2026-09-22T00:33:30Z https://www.ideals.illinois.edu/oai-pmh

oai:www.ideals.illinois.edu:2142/99088 2023-07-11 col_2142_5131 col_2142_25441 com_2142_5130 com_2142_25440 com_2142_14833

Fan, Timothy M. Driskell, Elizabeth Barger, Anne Hergenrother, Paul Schlein, Lisa Janelle 2018-03-02T19:59:33Z 2018-03-02T19:59:33Z 2020-03-03T10:15:39Z 2017-07-14 2017-08 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. 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). No. of bitstreams: 2 SCHLEIN-THESIS-2017.pdf: 4267475 bytes, checksum: 3fc99ecd40cc129b7a57c72724bd3abd (MD5) LICENSE.txt: 4209 bytes, checksum: e87e33fb20a3edb3a03ae43800fc7148 (MD5) Previous issue date: 2017-07-14 Embargo set by: Seth Robbins for item 105042 Lift date: 2020-03-02T19:59:52Z Reason: Author requested U of Illinois access only (OA after 2yrs) in Vireo ETD system Embargo set by: Seth Robbins for item 105042 Lift date: 2020-03-02T20:02:46Z Reason: Author requested U of Illinois access only (OA after 2yrs) in Vireo ETD system U of I Only Restriction Lifted for Item 105042 on 2020-03-03T10:15:39Z. application/pdf http://hdl.handle.net/2142/99088 en Copyright 2017 Lisa J. Schlein Cancer Brain cancer Intracranial neoplasia Canine neoplasia Human neoplasia Novel therapeutics First procaspase-activating compound (PAC-1) Evaluation of therapy for canine intracranial neoplasia using PAC-1, a novel and potent procaspase-3 activator text text Pathobiology VMS - Pathobiology University of Illinois at Urbana-Champaign Thesis M.S.