of HDAC inhibitors (SK7041, SBHA and vorinostat) at pre- and post-transductional periods with CRAd enhanced the transduction of CRAd and expression of luciferase expression from Δ24-luc in vitro. However, suppression of luciferase expression from Δ24-luc injected tumor mass was observed by in vivo tumor bioluminescence imaging and drug interaction analysis also showed an antagonistic interaction that was probably related with the inhibitory effect of the HDAC inhibitor on adenoviral replication. Suppression of p21 induction by p21 siRNA reversed the suppressive effect of vorinostat on the replication of CRAd, but still failed to reverse the antagonistic interaction. Addition of vorinostat at the pre-transductional period revealed an improvement in the transduction efficiency of CRAd and also induced a synergistic interaction between CRAd and vorinostat, which was possibly related with prevention of the suppressive effect of vorinostat on adenoviral replication. In conclusion, the addition of HDAC inhibitor before CRAd injection showed synergistic antitumor effects, which warrants further investigation on the sequence of HDAC inhibitor and CRAd treatment in an animal tumor model.

  • genetic immunotherapy of lung cancer using Conditionally Replicating Adenovirus and Adenovirus interferon beta
    Cancer Gene Therapy, 2010
    Co-Authors: M Y Park, Dal Rae Kim, Hoil Yoon, Choontaek Lee, Heewon Jung, Jin Hak Lee
    Abstract:

    Genetic immunotherapy is considered an ideal treatment modality for cancer because of its systemic nature. This study was designed to develop a potent novel genetic immunotherapy by combining Conditionally Replicating Adenovirus (CRAd) and replication-defective Adenovirus expressing interferon-beta (ad-IFN-beta). We investigated the efficacy of this therapy in an immunocompetent mouse tumor model. Transduction with CRAd (Delta24RGD) induced cytolysis in a mouse lung cancer cell line (Lewis lung carcinoma (LLC)). Combined transduction of ad-IFN-beta and Delta24RGD in the LLC cells induced a greater and more prolonged production of IFN-beta. Media transfer from the LLC-Delta24RGD-ad-IFN-beta to untransduced LLC cells induced the production of IFN-beta; these results confirmed the replication and release of ad-IFN-beta. LLC cells transduced with ad-IFN-beta and Delta24RGD had decreased tumorigenicity in syngeneic mice. Tumor vaccination with irradiated LLC-ad-IFN-beta-Delta24RGD showed a significant increase in the survival of tumor-bearing syngeneic mice compared with mice with a single transduced LLC vaccination; this was mediated by an enhanced cytotoxic T-lymphocyte response against the LLC cells. The results of this study showed that cotransduced Delta24RGD to ad-IFN-beta aided the replication of ad-IFN-beta in the LLC cells. A high local concentration of IFN-beta and local release of tumor antigen by CRAd induced strong antitumor immunity. This combination strategy might provide a powerful means by which ad-cytokines and CRAd can be combined and other Adenoviruses expressing different cytokines might also be used.

  • combination gene therapy of lung cancer with Conditionally Replicating Adenovirus and Adenovirus herpes simplex virus thymidine kinase
    International Journal of Molecular Medicine, 2010
    Co-Authors: Miyoung Park, Dal Rae Kim, Hoil Yoon, Jaeho Lee, Yeon Soo Kim, Junghee Lee, Seonhui Shim, Jinhaeng Chung, Myungwhun Sung, Choontaek Lee
    Abstract:

    A major obstacle to the success of gene therapy strategies that directly target cancer cells is the low gene transfer rate. To address this problem, we had previously proposed a combination adenoviral gene therapy containing a Conditionally Replicating Adenovirus (CRAD) expressing mutant E1 (Δ24RGD), and a replication-defective E1-deleted Adenovirus to enhance the efficiency of gene transfer. Suicide/pro-drug gene therapy has an important additional benefit to the therapy of cancer. This relates to the transfer and expression of non-mammalian genes encoding enzymes that convert non-toxic pro-drugs into cellular toxins. We investigated the interaction between CRAD (Δ24RGD) and a replication-defective E1-deleted Adenovirus (ad-HSTK) containing a suicide gene (HSTK: herpes simplex virus thymidine kinase gene) with respect to therapeutic gene production and tumor cell killing efficacy. Combined transduction of CRAD and ad-HSTK increased the transduction efficiency of HSTK and increased its sensitivity to ganciclovir (GCV) more efficiently than ad-HSTK alone. Transfer of medium of CRAD and ad-HSTK co-transduced cells induced the transfer of HSTK (media transferable bystander effect), and enhanced its sensitivity to GCV. In an animal tumor model, combined intratumoral injection of CRAD and ad-HSTK followed by GCV administration induced prolonged expression of HSTK and stronger growth suppression of established lung cancer xenografts than single injections. These data demonstrate that the selective replication of ad-HSTK due to the presence of mutant E1, produced by a Δ24RGD and HSTK/GCV suicide gene system, resulted in a striking improvement in anti-tumor effects in vitro and in vivo.

