{"id":{"repo_id":"uiuc","oai_identifier":"oai:www.ideals.illinois.edu:2142/99088"},"canonical_url":"https://search.dev.ndltd.org/etd/uiuc/oai:www.ideals.illinois.edu:2142/99088","repository":{"repo_id":"uiuc","name":"University of Illinois - Urbana-Champaign","base_url":"https://www.ideals.illinois.edu/oai-pmh"},"display":{"title":"Evaluation of therapy for canine intracranial neoplasia using PAC-1, a novel and potent procaspase-3 activator","abstract":"Canine central nervous system tumors can develop deeply within the brain parenchyma, precluding surgical resection and limiting therapeutic options. PAC-1 is a novel, blood-brain barrier penetrant, pro-apoptotic small molecule activator of procaspase-3 (PC-3), with orphan drug status for the treatment of human glioblastoma multiforme. PC-3 is frequently overexpressed in malignantly transformed tissues, providing an opportunity to selectively induce apoptosis in cancer cells with dysregulated upstream apoptotic circuitry. This study evaluates the in vitro activity of PAC-1 against a panel of brain tumor cells, and the feasibility of combining PAC-1 with radiation therapy in an in vivo murine glioma model. Immunohistochemical characterization of PC-3 was performed in 21 normal canine brains and approximately 700 canine and human intracranial neoplasms. Murine, canine, and human glioma cell lines were evaluated for PC-3 expression and in vitro sensitivity to PAC-1 and radiation. PC-3 is overexpressed in canine intracranial neoplasms and high-grade human astrocytomas relative to normal brain tissues. Immortalized glioma cell lines show in vitro sensitivity to PAC-1 and radiation monotherapies at biologically relevant exposures. Murine gliomas appear to be sensitive to PAC-1 and radiation monotherapies, as well as to combination therapy with both PAC-1 and radiation therapy; however, murine study results are not statistically significant at this time. Investigation of therapeutic approaches that combine PAC-1 with radiation therapy and/or temozolomide will further elucidate its therapeutic potential in murine models and canine patients.","abstract_html":"Canine central nervous system tumors can develop deeply within the brain parenchyma, precluding surgical resection and limiting therapeutic options. PAC-1 is a novel, blood-brain barrier penetrant, pro-apoptotic small molecule activator of procaspase-3 (PC-3), with orphan drug status for the treatment of human glioblastoma multiforme. PC-3 is frequently overexpressed in malignantly transformed tissues, providing an opportunity to selectively induce apoptosis in cancer cells with dysregulated upstream apoptotic circuitry. This study evaluates the in vitro activity of PAC-1 against a panel of brain tumor cells, and the feasibility of combining PAC-1 with radiation therapy in an in vivo murine glioma model. Immunohistochemical characterization of PC-3 was performed in 21 normal canine brains and approximately 700 canine and human intracranial neoplasms. Murine, canine, and human glioma cell lines were evaluated for PC-3 expression and in vitro sensitivity to PAC-1 and radiation. PC-3 is overexpressed in canine intracranial neoplasms and high-grade human astrocytomas relative to normal brain tissues. Immortalized glioma cell lines show in vitro sensitivity to PAC-1 and radiation monotherapies at biologically relevant exposures. Murine gliomas appear to be sensitive to PAC-1 and radiation monotherapies, as well as to combination therapy with both PAC-1 and radiation therapy; however, murine study results are not statistically significant at this time. Investigation of therapeutic approaches that combine PAC-1 with radiation therapy and/or temozolomide will further elucidate its therapeutic potential in murine models and canine patients.","abstract_has_math":false,"creators":["Schlein, Lisa Janelle"],"institution":"University of Illinois at Urbana-Champaign","degree_name":"M.S.","degree_level":"Thesis","degree_discipline":"VMS - Pathobiology","degree_department":null,"school":null,"contributors":["Fan, Timothy M.","Driskell, Elizabeth","Barger, Anne","Hergenrother, Paul"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2018,"date_issued":"2018-03-02T19:59:33Z","date_published":"2018-03-02T19:59:33Z","updated_at":"2026-07-22T22:24:37Z","subjects":["Cancer","Brain cancer","Intracranial neoplasia","Canine neoplasia","Human neoplasia","Novel therapeutics","First procaspase-activating compound (PAC-1)"],"languages":["en"],"rights":["Copyright 2017 Lisa J. 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Immunohistochemical characterization of PC-3 was performed in 21 normal canine brains and approximately 700 canine and human intracranial neoplasms. Murine, canine, and human glioma cell lines were evaluated for PC-3 expression and in vitro sensitivity to PAC-1 and radiation. PC-3 is overexpressed in canine intracranial neoplasms and high-grade human astrocytomas relative to normal brain tissues. Immortalized glioma cell lines show in vitro sensitivity to PAC-1 and radiation monotherapies at biologically relevant exposures. Murine gliomas appear to be sensitive to PAC-1 and radiation monotherapies, as well as to combination therapy with both PAC-1 and radiation therapy; however, murine study results are not statistically significant at this time. Investigation of therapeutic approaches that combine PAC-1 with radiation therapy and/or temozolomide will further elucidate its therapeutic potential in murine models and canine patients.","Submission published under a 24 month embargo labeled 'U of I Access', the embargo will last until 2019-08-01","The student, Lisa Schlein, accepted the attached license on 2017-07-11 at 14:50.","The student, Lisa Schlein, submitted this Thesis for approval on 2017-07-11 at 14:54.","This Thesis was approved for publication on 2017-07-14 at 11:05.","DSpace SAF Submission Ingestion Package generated from Vireo submission #11403 on 2018-03-02 at 13:01:30","Made available in DSpace on 2018-03-02T19:59:33Z (GMT). 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PAC-1 is a novel, blood-brain barrier penetrant, pro-apoptotic small molecule activator of procaspase-3 (PC-3), with orphan drug status for the treatment of human glioblastoma multiforme. PC-3 is frequently overexpressed in malignantly transformed tissues, providing an opportunity to selectively induce apoptosis in cancer cells with dysregulated upstream apoptotic circuitry. This study evaluates the in vitro activity of PAC-1 against a panel of brain tumor cells, and the feasibility of combining PAC-1 with radiation therapy in an in vivo murine glioma model. Immunohistochemical characterization of PC-3 was performed in 21 normal canine brains and approximately 700 canine and human intracranial neoplasms. Murine, canine, and human glioma cell lines were evaluated for PC-3 expression and in vitro sensitivity to PAC-1 and radiation. PC-3 is overexpressed in canine intracranial neoplasms and high-grade human astrocytomas relative to normal brain tissues. Immortalized glioma cell lines show in vitro sensitivity to PAC-1 and radiation monotherapies at biologically relevant exposures. Murine gliomas appear to be sensitive to PAC-1 and radiation monotherapies, as well as to combination therapy with both PAC-1 and radiation therapy; however, murine study results are not statistically significant at this time. Investigation of therapeutic approaches that combine PAC-1 with radiation therapy and/or temozolomide will further elucidate its therapeutic potential in murine models and canine patients.","Submission published under a 24 month embargo labeled 'U of I Access', the embargo will last until 2019-08-01","The student, Lisa Schlein, accepted the attached license on 2017-07-11 at 14:50.","The student, Lisa Schlein, submitted this Thesis for approval on 2017-07-11 at 14:54.","This Thesis was approved for publication on 2017-07-14 at 11:05.","DSpace SAF Submission Ingestion Package generated from Vireo submission #11403 on 2018-03-02 at 13:01:30","Made available in DSpace on 2018-03-02T19:59:33Z (GMT). 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