In Vitro and In Vivo Enhancement of Chemoradiation Using the Oral PARP Inhibitor ABT-888 in Colorectal Cancer Cells
Purpose Poly(ADP-ribose) polymerase plays a critical role in the recognition and repair of DNA single-strand breaks and double-strand breaks (DSBs). ABT-888 is an orally available inhibitor of this enzyme. This study seeks to evaluate the use of ABT-888 combined with chemotherapy and radiation thera...
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| Veröffentlicht in: | International journal of radiation oncology, biology, physics biology, physics, 2013-07, Vol.86 (3), p.469-476 |
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| creator | Shelton, Joseph W., MD Waxweiler, Timothy V., MD Landry, Jerome, MD Gao, Huiying, MS Xu, Yanbo, PhD Wang, Lanfang, MS El-Rayes, Bassel, MD Shu, Hui-Kuo G., MD, PhD |
| description | Purpose Poly(ADP-ribose) polymerase plays a critical role in the recognition and repair of DNA single-strand breaks and double-strand breaks (DSBs). ABT-888 is an orally available inhibitor of this enzyme. This study seeks to evaluate the use of ABT-888 combined with chemotherapy and radiation therapy (RT) in colorectal carcinoma models. Methods and Materials RT clonogenic assays were performed on HCT116 and HT29 cells treated with 5-fluorouracil, irinotecan, or oxaliplatin with or without ABT. The surviving fraction at 2 Gy and dose-modifying factor at 10% survival were analyzed. Synergism was assessed by isobologram analysis for combination therapies. γH2AX and neutral comet assays were performed to assess the effect of therapy on DSB formation/repair. In vivo assessments were made by use of HCT116 cells in a xenograft mouse model. Tumor growth delay was measured at a volume of 500 mm3. Results Both lines were radiosensitized by ABT alone, and ABT further increased chemotherapy dose-modifying factors to the 1.6 to 1.8 range. All combinations were synergistic (combination indices |
| doi_str_mv | 10.1016/j.ijrobp.2013.02.015 |
| format | Article |
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ABT-888 is an orally available inhibitor of this enzyme. This study seeks to evaluate the use of ABT-888 combined with chemotherapy and radiation therapy (RT) in colorectal carcinoma models. Methods and Materials RT clonogenic assays were performed on HCT116 and HT29 cells treated with 5-fluorouracil, irinotecan, or oxaliplatin with or without ABT. The surviving fraction at 2 Gy and dose-modifying factor at 10% survival were analyzed. Synergism was assessed by isobologram analysis for combination therapies. γH2AX and neutral comet assays were performed to assess the effect of therapy on DSB formation/repair. In vivo assessments were made by use of HCT116 cells in a xenograft mouse model. Tumor growth delay was measured at a volume of 500 mm3. Results Both lines were radiosensitized by ABT alone, and ABT further increased chemotherapy dose-modifying factors to the 1.6 to 1.8 range. All combinations were synergistic (combination indices <0.9). ABT treatment significantly increased DSB after RT (γH2AX, 69% vs 43%; P =.017) and delayed repair. We found tumor growth delays of 7.22 days for RT; 11.90 days for RT and ABT; 13.5 days for oxaliplatin, RT, and ABT; 14.17 days for 5-fluorouracil, RT, and ABT; and 23.81 days for irinotecan, RT, and ABT. Conclusion ABT-888 radiosensitizes at similar or higher levels compared with classic chemotherapies and acts synergistically with these chemotherapies to enhance RT effects. In vivo confirmation of these results indicates a potential role for combining its use with existing chemoradiation regimens.