Total marrow irradiation reduces organ damage and enhances tissue repair with the potential to increase the targeted dose of bone marrow in both young and old mice
Total body irradiation (TBI) is a commonly used conditioning regimen for hematopoietic stem cell transplant (HCT), but dose heterogeneity and long-term organ toxicity pose significant challenges. Total marrow irradiation (TMI), an evolving radiation conditioning regimen for HCT can overcome the limi...
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| Format: | Article |
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Frontiers Media S.A.
2022-11-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.1045016/full |
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| author | Ji Eun Lim Srideshikan Sargur Madabushi Paresh Vishwasrao Joo Y. Song Amr M. H. Abdelhamid Amr M. H. Abdelhamid Amr M. H. Abdelhamid Hemendra Ghimire V. L. Vanishree Jatinder K. Lamba Savita Dandapani Amandeep Salhotra Mengistu Lemecha Antonio Pierini Daohong Zhao Guy Storme Shernan Holtan Cynthia Aristei Dorthe Schaue Monzr Al Malki Susanta K. Hui |
| author_facet | Ji Eun Lim Srideshikan Sargur Madabushi Paresh Vishwasrao Joo Y. Song Amr M. H. Abdelhamid Amr M. H. Abdelhamid Amr M. H. Abdelhamid Hemendra Ghimire V. L. Vanishree Jatinder K. Lamba Savita Dandapani Amandeep Salhotra Mengistu Lemecha Antonio Pierini Daohong Zhao Guy Storme Shernan Holtan Cynthia Aristei Dorthe Schaue Monzr Al Malki Susanta K. Hui |
| author_sort | Ji Eun Lim |
| collection | DOAJ |
| description | Total body irradiation (TBI) is a commonly used conditioning regimen for hematopoietic stem cell transplant (HCT), but dose heterogeneity and long-term organ toxicity pose significant challenges. Total marrow irradiation (TMI), an evolving radiation conditioning regimen for HCT can overcome the limitations of TBI by delivering the prescribed dose targeted to the bone marrow (BM) while sparing organs at risk. Recently, our group demonstrated that TMI up to 20 Gy in relapsed/refractory AML patients was feasible and efficacious, significantly improving 2-year overall survival compared to the standard treatment. Whether such dose escalation is feasible in elderly patients, and how the organ toxicity profile changes when switching to TMI in patients of all ages are critical questions that need to be addressed. We used our recently developed 3D image-guided preclinical TMI model and evaluated the radiation damage and its repair in key dose-limiting organs in young (~8 weeks) and old (~90 weeks) mice undergoing congenic bone marrow transplant (BMT). Engraftment was similar in both TMI and TBI-treated young and old mice. Dose escalation using TMI (12 to 16 Gy in two fractions) was well tolerated in mice of both age groups (90% survival ~12 Weeks post-BMT). In contrast, TBI at the higher dose of 16 Gy was particularly lethal in younger mice (0% survival ~2 weeks post-BMT) while old mice showed much more tolerance (75% survival ~13 weeks post-BMT) suggesting higher radio-resistance in aged organs. Histopathology confirmed worse acute and chronic organ damage in mice treated with TBI than TMI. As the damage was alleviated, the repair processes were augmented in the TMI-treated mice over TBI as measured by average villus height and a reduced ratio of relative mRNA levels of amphiregulin/epidermal growth factor (areg/egf). These findings suggest that organ sparing using TMI does not limit donor engraftment but significantly reduces normal tissue damage and preserves repair capacity with the potential for dose escalation in elderly patients. |
| first_indexed | 2024-04-13T21:57:37Z |
| format | Article |
| id | doaj.art-a65aed3895a94887b4768ac32b94c4ab |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-13T21:57:37Z |
| publishDate | 2022-11-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Oncology |
| spelling | doaj.art-a65aed3895a94887b4768ac32b94c4ab2022-12-22T02:28:13ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-11-011210.3389/fonc.2022.10450161045016Total marrow irradiation reduces organ damage and enhances tissue repair with the potential to increase the targeted dose of bone marrow in both young and old miceJi Eun Lim0Srideshikan Sargur Madabushi1Paresh Vishwasrao2Joo Y. Song3Amr M. H. Abdelhamid4Amr M. H. Abdelhamid5Amr M. H. Abdelhamid6Hemendra Ghimire7V. L. Vanishree8Jatinder K. Lamba9Savita Dandapani10Amandeep Salhotra11Mengistu Lemecha12Antonio Pierini13Daohong Zhao14Guy Storme15Shernan Holtan16Cynthia Aristei17Dorthe Schaue18Monzr Al Malki19Susanta K. Hui20Department of Radiation Oncology, City of Hope National Medical Center, Duarte, CA, United StatesDepartment of Radiation Oncology, City of Hope National Medical Center, Duarte, CA, United StatesDepartment of Radiation Oncology, City of Hope National Medical Center, Duarte, CA, United StatesDepartment of Pathology, City of Hope Comprehensive Cancer Center, Duarte, CA, United StatesDepartment of Radiation Oncology, City of Hope National Medical Center, Duarte, CA, United StatesRadiation Oncology Section, Department of Medicine and Surgery, Perugia University and General Hospital, Perugia, ItalyDepartment of Oncology and Nuclear Medicine, Faculty of Medicine, Ain Shams University, Cairo, EgyptDepartment of Radiation Oncology, City of Hope National Medical Center, Duarte, CA, United StatesDepartment of Radiation Oncology, City of Hope National Medical