title: Induced phenotype targeted therapy: radiation-induced apoptosis-targeted chemotherapy.
abstract: BACKGROUND
  Tumor heterogeneity and evolutionary complexity may underlie treatment failure in spite of the development of many targeted agents. We suggest a novel strategy termed induced phenotype targeted therapy (IPTT) to simplify complicated targets because of tumor heterogeneity and overcome tumor evolutionary complexity.
  
  
  METHODS
  We designed a caspase-3 specific activatable prodrug, DEVD-S-DOX, containing doxorubicin linked to a peptide moiety (DEVD) cleavable by caspase-3 upon apoptosis. To induce apoptosis locally in the tumor, we used a gamma knife, which can irradiate a very small, defined target area. The in vivo antitumor activity of the caspase-3-specific activatable prodrug combined with radiation was investigated in C3H/HeN tumor-bearing mice (n = 5 per group) and analyzed with the Student's t test or Mann-Whitney U test. All statistical tests were two-sided. We confirmed the basic principle using a caspase-sensitive nanoprobe (Apo-NP).
  
  
  RESULTS
  A single exposure of radiation was able to induce apoptosis in a small, defined region of the tumor, resulting in expression of caspase-3. Caspase-3 cleaved DEVD and activated the prodrug. The released free DOX further activated DEVD-S-DOX by exerting cytotoxic effects on neighboring tumor or supporting cells, which repetitively induced the expression of caspase-3 and the activation of DEVD-S-DOX. This sequential and repetitive process propagated the induction of apoptosis. This novel therapeutic strategy showed not only high efficacy in inhibiting tumor growth (14-day tumor volume [mm(3)] vs radiation alone: 848.21 ± 143.24 vs 2511.50 ± 441.89, P < .01) but also low toxicity to normal cells and tissues.
  
  
  CONCLUSIONS
  Such a phenotype induction strategy represents a conceptually novel approach to overcome tumor heterogeneity and complexity as well as to substantially improve current conventional chemoradiotherapy with fewer sequelae and side effects.
authors.affiliation: Department of Otolaryngology (BSL, GCK, SYK) and Department of Neurosurgery (DHL, CJK), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea (BSL, YWC, KK, ISK, ICK, SYK); Department of Chemical Engineering, Hanyang University, Gyeonggido, Republic of Korea (YWC); Department of Chemistry, Sogang University, Seoul, Republic of Korea (HSK, DYC); Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergent Science and Technology, Seoul National University, Seoul, Republic of Korea (YB); College of Pharmacy, Korea University, Sejong, Republic of Korea (SHY); Department of Biochemistry and Cell Biology, School of Medicine and Cell and Matrix Research Institute, Kyungpook National University, Daegu, Republic of Korea (ISK); KU-KIST School, Korea University, Seoul, Republic of Korea (ICK).
authors.forename: Beom Suk
authors.initials: BS
authors.lastname: Lee
authors.affiliation: Department of Otolaryngology (BSL, GCK, SYK) and Department of Neurosurgery (DHL, CJK), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea (BSL, YWC, KK, ISK, ICK, SYK); Department of Chemical Engineering, Hanyang University, Gyeonggido, Republic of Korea (YWC); Department of Chemistry, Sogang University, Seoul, Republic of Korea (HSK, DYC); Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergent Science and Technology, Seoul National University, Seoul, Republic of Korea (YB); College of Pharmacy, Korea University, Sejong, Republic of Korea (SHY); Department of Biochemistry and Cell Biology, School of Medicine and Cell and Matrix Research Institute, Kyungpook National University, Daegu, Republic of Korea (ISK); KU-KIST School, Korea University, Seoul, Republic of Korea (ICK).
authors.forename: Yong Woo
authors.initials: YW
authors.lastname: Cho
authors.affiliation: Department of Otolaryngology (BSL, GCK, SYK) and Department of Neurosurgery (DHL, CJK), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea (BSL, YWC, KK, ISK, ICK, SYK); Department of Chemical Engineering, Hanyang University, Gyeonggido, Republic of Korea (YWC); Department of Chemistry, Sogang University, Seoul, Republic of Korea (HSK, DYC); Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergent Science and Technology, Seoul National University, Seoul, Republic of Korea (YB); College of Pharmacy, Korea University, Sejong, Republic of Korea (SHY); Department of Biochemistry and Cell Biology, School of Medicine and Cell and Matrix Research Institute, Kyungpook National University, Daegu, Republic of Korea (ISK); KU-KIST School, Korea University, Seoul, Republic of Korea (ICK).