</description><identifier>ISSN: 0360-3016</identifier><identifier>EISSN: 1879-355X</identifier><identifier>DOI: 10.1016/j.ijrobp.2013.02.015</identifier><identifier>PMID: 23540347</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>ADP ; Animals ; Antineoplastic Agents - therapeutic use ; Benzimidazoles - therapeutic use ; BIOLOGICAL REPAIR ; Camptothecin - analogs & derivatives ; Camptothecin - therapeutic use ; CARCINOMAS ; Chemoradiotherapy - methods ; CHEMOTHERAPY ; Colorectal Neoplasms - enzymology ; Colorectal Neoplasms - genetics ; Colorectal Neoplasms - pathology ; Colorectal Neoplasms - therapy ; Comet Assay - methods ; DNA ; DNA Damage ; ENZYMES ; Female ; Fluorouracil - therapeutic use ; HCT116 Cells ; Hematology, Oncology and Palliative Medicine ; Histones - analysis ; HT29 Cells ; Humans ; IN VITRO ; IN VIVO ; Irinotecan ; MICE ; Mice, Nude ; Neoplasm Proteins - antagonists & inhibitors ; Organoplatinum Compounds - therapeutic use ; Oxaliplatin ; Poly(ADP-ribose) Polymerase Inhibitors ; RADIATION DOSES ; Radiology ; RADIOLOGY AND NUCLEAR MEDICINE ; RADIOTHERAPY ; RIBOSE ; STRAND BREAKS ; SYNERGISM ; Tumor Burden ; URACILS ; Xenograft Model Antitumor Assays</subject><ispartof>International journal of radiation oncology, biology, physics, 2013-07, Vol.86 (3), p.469-476</ispartof><rights>Elsevier Inc.</rights><rights>2013 Elsevier Inc.</rights><rights>Copyright © 2013 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c511t-969ed3a49068802714ba9df3ad82a4b15ea9a6cb604204b57d4870a9f7e774533</citedby><cites>FETCH-LOGICAL-c511t-969ed3a49068802714ba9df3ad82a4b15ea9a6cb604204b57d4870a9f7e774533</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0360301613001831$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,776,780,881,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23540347$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/biblio/22224498$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>Shelton, Joseph W., MD</creatorcontrib><creatorcontrib>Waxweiler, Timothy V., MD</creatorcontrib><creatorcontrib>Landry, Jerome, MD</creatorcontrib><creatorcontrib>Gao, Huiying, MS</creatorcontrib><creatorcontrib>Xu, Yanbo, PhD</creatorcontrib><creatorcontrib>Wang, Lanfang, MS</creatorcontrib><creatorcontrib>El-Rayes, Bassel, MD</creatorcontrib><creatorcontrib>Shu, Hui-Kuo G., MD, PhD</creatorcontrib><title>In Vitro and In Vivo Enhancement of Chemoradiation Using the Oral PARP Inhibitor ABT-888 in Colorectal Cancer Cells</title><title>International journal of radiation oncology, biology, physics</title><addtitle>Int J Radiat Oncol Biol Phys</addtitle><description>Purpose Poly(ADP-ribose) polymerase plays a critical role in the recognition and repair of DNA single-strand breaks and double-strand breaks (DSBs). ABT-888 is an orally available inhibitor of this enzyme. This study seeks to evaluate the use of ABT-888 combined with chemotherapy and radiation therapy (RT) in colorectal carcinoma models. Methods and Materials RT clonogenic assays were performed on HCT116 and HT29 cells treated with 5-fluorouracil, irinotecan, or oxaliplatin with or without ABT. The surviving fraction at 2 Gy and dose-modifying factor at 10% survival were analyzed. Synergism was assessed by isobologram analysis for combination