Preclinical Risk Evaluation of Normal Tissue Injury With Novel Radiosensitizers

Genotoxic damage induced by radiation triggers a highly coordinated DNA damage response, and molecular inhibitors of key nodes within this complex response network can profoundly enhance the antitumor efficacy of radiation. This is especially true for drugs targeting the catalytic subunit of DNA-dep...

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Published in:	International journal of radiation oncology, biology, physics Vol. 111; no. 5; pp. e54 - e62
Main Authors:	Dragojevic, Sonja, Ji, Jianxiong, Singh, Pankaj K., Connors, Margaret A., Mutter, Robert W., Lester, Scott C., Talele, Surabhi M., Zhang, Wenjuan, Carlson, Brett L., Remmes, Nicholas B., Park, Sean S., Elmquist, William F., Krishnan, Sunil, Tryggestad, Erik J., Sarkaria, Jann N.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01-12-2021
Subjects:	Animals APOPTOSIS Ataxia Telangiectasia Ataxia Telangiectasia Mutated Proteins - metabolism BIOLOGICAL PATHWAYS CELL CYCLE Cell Cycle Proteins - metabolism CLINICAL TRIALS DNA DNA Damage DNA DAMAGES DNA REPAIR DNA-Activated Protein Kinase - metabolism FLUOROURACILS Humans IN VITRO MICE NEOPLASMS PHOSPHOTRANSFERASES RADIATION INJURIES Radiation-Sensitizing Agents - therapeutic use RADIOLOGY AND NUCLEAR MEDICINE RADIOSENSITIZERS SMALL INTESTINE TOXICITY
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Summary:	Genotoxic damage induced by radiation triggers a highly coordinated DNA damage response, and molecular inhibitors of key nodes within this complex response network can profoundly enhance the antitumor efficacy of radiation. This is especially true for drugs targeting the catalytic subunit of DNA-dependent protein kinase, which is a core component of the nonhomologous end-joining DNA repair pathway, and ataxia telangiectasia mutated, which coordinates cell cycle arrest, apoptosis, and DNA repair functionalities after radiation exposure. Unlike the more modest in vitro radiosensitizing effects seen with classic sensitizing agents such as cisplatin, 5-fluorouracil, or taxanes, DNA-dependent protein kinase or ataxia telangiectasia mutated inhibitors provide much more robust sensitizing effects in vitro, as might be anticipated from targeting these key DNA repair modulators. However, patients with homozygous inactivating mutations of ataxia telangiectasia mutated or mice with homozygous defects in DNA-dependent protein kinase (severe combined immunodeficiency) have profoundly enhanced acute normal tissue radiation reactions. Therefore, there is significant potential that the combination of small molecule inhibitors of these kinases with radiation could cause similar dose-limiting acute normal tissue toxicities. Similarly, although less understood, inhibition of these DNA repair response pathways could markedly increase the risk of late radiation toxicities. Because these potent radiosensitizers could be highly useful to improve local control of otherwise radiation-resistant tumors, understanding the potential for elevated risks of radiation injury is essential for optimizing therapeutic ratio and developing safe and informative clinical trials. In this review, we will discuss 2 straightforward models to assess the potential for enhanced mucosal toxicity in the oral cavity and small intestine established in our laboratories. We also will discuss similar strategies for evaluating potential drug–radiation interactions with regard to increased risks of debilitating late effects.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 ObjectType-Review-3 content type line 23 Sonya Dragojevic and Jianxiong Ji made equal contributions to this study.
ISSN:	0360-3016 1879-355X 1879-355X
DOI:	10.1016/j.ijrobp.2021.08.003