Center, Duarte, CA, United StatesDepartment of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gianesville, FL, United StatesDepartment of Radiation Oncology, City of Hope National Medical Center, Duarte, CA, United StatesDepartment of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA, United StatesDepartment of Molecular and Cellular Biology, Beckman Research Institute, Duarte, CA, United StatesDivision of Hematology and Bone Marrow Transplantation, Perugia General Hospital, Perugia, ItalyDepartment of Biochemistry and Structural Biology, Univeristy of Texas (UT) Health San Antonio, San Antonio, TX, United States0Department of Radiotherapy Universitair Ziekenhuis (UZ) Brussels, Brussels, Belgium1Blood and Marrow Transplant Program, Department of Medicine, University of Minnesota, Minneapolis, MN, United StatesRadiation Oncology Section, Department of Medicine and Surgery, Perugia University and General Hospital, Perugia, Italy2Department of Radiation Oncology, University of California, Los Angeles (UCLA), Los Angeles, CA, United StatesDepartment of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA, United StatesDepartment of Radiation Oncology, City of Hope National Medical Center, Duarte, CA, United StatesTotal body irradiation (TBI) is a commonly used conditioning regimen for hematopoietic stem cell transplant (HCT), but dose heterogeneity and long-term organ toxicity pose significant challenges. Total marrow irradiation (TMI), an evolving radiation conditioning regimen for HCT can overcome the limitations of TBI by delivering the prescribed dose targeted to the bone marrow (BM) while sparing organs at risk. Recently, our group demonstrated that TMI up to 20 Gy in relapsed/refractory AML patients was feasible and efficacious, significantly improving 2-year overall survival compared to the standard treatment. Whether such dose escalation is feasible in elderly patients, and how the organ toxicity profile changes when switching to TMI in patients of all ages are critical questions that need to be addressed. We used our recently developed 3D image-guided preclinical TMI model and evaluated the radiation damage and its repair in key dose-limiting organs in young (~8 weeks) and old (~90 weeks) mice undergoing congenic bone marrow transplant (BMT). Engraftment was similar in both TMI and TBI-treated young and old mice. Dose escalation using TMI (12 to 16 Gy in two fractions) was well tolerated in mice of both age groups (90% survival ~12 Weeks post-BMT). In contrast, TBI at the higher dose of 16 Gy was particularly lethal in younger mice (0% survival ~2 weeks post-BMT) while old mice showed much more tolerance (75% survival ~13 weeks post-BMT) suggesting higher radio-resistance in aged organs. Histopathology confirmed worse acute and chronic organ damage in mice treated with TBI than TMI. As the damage was alleviated, the repair processes were augmented in the TMI-treated mice over TBI as measured by average villus height and a reduced ratio of relative mRNA levels of amphiregulin/epidermal growth factor (areg/egf). These findings suggest that organ sparing using TMI does not limit donor engraftment but significantly reduces normal tissue damage and preserves repair capacity with the potential for dose escalation in elderly patients.https://www.frontiersin.org/articles/10.3389/fonc.2022.1045016/fulltotal marrow irradiationbone marrow transplantationagingtissue damagetissue repairDNA damage |
| spellingShingle | Ji Eun Lim Srideshikan Sargur Madabushi Paresh Vishwasrao Joo Y. Song Amr M. H. Abdelhamid Amr M. H. Abdelhamid Amr M. H. Abdelhamid Hemendra Ghimire V. L. Vanishree Jatinder K. Lamba Savita Dandapani Amandeep Salhotra Mengistu Lemecha Antonio Pierini Daohong Zhao Guy Storme Shernan Holtan Cynthia Aristei Dorthe Schaue Monzr Al Malki Susanta K. Hui Total marrow irradiation reduces organ damage and enhances tissue repair with the potential to increase the targeted dose of bone marrow in both young and old mice Frontiers in Oncology total marrow irradiation bone marrow transplantation aging tissue damage tissue repair DNA damage |
| title | Total marrow irradiation reduces organ damage and enhances tissue repair with the potential to increase the targeted dose of bone marrow in both young and old mice |
| title_full | Total marrow irradiation reduces organ damage and enhances tissue repair with the potential to increase the targeted dose of bone marrow in both young and old mice |
| title_fullStr | Total marrow irradiation reduces organ damage and enhances tissue repair with the potential to increase the targeted dose of bone marrow in both young and old mice |
| title_full_unstemmed | Total marrow irradiation reduces organ damage and enhances tissue repair with the potential to increase the targeted dose of bone marrow in both young and old mice |
| title_short | Total marrow irradiation reduces organ damage and enhances tissue repair with the potential to increase the targeted dose of bone marrow in both young and old mice |
| title_sort | total marrow irradiation reduces organ damage and enhances tissue repair with the potential to increase the targeted dose of bone marrow in both young and old mice |
| topic | total marrow irradiation bone marrow transplantation aging tissue damage tissue repair DNA damage |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.1045016/full |
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