  • Combination gene therapy of lung cancer with Conditionally Replicating Adenovirus and Adenovirus-herpes simplex virus thymidine kinase
    'Spandidos Publications', 2010
    Co-Authors: Oh, Jin Young, Jaeho Lee, Lee Choon-taek, Park, Mi Young, Kim, Dal Rae, Lee, Jung Hee, Chung Jin-haeng, Kim Yeon-soo, Sung Myung-whun, Hoil Yoon
    Abstract:

    A major obstacle to the success of gene therapy strategies that directly target cancer cells is the low gene transfer rate. To address this problem, we had previously proposed a combination adenoviral gene therapy containing a Conditionally Replicating Adenovirus (CRAD) expressing mutant E1 (Delta 24RGD), and a replication-defective E1-deleted Adenovirus to enhance the efficiency of gene transfer. Suicide/pro-drug gene therapy has an important additional benefit to the therapy of cancer. This relates to the transfer and expression of non-mammalian genes encoding enzymes that convert non-toxic pro-drugs into cellular toxins. We investigated the interaction between CRAD (Delta 24RGD) and a replication-defective E1-deleted Adenovirus (ad-HSTK) containing a suicide gene (HSTK: herpes simplex virus thymidine kinase gene) with respect to therapeutic gene production and tumor cell killing efficacy. Combined transduction of CRAD and ad-HSTK increased the transduction efficiency of HSTK and increased its sensitivity to ganciclovir (GCV) more efficiently than ad-HSTK alone. Transfer of medium of CRAD and ad-HSTK co-transduced cells induced the transfer of HSTK (media transferable bystander effect), and enhanced its sensitivity to GCV. In an animal tumor model, combined intratumoral injection of CRAD and ad-HSTK followed by GCV administration induced prolonged expression of HSTK and stronger growth suppression of established lung cancer xenografts than single injections. These data demonstrate that the selective replication of ad-HSTK due to the presence of mutant E1, produced by a Delta 24RGD and HSTK/GCV suicide gene system, resulted in a striking improvement in anti-tumor effects in vitro and in vivo.This study was supported by grants from the Korea Science and Engineering Foundation (2008-00728) to C.-T. Lee.Lee CT, 2006, CANCER RES, V66, P372, DOI 10.1158/0008-5272.CAN-05-1515Lee CT, 2004, CANCER RES, V64, P6660Park KH, 2003, ANTICANCER RES, V23, P1559Hermiston TW, 2002, CANCER GENE THER, V9, P1022, DOI 10.1038/sj.cgt.7700542Reid T, 2002, CANCER GENE THER, V9, P979, DOI 10.1038/sj.cgt.7700539Suzuki K, 2002, CLIN CANCER RES, V8, P3348Habib NA, 2002, CANCER GENE THER, V9, P651, DOI 10.1038/sj.cgt.7700481Ries S, 2002, BRIT J CANCER, V86, P5, DOI 10.1038/sj/bjc/6600006Nanda D, 2001, CANCER RES, V61, P8743Hawkins LK, 2001, GENE THER, V8, P1123Suzuki K, 2001, CLIN CANCER RES, V7, P120Kirn D, 2000, ONCOGENE, V19, P6660Mesnil M, 2000, CANCER RES, V60, P3989Hermiston T, 2000, J CLIN INVEST, V105, P1169Wildner O, 1999, CANCER RES, V59, P410Yang L, 1998, HUM GENE THER, V9, P719Ram Z, 1997, NAT MED, V3, P1354Bischoff JR, 1996, SCIENCE, V274, P373PITTS JD, 1994, MOL CARCINOGEN, V11, P127GOLDBERG G, 1994, CANCER RES, V54, P3947CULVER KW, 1992, SCIENCE, V256, P1550BARKER DD, 1987, VIROLOGY, V156, P107MOOLTEN FL, 1986, CANCER RES, V46, P5276

  • histone deacetylase inhibitors improve the antitumor effect of Conditionally Replicating Adenovirus by increasing car expression
    Cancer Research, 2007
    Co-Authors: Miyoung Park, Hoil Yoon, Jaeho Lee, Yoon Jin Lee, Sungyoun Kwon, Yungjue Bang, Choontaek Lee
    Abstract:

