Use of angiotensin converting enzyme inhibitors is associated with reduced risk of late bladder toxicity following radiotherapy for prostate cancer

Kerns, Sarah L.; Morlang, Ashley Amidon; Lee, Sharon M.; Peterson, Derick R.; Marples, Brian; Zhang, Hong; Bylund, Kevin; Rosenzweig, Doug; Hall, William A.; Ruyck, Kim De; Rosenstein, Barry S.; Stock, Richard G.; Caamaño, Antonio Gómez; Vega, Ana; Sosa-Fajardo, Paloma; Taboada-Valladares, Begoña; Aguado-Barrera, Miguel E.; Parker, Chris; Veldeman, Liv; Fonteyne, Valérie; Bultijnck, Renée; Johnson, Kerstie; Webb, Adam; Lambrecht, Maarten; Ruysscher, Dirk De; Vanneste, Ben; Choudhury, Ananya; Elliott, Rebecca; Sperk, Elena; Herskind, Carsten; Veldwijk, Marlon R.; Rancati, T.; Avuzzi, B.; Valdagni, Riccardo; Azria, D.; Jacquet, Marie-Pierre Farcy; Chang‐Claude, Jenny; Seibold, Petra; West, Catharine; Janelsins, Michelle Christine; Chen, Yuhchyau; Messing, Edward M.; Morrow, Gary R.; Briers, Erik; Dunning, Alison M.; Gutiérrez-Enríquez, S.; Rattay, Tim; Symonds, R. Paul; Stobart, Hilary; Talbot, Christopher J.; Ward, Tim

doi:10.1016/j.radonc.2022.01.014

Cited by 11 publications

(2 citation statements)

References 31 publications

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“…We characterized expression of the RAS enzymes ACE and ACE2 to see if differential regulation of the RAS system may play a role in mediating this sex difference. The RAS system is known to be a crucial regulator of the pathogenesis of radiationinduced toxicities as ACE inhibitors have been shown to reduce multi-organ toxicity in animal models (Kma et al, 2012;Medhora et al, 2012;Fish et al, 2016;Mungunsukh et al, 2021) and the incidental use of lisinopril in cancer patients undergoing radiation therapy is associated with decreased normal tissue toxicity (Kharofa et al, 2012;Kerns et al, 2022). Additionally, we have recently demonstrated that pharmacologic agonism of ACE2 also significantly improves survival during pneumonitis (Gasperetti et al, 2022).…”

Section: Discussionmentioning

confidence: 98%

Biological sex differences in renin angiotensin system enzymes ACE and ACE2 regulate normal tissue response to radiation injury

et al. 2023

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Introduction: In experimental animal models, biological sex-differences in the manifestation and severity of normal tissue radiation injury have been well-documented. Previously we demonstrated male and female rats have differential and highly reproducible responses to high-dose partial body irradiation (PBI) with male rats having greater susceptibility to both gastrointestinal acute radiation syndrome (GI-ARS) and radiation pneumonitis than female rats.Methods: In the current study, we have investigated whether differential expression of the renin-angiotensin system (RAS) enzymes angiotensin converting enzyme (ACE) and ACE2 contribute to the observed sex-related differences in radiation response.Results: During the period of symptomatic pneumonitis, the relative ratio of ACE to ACE2 (ACE/ACE2) protein in the whole lung was significantly increased by radiation in male rats alone. Systemic treatment with small molecule ACE2 agonist diminazene aceturate (DIZE) increased lung ACE2 activity and reduced morbidity during radiation pneumonitis in both sexes. Notably DIZE treatment also abrogated morbidity in male rats during GI-ARS. We then evaluated the contribution of the irradiated bone marrow (BM) compartment on lung immune cell infiltration and ACE imbalance during pneumonitis. Transplantation of bone marrow from irradiated donors increased both ACE-expressing myeloid cell infiltration and immune ACE activity in the lung during pneumonitis compared to non-irradiated donors.Discussion: Together, these data demonstrate radiation induces a sex-dependent imbalance in the renin-angiotensin system enzymes ACE and ACE2. Additionally, these data suggest a role for ACE-expressing myeloid cells in the pathogenesis of radiation pneumonitis. Finally, the observed sex-differences underscore the need for consideration of sex as a biological variable in the development of medical countermeasures for radiation exposure.

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Section: Discussionmentioning

confidence: 98%

Biological sex differences in renin angiotensin system enzymes ACE and ACE2 regulate normal tissue response to radiation injury

et al. 2023

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“…Recently, involved-field irradiation with a total dose of 60 Gy in 30 fractions for Stage I esophageal cancer has often been performed at our institution. Fourth, it has been shown that the renin–angiotensin system affects RT-induced blood vessel injury and fibrosis, and animal and human studies demonstrated that the angiotensin-converting enzyme (ACE) inhibitors were effective in preventing late toxicities including cardiopulmonary complications [ 39 , 40 ]. ACE inhibitors have a role in protecting from adverse cardiac remodeling and heart failure [ 40 ] and might be one of the measures to reduce cardiac events.…”

Section: Discussionmentioning

confidence: 99%

Clinical impact of radiation-induced myocardial damage detected by cardiac magnetic resonance imaging and dose-volume histogram parameters of the left ventricle as prognostic factors of cardiac events after chemoradiotherapy for esophageal cancer

Umezawa

Ota

Takagi

et al. 2023

Journal of Radiation Research

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This prospective study aimed to evaluate whether radiation (RT)-induced myocardial damage by cardiac magnetic resonance (CMR) imaging could be a predictor of cardiac events after chemoradiotherapy (CRT) for esophageal cancer and determine the dose-volume histogram (DVH) parameters of the left ventricle (LV) in predicting cardiac events. CMR imaging was performed before and 6 months after CRT in patients receiving definitive CRT. RT-induced myocardial damage was defined as abnormal CMR findings indicating myocardial fibrosis corresponding to an isodose line of ≥30 Gy. The cutoff values of the LV DVH parameters were calculated using the receiver operating characteristic curve based on the presence of RT-induced myocardial damage. The prognostic factors related to cardiac events of Grade 3 or higher were examined. Twenty-three patients were enrolled in the study. RT-induced myocardial damage by late gadolinium enhancement and/or an increase of 100 ms or higher in native T1 post-CRT was detected in 10 of the 23 patients. LV V45 was the best predictive factor for RT-induced myocardial damage with a cutoff value of 2.1% and an area under the curve of 0.75. The median follow-up period was 82.1 months. The 5- and 7-year cumulative incidences of cardiac events of Grade 3 or higher were 14.7 and 22.4%, respectively. RT-induced myocardial damage and LV V45 were significant risk factors (P = 0.015 and P = 0.013, respectively). RT-induced myocardial damage is a significant predictor of cardiac events. LV V45 is associated with RT-induced myocardial damage and subsequent cardiac events.

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Angiotensin-converting enzyme

Arrighi,

Berrino,

Secci

2024

Metalloenzymes

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Use of angiotensin converting enzyme inhibitors is associated with reduced risk of late bladder toxicity following radiotherapy for prostate cancer

Cited by 11 publications

References 31 publications

Biological sex differences in renin angiotensin system enzymes ACE and ACE2 regulate normal tissue response to radiation injury

Biological sex differences in renin angiotensin system enzymes ACE and ACE2 regulate normal tissue response to radiation injury

Clinical impact of radiation-induced myocardial damage detected by cardiac magnetic resonance imaging and dose-volume histogram parameters of the left ventricle as prognostic factors of cardiac events after chemoradiotherapy for esophageal cancer

Angiotensin-converting enzyme

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