therapies. γH2AX and neutral comet assays were performed to assess the effect of therapy on DSB formation/repair. In vivo assessments were made by use of HCT116 cells in a xenograft mouse model. Tumor growth delay was measured at a volume of 500 mm3. Results Both lines were radiosensitized by ABT alone, and ABT further increased chemotherapy dose-modifying factors to the 1.6 to 1.8 range. All combinations were synergistic (combination indices <0.9). ABT treatment significantly increased DSB after RT (γH2AX, 69% vs 43%; P =.017) and delayed repair. We found tumor growth delays of 7.22 days for RT; 11.90 days for RT and ABT; 13.5 days for oxaliplatin, RT, and ABT; 14.17 days for 5-fluorouracil, RT, and ABT; and 23.81 days for irinotecan, RT, and ABT. Conclusion ABT-888 radiosensitizes at similar or higher levels compared with classic chemotherapies and acts synergistically with these chemotherapies to enhance RT effects. In vivo confirmation of these results indicates a potential role for combining its use with existing chemoradiation regimens.</description><subject>ADP</subject><subject>Animals</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Benzimidazoles - therapeutic use</subject><subject>BIOLOGICAL REPAIR</subject><subject>Camptothecin - analogs & derivatives</subject><subject>Camptothecin - therapeutic use</subject><subject>CARCINOMAS</subject><subject>Chemoradiotherapy - methods</subject><subject>CHEMOTHERAPY</subject><subject>Colorectal Neoplasms - enzymology</subject><subject>Colorectal Neoplasms - genetics</subject><subject>Colorectal Neoplasms - pathology</subject><subject>Colorectal Neoplasms - therapy</subject><subject>Comet Assay - methods</subject><subject>DNA</subject><subject>DNA Damage</subject><subject>ENZYMES</subject><subject>Female</subject><subject>Fluorouracil - therapeutic use</subject><subject>HCT116 Cells</subject><subject>Hematology, Oncology and Palliative Medicine</subject><subject>Histones - analysis</subject><subject>HT29 Cells</subject><subject>Humans</subject><subject>IN VITRO</subject><subject>IN VIVO</subject><subject>Irinotecan</subject><subject>MICE</subject><subject>Mice, Nude</subject><subject>Neoplasm Proteins - antagonists & inhibitors</subject><subject>Organoplatinum Compounds - therapeutic use</subject><subject>Oxaliplatin</subject><subject>Poly(ADP-ribose) Polymerase Inhibitors</subject><subject>RADIATION DOSES</subject><subject>Radiology</subject><subject>RADIOLOGY AND NUCLEAR MEDICINE</subject><subject>RADIOTHERAPY</subject><subject>RIBOSE</subject><subject>STRAND BREAKS</subject><subject>SYNERGISM</subject><subject>Tumor Burden</subject><subject>URACILS</subject><subject>Xenograft Model Antitumor Assays</subject><issn>0360-3016</issn><issn>1879-355X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFksGK1TAUhoMoznX0DUQCbty0njRpm26Eaxl1YGAGnRF3IU1Tm9qb3EnSgXkbn8UnM6WjCzdmcwh8_zmH_z8IvSSQEyDV2yk3k3fdMS-A0ByKHEj5CO0Ir5uMluW3x2gHtIKMJvgEPQthAgBCavYUnRS0ZEBZvUPLuf3186uJ3mFpe7z97hw-s6O0Sh-0jdgNuB31wXnZGxmNs_gmGPsdx1HjSy9nfLX_fJWko-lMdB7v319nnHNsLG7d7LxWMUHt2s_jVs9zeI6eDHIO-sVDPUU3H86u20_ZxeXH83Z_kamSkJg1VaN7KlkDFedQ1IR1sukHKnteSNaRUstGVqqrgBXAurLuGa9BNkOt65qVlJ6i11tfF6IRQZmo1aictWklUaTHWMMT9Wajjt7dLjpEcTBBpT2l1W4JgtCyog0UAAllG6q8C8HrQRy9OUh_LwiINRYxiS0WscYioBApliR79TBh6Q66_yv6k0MC3m2ATm7cGe3XZXUyrDerfaJ35n8T_m2gZmONkvMPfa_D5BZvk9OCiJAE4st6GutlEJqOglNCfwMxXrOw</recordid><startdate>20130701</startdate><enddate>20130701</enddate><creator>Shelton, Joseph