    3300 The efficacy of adenoviral gene therapy was partly influenced by the infectivity of Adenovirus which was determined by CAR expression on cancer cells. The expression levels of CAR in cancer cells were extremely variable. In general, cancer cells in human tumor tissue showed lower level of CAR expression compared with corresponding cancer cell lines. We previously reported that sodium butyrate, histone deacetylase inhibitor(HDAC inhibitor), could increase the CAR expression in CAR deficient bladder cancer lines and made them vulnerable to Adenovirus-p16 (Lee CT et al. Clin Cancer Res 2001). In this study, we used new HDAC inhibitor (SK-7041, -7068) and Conditionally Replicating Adenovirus(CRAD: ad-Δ24) for the oncolytic adenoviral gene therapy in several CAR deficient cancer cell lines. Pretreatment of SK-7041 and SK-7068: Park JH et al. Clin Cancer Res 2004) increased the CAR expression in two human bladder cancer cell lines(J82, HT1376) and two human lung cancer cell lines (NCI H460 and NCI H2122). The luciferase expression from ad-Δ24-luc was markedly increased by pretreatment of SK-7041 and SK7068. Cell cytolysis due to ad-Δ24 was markedly increased by SK-7041 and SK-7068 in J82, HT1376, NCI H460 and NCI H2122. This finding suggests the value of combination therapy with HDAC inhibitor and CRAD. Further study will focus on the animal tumor models with different cell lines.

Anna Kanerva - One of the best experts on this subject based on the ideXlab platform.

  • 1010 a beta hcg expressing trackable and tumor targeted Conditionally Replicating Adenovirus for treatment of prostate cancer
    Molecular Therapy, 2005
    Co-Authors: Maria Rajecki, Anna Kanerva, Lotta Kangasniemi, Kahwhye Peng, Merja Sarkioja, Ulfhakan Stenman, Henrik Alfthan, Akseli Hemminki
    Abstract:

    Background: Prostate cancer is the most common cancer among males. Despite some recent advances in the treatment of advanced prostate cancer, disseminated hormone refractory disease remains incurable and causes significant mortality. The use of Conditionally Replicating Adenoviruses (CRAds) in the treatment of cancer is intriguing because of their capability to replicate and cause oncolysis of tumor cells. Moreover, they can be used as vectors to deliver a gene of interest into cancer cells. However, the transduction efficacy of native Ad5 is often low due to variable expression of the coxsackie-Adenovirus receptor (CAR) on advanced prostate tumor cells. Further, little data is available on the in vivo persistence or magnitude of virus replication. Such data might be obtainable by coupling virus replication to expression of a secretable marker, measurable in blood. One promising molecule in this regard is the human chorionic gonadotropin -chain (-hCG). Because men are unlikely to produce large amounts of this molecule (used routinely as a pregnancy test) and the baseline production in prostate tumor cells is low, the amount of -hCG in blood during treatment with a virus expressing -hCG could provide a non-invasive approach to evaluate the persistence and amplitude of virus replication.

  • a cyclooxygenase 2 promoter based Conditionally Replicating Adenovirus with enhanced infectivity for treatment of ovarian adenocarcinoma
    Gene Therapy, 2004
    Co-Authors: Masato Yamamoto, David T Curiel, Gene P. Siegal, John T Lam, Gerd J Bauerschmitz, Anna Kanerva, Ronald D Alvarez, Akseli Hemminki
    Abstract:

    Conditionally Replicating Adenoviruses (CRADs) take advantage of tumor-specific characteristics for preferential replication and subsequent oncolysis of cancer cells. The antitumor effect is determined by the capability to infect tumor cells. Here, we used RGDCRADcox-2R, which features the cyclooxygenase-2 promoter for replication control and an integrin binding RGD-4C motif for enhanced infectivity of ovarian cancer cells. RGDCRADcox-2R replicated in and killed human ovarian cancer cells effectively, while the replication in nonmalignant cells was low. Importantly, the therapeutic efficacy, as evaluated in an orthotopic model of peritoneally disseminated ovarian cancer, was significantly improved and toxicity was lower than with a wild-type virus. Thus, this CRAD could be tested for treatment of ovarian cancer in humans.