authors.forename: Gui Chul
authors.initials: GC
authors.lastname: Kim
authors.affiliation: Department of Otolaryngology (BSL, GCK, SYK) and Department of Neurosurgery (DHL, CJK), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea (BSL, YWC, KK, ISK, ICK, SYK); Department of Chemical Engineering, Hanyang University, Gyeonggido, Republic of Korea (YWC); Department of Chemistry, Sogang University, Seoul, Republic of Korea (HSK, DYC); Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergent Science and Technology, Seoul National University, Seoul, Republic of Korea (YB); College of Pharmacy, Korea University, Sejong, Republic of Korea (SHY); Department of Biochemistry and Cell Biology, School of Medicine and Cell and Matrix Research Institute, Kyungpook National University, Daegu, Republic of Korea (ISK); KU-KIST School, Korea University, Seoul, Republic of Korea (ICK).
authors.forename: Do Hee
authors.initials: DH
authors.lastname: Lee
authors.affiliation: Department of Otolaryngology (BSL, GCK, SYK) and Department of Neurosurgery (DHL, CJK), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea (BSL, YWC, KK, ISK, ICK, SYK); Department of Chemical Engineering, Hanyang University, Gyeonggido, Republic of Korea (YWC); Department of Chemistry, Sogang University, Seoul, Republic of Korea (HSK, DYC); Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergent Science and Technology, Seoul National University, Seoul, Republic of Korea (YB); College of Pharmacy, Korea University, Sejong, Republic of Korea (SHY); Department of Biochemistry and Cell Biology, School of Medicine and Cell and Matrix Research Institute, Kyungpook National University, Daegu, Republic of Korea (ISK); KU-KIST School, Korea University, Seoul, Republic of Korea (ICK).
authors.forename: Chang Jin
authors.initials: CJ
authors.lastname: Kim
authors.affiliation: Department of Otolaryngology (BSL, GCK, SYK) and Department of Neurosurgery (DHL, CJK), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea (BSL, YWC, KK, ISK, ICK, SYK); Department of Chemical Engineering, Hanyang University, Gyeonggido, Republic of Korea (YWC); Department of Chemistry, Sogang University, Seoul, Republic of Korea (HSK, DYC); Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergent Science and Technology, Seoul National University, Seoul, Republic of Korea (YB); College of Pharmacy, Korea University, Sejong, Republic of Korea (SHY); Department of Biochemistry and Cell Biology, School of Medicine and Cell and Matrix Research Institute, Kyungpook National University, Daegu, Republic of Korea (ISK); KU-KIST School, Korea University, Seoul, Republic of Korea (ICK).
authors.forename: Hee Seup
authors.initials: HS
authors.lastname: Kil
authors.affiliation: Department of Otolaryngology (BSL, GCK, SYK) and Department of Neurosurgery (DHL, CJK), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea (BSL, YWC, KK, ISK, ICK, SYK); Department of Chemical Engineering, Hanyang University, Gyeonggido, Republic of Korea (YWC); Department of Chemistry, Sogang University, Seoul, Republic of Korea (HSK, DYC); Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergent Science and Technology, Seoul National University, Seoul, Republic of Korea (YB); College of Pharmacy, Korea University, Sejong, Republic of Korea (SHY); Department of Biochemistry and Cell Biology, School of Medicine and Cell and Matrix Research Institute, Kyungpook National University, Daegu, Republic of Korea (ISK); KU-KIST School, Korea University, Seoul, Republic of Korea (ICK).
authors.forename: Dae Yoon
authors.initials: DY
authors.lastname: Chi
authors.affiliation: Department of Otolaryngology (BSL, GCK, SYK) and Department of Neurosurgery (DHL, CJK), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea (BSL, YWC, KK, ISK, ICK, SYK); Department of Chemical Engineering, Hanyang University, Gyeonggido, Republic of Korea (YWC); Department of Chemistry, Sogang University, Seoul, Republic of Korea (HSK, DYC); Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergent Science and Technology, Seoul National University, Seoul, Republic of Korea (YB); College of Pharmacy, Korea University, Sejong, Republic of Korea (SHY); Department of Biochemistry and Cell Biology, School of Medicine and Cell and Matrix Research Institute, Kyungpook National University, Daegu, Republic of Korea (ISK); KU-KIST School, Korea University, Seoul, Republic of Korea (ICK).
authors.forename: Youngro
authors.initials: Y
authors.lastname: Byun
authors.affiliation: Department of Otolaryngology (BSL, GCK, SYK) and Department of Neurosurgery (DHL, CJK), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea (BSL, YWC, KK, ISK, ICK, SYK); Department of Chemical Engineering, Hanyang University, Gyeonggido, Republic of Korea (YWC); Department of Chemistry, Sogang University, Seoul, Republic of Korea (HSK, DYC); Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergent Science and Technology, Seoul National University, Seoul, Republic of Korea (YB); College of Pharmacy, Korea University, Sejong, Republic of Korea (SHY); Department of Biochemistry and Cell Biology, School of Medicine and Cell and Matrix Research Institute, Kyungpook National University, Daegu, Republic of Korea (ISK); KU-KIST School, Korea University, Seoul, Republic of Korea (ICK).