W., MD</creator><creator>Waxweiler, Timothy V., MD</creator><creator>Landry, Jerome, MD</creator><creator>Gao, Huiying, MS</creator><creator>Xu, Yanbo, PhD</creator><creator>Wang, Lanfang, MS</creator><creator>El-Rayes, Bassel, MD</creator><creator>Shu, Hui-Kuo G., MD, PhD</creator><general>Elsevier Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>OTOTI</scope></search><sort><creationdate>20130701</creationdate><title>In Vitro and In Vivo Enhancement of Chemoradiation Using the Oral PARP Inhibitor ABT-888 in Colorectal Cancer Cells</title><author>Shelton, Joseph W., MD ; Waxweiler, Timothy V., MD ; Landry, Jerome, MD ; Gao, Huiying, MS ; Xu, Yanbo, PhD ; Wang, Lanfang, MS ; El-Rayes, Bassel, MD ; Shu, Hui-Kuo G., MD, PhD</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c511t-969ed3a49068802714ba9df3ad82a4b15ea9a6cb604204b57d4870a9f7e774533</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>ADP</topic><topic>Animals</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Benzimidazoles - therapeutic use</topic><topic>BIOLOGICAL REPAIR</topic><topic>Camptothecin - analogs & derivatives</topic><topic>Camptothecin - therapeutic use</topic><topic>CARCINOMAS</topic><topic>Chemoradiotherapy - methods</topic><topic>CHEMOTHERAPY</topic><topic>Colorectal Neoplasms - enzymology</topic><topic>Colorectal Neoplasms - genetics</topic><topic>Colorectal Neoplasms - pathology</topic><topic>Colorectal Neoplasms - therapy</topic><topic>Comet Assay - methods</topic><topic>DNA</topic><topic>DNA Damage</topic><topic>ENZYMES</topic><topic>Female</topic><topic>Fluorouracil - therapeutic use</topic><topic>HCT116 Cells</topic><topic>Hematology, Oncology and Palliative Medicine</topic><topic>Histones - analysis</topic><topic>HT29 Cells</topic><topic>Humans</topic><topic>IN VITRO</topic><topic>IN VIVO</topic><topic>Irinotecan</topic><topic>MICE</topic><topic>Mice, Nude</topic><topic>Neoplasm Proteins - antagonists & inhibitors</topic><topic>Organoplatinum Compounds - therapeutic use</topic><topic>Oxaliplatin</topic><topic>Poly(ADP-ribose) Polymerase Inhibitors</topic><topic>RADIATION DOSES</topic><topic>Radiology</topic><topic>RADIOLOGY AND NUCLEAR MEDICINE</topic><topic>RADIOTHERAPY</topic><topic>RIBOSE</topic><topic>STRAND BREAKS</topic><topic>SYNERGISM</topic><topic>Tumor Burden</topic><topic>URACILS</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shelton, Joseph W., MD</creatorcontrib><creatorcontrib>Waxweiler, Timothy V., MD</creatorcontrib><creatorcontrib>Landry, Jerome, MD</creatorcontrib><creatorcontrib>Gao, Huiying, MS</creatorcontrib><creatorcontrib>Xu, Yanbo, PhD</creatorcontrib><creatorcontrib>Wang, Lanfang, MS</creatorcontrib><creatorcontrib>El-Rayes, Bassel, MD</creatorcontrib><creatorcontrib>Shu, Hui-Kuo G., MD, PhD</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>OSTI.GOV</collection><jtitle>International journal of radiation oncology, biology, physics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shelton, Joseph W., MD</au><au>Waxweiler, Timothy V., MD</au><au>Landry, Jerome, MD</au><au>Gao, Huiying, MS</au><au>Xu, Yanbo, PhD</au><au>Wang, Lanfang, MS</au><au>El-Rayes, Bassel, MD</au><au>Shu, Hui-Kuo G., MD, PhD</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>In Vitro and In Vivo Enhancement of Chemoradiation Using the Oral PARP Inhibitor ABT-888 in Colorectal Cancer Cells</atitle><jtitle>International journal of radiation oncology, biology, physics</jtitle><addtitle>Int