  • enhanced therapeutic efficacy for ovarian cancer with a serotype 3 receptor targeted oncolytic Adenovirus
    Molecular Therapy, 2003
    Co-Authors: Anna Kanerva, Minghui Wang, John T Lam, Gerd J Bauerschmitz, Tanja Hakkarainen, Kaori Suzuki, Kurt R Zinn, Tandra R Chaudhuri, Taco Gilles Uil, Bin Liu
    Abstract:

    Oncolytic viruses that are replication competent in tumor but not in normal cells represent a novel approach for treating neoplastic diseases. However, the oncolytic potency of Replicating agents is determined directly by their capability of infecting target cells. Most Adenoviruses used for gene therapy or virotherapy have been based on serotype 5 (Ad5). Unfortunately, expression of the primary receptor for Ad5 (the coxsackie-Adenovirus receptor, or CAR) is highly variable on ovarian and other cancer cells. By performing genetic fiber pseudotyping, we created Ad5/3-Delta24, a Conditionally Replicating Adenovirus that does not bind CAR but facilitates entry into and killing of ovarian cancer cells. We show replication of Ad5/3-Delta24 and subsequent oncolysis of ovarian adenocarcinoma lines. Replication was also analyzed with quantitative PCR on three-dimensional primary tumor cell spheroids purified from patient samples. Moreover, in a therapeutic orthotopic model of peritoneal carcinomatosis, dramatically enhanced survival was noted. Finally, Ad5/3-Delta24 achieved a significant antitumor effect as assessed by noninvasive, in vivo bioluminescence imaging. Therefore, the preclinical therapeutic efficacy of Ad5/3-Delta24 is improved over the respective CAR- and integrin-binding controls. Taken together with promising biodistribution and toxicity data, this approach could translate into successful clinical interventions for ovarian cancer patients.

  • Replication of an integrin targeted Conditionally Replicating Adenovirus on primary ovarian cancer spheroids
    Cancer Gene Therapy, 2003
    Co-Authors: John T Lam, Minghui Wang, Gene P. Siegal, Gerd J Bauerschmitz, Anna Kanerva, Shannon D Barker, J Michael Straughn, Mack N Barnes, Jerry L Blackwell, Ronald D Alvarez
    Abstract:

    Replication competent viruses hold promise for treatment of advanced cancers resistant to available therapeutic modalities. Although preliminary clinical results have substantiated their efficacy, preclinical development of these novel approaches is limited by assay substrates. The evaluation of candidate agents could be confounded by differences between primary tumor cells and tumor cell lines, as discordance in the levels of surface receptors relevant for viral entry has been reported. Since primary tumor cells are difficult to analyze ex vivo for longitudinal observation of virus replication, we developed three-dimensional aggregates or spheroids of unpassaged and purified ovarian cancer cells as a means for prolonging primary tumor cell viability and as a three-dimensional in vitro model for replicative viral infection. Ovarian cancer cells purified from ascites samples were sustained for 30 days while retaining the infection profile with tropism modified and unmodified Adenoviruses (Ads). Cell line and primary cell spheroids were used to quantitate the replication and oncolytic potency of replicative Ads in preclinical testing for human ovarian cancer trials. Therefore, spheroids provide a method to sustain purified unpassaged primary ovarian cancer cells for extended periods and to allow evaluation of replicative viruses in a three-dimensional model.

  • A canine Conditionally Replicating Adenovirus for evaluating oncolytic virotherapy in a syngeneic animal model.
    Molecular Therapy, 2003
    Co-Authors: Gene Hemminki, Minghui Wang, Anna Kanerva, Eric Kremer, Gerd Bauerschmitz, Bruce Smith, Bin Liu, Renee Desmond, Anne Keriel, Brian Barnett
    Abstract:

    Oncolytic Adenoviruses, which selectively replicate in and subsequently kill cancer cells, have emerged as a promising approach for treatment of tumors resistant to other modalities. Although preclinical results have been exciting, single-agent clinical efficacy has been less impressive heretofore. The immunogenicity of Adenoviruses, and consequent premature abrogation of replication, may have been a partial reason. Improving the oncolytic potency of agents has been hampered by the inability to study host-vector interactions in immune-competent systems, since human serotype Adenoviruses do not productively replicate in animal tissues. Therefore, approaches such as immunomodulation, which could result in sustained replication and subsequently increased oncolysis, have not been studied. Utilizing the osteocalcin promoter for restricting the replication of a canine Adenovirus to dog osteosarcoma cells, we generated and tested the first nonhuman oncolytic Adenovirus. This virus effectively killed canine osteosarcoma cells in vitro and yielded a therapeutic benefit in vivo. Canine osteosarcoma is the most frequent malignant disease in large dogs, with over 8000 cases in the United States annually, and there is no curative treatment. Therefore, immunomodulation for increased oncolytic potency could be studied with clinical trials in this population. This could eventually translate into human trials.