authors.forename: Soon Hong
authors.initials: SH
authors.lastname: Yuk
authors.affiliation: Department of Otolaryngology (BSL, GCK, SYK) and Department of Neurosurgery (DHL, CJK), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea (BSL, YWC, KK, ISK, ICK, SYK); Department of Chemical Engineering, Hanyang University, Gyeonggido, Republic of Korea (YWC); Department of Chemistry, Sogang University, Seoul, Republic of Korea (HSK, DYC); Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergent Science and Technology, Seoul National University, Seoul, Republic of Korea (YB); College of Pharmacy, Korea University, Sejong, Republic of Korea (SHY); Department of Biochemistry and Cell Biology, School of Medicine and Cell and Matrix Research Institute, Kyungpook National University, Daegu, Republic of Korea (ISK); KU-KIST School, Korea University, Seoul, Republic of Korea (ICK).
authors.forename: Kwangmeyung
authors.initials: K
authors.lastname: Kim
authors.affiliation: Department of Otolaryngology (BSL, GCK, SYK) and Department of Neurosurgery (DHL, CJK), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea (BSL, YWC, KK, ISK, ICK, SYK); Department of Chemical Engineering, Hanyang University, Gyeonggido, Republic of Korea (YWC); Department of Chemistry, Sogang University, Seoul, Republic of Korea (HSK, DYC); Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergent Science and Technology, Seoul National University, Seoul, Republic of Korea (YB); College of Pharmacy, Korea University, Sejong, Republic of Korea (SHY); Department of Biochemistry and Cell Biology, School of Medicine and Cell and Matrix Research Institute, Kyungpook National University, Daegu, Republic of Korea (ISK); KU-KIST School, Korea University, Seoul, Republic of Korea (ICK).
authors.forename: In-San
authors.initials: IS
authors.lastname: Kim
authors.affiliation: Department of Otolaryngology (BSL, GCK, SYK) and Department of Neurosurgery (DHL, CJK), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea (BSL, YWC, KK, ISK, ICK, SYK); Department of Chemical Engineering, Hanyang University, Gyeonggido, Republic of Korea (YWC); Department of Chemistry, Sogang University, Seoul, Republic of Korea (HSK, DYC); Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergent Science and Technology, Seoul National University, Seoul, Republic of Korea (YB); College of Pharmacy, Korea University, Sejong, Republic of Korea (SHY); Department of Biochemistry and Cell Biology, School of Medicine and Cell and Matrix Research Institute, Kyungpook National University, Daegu, Republic of Korea (ISK); KU-KIST School, Korea University, Seoul, Republic of Korea (ICK). sykim2@amc.seoul.kr ikwon@kist.re.kr.
authors.forename: Ick Chan
authors.initials: IC
authors.lastname: Kwon
authors.affiliation: Department of Otolaryngology (BSL, GCK, SYK) and Department of Neurosurgery (DHL, CJK), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea (BSL, YWC, KK, ISK, ICK, SYK); Department of Chemical Engineering, Hanyang University, Gyeonggido, Republic of Korea (YWC); Department of Chemistry, Sogang University, Seoul, Republic of Korea (HSK, DYC); Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergent Science and Technology, Seoul National University, Seoul, Republic of Korea (YB); College of Pharmacy, Korea University, Sejong, Republic of Korea (SHY); Department of Biochemistry and Cell Biology, School of Medicine and Cell and Matrix Research Institute, Kyungpook National University, Daegu, Republic of Korea (ISK); KU-KIST School, Korea University, Seoul, Republic of Korea (ICK). sykim2@amc.seoul.kr ikwon@kist.re.kr.
authors.forename: Sang Yoon
authors.initials: SY
authors.lastname: Kim
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects*; D015153:Blotting, Western; D053148:Caspase 3 / Q000187:drug effects / Q000378:metabolism*; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000528:radiation effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D007150:Immunohistochemistry; D051379:Mice; D008809:Mice, Inbred C3H; D008856:Microscopy, Fluorescence; D058990:Molecular Targeted Therapy / Q000379:methods*; D010447:Peptide Hydrolases / Q000008:administration & dosage / Q000494:pharmacology*; D010641:Phenotype; D011355:Prodrugs / Q000008:administration & dosage / Q000494:pharmacology; D016634:Radiosurgery; D018714:Radiotherapy, Adjuvant
chemical_list: D000903:Antibiotics, Antineoplastic; D011355:Prodrugs; D004317:Doxorubicin; D010447:Peptide Hydrolases; D053148:Caspase 3; C108711:DEVDase