J Radiat Oncol Biol Phys</addtitle><date>2013-07-01</date><risdate>2013</risdate><volume>86</volume><issue>3</issue><spage>469</spage><epage>476</epage><pages>469-476</pages><issn>0360-3016</issn><eissn>1879-355X</eissn><abstract>Purpose Poly(ADP-ribose) polymerase plays a critical role in the recognition and repair of DNA single-strand breaks and double-strand breaks (DSBs). ABT-888 is an orally available inhibitor of this enzyme. This study seeks to evaluate the use of ABT-888 combined with chemotherapy and radiation therapy (RT) in colorectal carcinoma models. Methods and Materials RT clonogenic assays were performed on HCT116 and HT29 cells treated with 5-fluorouracil, irinotecan, or oxaliplatin with or without ABT. The surviving fraction at 2 Gy and dose-modifying factor at 10% survival were analyzed. Synergism was assessed by isobologram analysis for combination therapies. γH2AX and neutral comet assays were performed to assess the effect of therapy on DSB formation/repair. In vivo assessments were made by use of HCT116 cells in a xenograft mouse model. Tumor growth delay was measured at a volume of 500 mm3. Results Both lines were radiosensitized by ABT alone, and ABT further increased chemotherapy dose-modifying factors to the 1.6 to 1.8 range. All combinations were synergistic (combination indices <0.9). ABT treatment significantly increased DSB after RT (γH2AX, 69% vs 43%; P =.017) and delayed repair. We found tumor growth delays of 7.22 days for RT; 11.90 days for RT and ABT; 13.5 days for oxaliplatin, RT, and ABT; 14.17 days for 5-fluorouracil, RT, and ABT; and 23.81 days for irinotecan, RT, and ABT. Conclusion ABT-888 radiosensitizes at similar or higher levels compared with classic chemotherapies and acts synergistically with these chemotherapies to enhance RT effects. In vivo confirmation of these results indicates a potential role for combining its use with existing chemoradiation regimens.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>23540347</pmid><doi>10.1016/j.ijrobp.2013.02.015</doi><tpages>8</tpages></addata></record> |
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| ispartof | International journal of radiation oncology, biology, physics, 2013-07, Vol.86 (3), p.469-476 |
| issn | 0360-3016 1879-355X |
| language | eng |
| recordid | cdi_osti_scitechconnect_22224498 |
| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | ADP Animals Antineoplastic Agents - therapeutic use Benzimidazoles - therapeutic use BIOLOGICAL REPAIR Camptothecin - analogs & derivatives Camptothecin - therapeutic use CARCINOMAS Chemoradiotherapy - methods CHEMOTHERAPY Colorectal Neoplasms - enzymology Colorectal Neoplasms - genetics Colorectal Neoplasms - pathology Colorectal Neoplasms - therapy Comet Assay - methods DNA DNA Damage ENZYMES Female Fluorouracil - therapeutic use HCT116 Cells Hematology, Oncology and Palliative Medicine Histones - analysis HT29 Cells Humans IN VITRO IN VIVO Irinotecan MICE Mice, Nude Neoplasm Proteins - antagonists & inhibitors Organoplatinum Compounds - therapeutic use Oxaliplatin Poly(ADP-ribose) Polymerase Inhibitors RADIATION DOSES Radiology RADIOLOGY AND NUCLEAR MEDICINE RADIOTHERAPY RIBOSE STRAND BREAKS SYNERGISM Tumor Burden URACILS Xenograft Model Antitumor Assays |
| title | In Vitro and In Vivo Enhancement of Chemoradiation Using the Oral PARP Inhibitor ABT-888 in Colorectal Cancer Cells |
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