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International Journal of Radiation... May 2021Spinal cord tolerance data for stereotactic body radiation therapy (SBRT) were extracted from published reports, reviewed, and modelled. For de novo SBRT delivered in 1... (Review)
Review
Spinal cord tolerance data for stereotactic body radiation therapy (SBRT) were extracted from published reports, reviewed, and modelled. For de novo SBRT delivered in 1 to 5 fractions, the following spinal cord point maximum doses (D) are estimated to be associated with a 1% to 5% risk of radiation myelopathy (RM): 12.4 to 14.0 Gy in 1 fraction, 17.0 Gy in 2 fractions, 20.3 Gy in 3 fractions, 23.0 Gy in 4 fractions, and 25.3 Gy in 5 fractions. For reirradiation SBRT delivered in 1 to 5 fractions, reported factors associated with a lower risk of RM include cumulative thecal sac equivalent dose in 2 Gy fractions with an alpha/beta of 2 (EQD2) D ≤70 Gy; SBRT thecal sac EQD2 D ≤25 Gy, thecal sac SBRT EQD2 D to cumulative EQD2 D ratio ≤0.5, and a minimum time interval to reirradiation of ≥5 months. Larger studies containing complete institutional cohorts with dosimetric data of patients treated with spine SBRT, with and without RM, are required to refine RM risk estimates.
Topics: Dose-Response Relationship, Radiation; Humans; Models, Biological; Models, Theoretical; Organs at Risk; Radiation Dose Hypofractionation; Radiation Tolerance; Radiosurgery; Radiotherapy Dosage; Re-Irradiation; Spinal Cord; Spinal Cord Diseases
PubMed: 31606528
DOI: 10.1016/j.ijrobp.2019.09.038 -
Molecular Cell May 2017Both embryonic and adult stem cells are endowed with a superior capacity to prevent the accumulation of genetic lesions, repair them, or avoid their propagation to... (Review)
Review
Both embryonic and adult stem cells are endowed with a superior capacity to prevent the accumulation of genetic lesions, repair them, or avoid their propagation to daughter cells, which would be particularly detrimental to the whole organism. Inducible pluripotent stem cells also display a robust DNA damage response, but the stability of their genome is often conditioned by the mutational history of the cell population of origin, which constitutes an obstacle to clinical applications. Cancer stem cells are particularly tolerant to DNA damage and fail to undergo senescence or regulated cell death upon accumulation of genetic lesions. Such a resistance contributes to the genetic drift of evolving tumors as well as to their limited sensitivity to chemo- and radiotherapy. Here, we discuss the pathophysiological and therapeutic implications of the molecular pathways through which stem cells cope with DNA damage.
Topics: Adult Stem Cells; Animals; DNA Damage; DNA Repair; Embryonic Stem Cells; Genetic Drift; Genomic Instability; Humans; Mutation; Neoplasms; Neoplastic Stem Cells; Pluripotent Stem Cells; Radiation Tolerance
PubMed: 28475867
DOI: 10.1016/j.molcel.2017.04.006 -
Journal of Thoracic Oncology : Official... May 2021
Topics: Genomics; Humans; Lung Neoplasms; Prescriptions; Radiation Tolerance
PubMed: 33896574
DOI: 10.1016/j.jtho.2021.02.027 -
Journal of Translational Medicine Jun 2023Tumor cells with the capability of radiation resistance can escape the fate of cell death after radiotherapy, serving as the main cause of treatment failure....
BACKGROUND
Tumor cells with the capability of radiation resistance can escape the fate of cell death after radiotherapy, serving as the main cause of treatment failure. Repopulation of tumors after radiotherapy is dominated by this group of residual cells, which greatly reduce the sensitivity of recurrent tumors to the therapy, resulting in poor clinical outcomes. Therefore, revealing the mechanism of radiation resistant cells participating in tumor repopulation is of vital importance for cancer patients to obtain a better prognosis.
METHODS
Co-expressed genes were searched by using genetic data of radiation resistant cells (from GEO database) and TCGA colorectal cancer. Univariate and multivariate Cox regression analysis were performed to define the most significant co-expressed genes for establishing prognostic indicator. Logistic analysis, WGCNA analysis, and other types of tumors were included to verify the predictive ability of the indicator. RT-qPCR was carried out to test expression level of key genes in colorectal cancer cell lines. Colongenic assay was utilized to test the radio-sensitivity and repopulation ability of key gene knockdown cells.
RESULTS
Prognostic indicator based on TCGA colorectal cancer patients containing four key radiation resistance genes (LGR5, KCNN4, TNS4, CENPH) was established. The indicator was shown to be significantly correlated with the prognosis of colorectal cancer patients undergoing radiotherapy, and also had an acceptable predictive effect in the other five types of cancer. RT-qPCR showed that expression level of key genes was basically consistent with the radiation resistance level of colorectal cancer cells. The clonogenic ability of all key gene knockdown cells decreased after radiation treatment compared with the control groups.
CONCLUSIONS
Our data suggest that LGR5, KCNN4, TNS4 and CENPH are correlated with radiation sensitivity of colorectal cancer cells, and the indicator composed by them can reflect the prognosis of colorectal cancer patients undergoing radiation therapy. Our data provide an evidence of radiation resistant tumor cells involved in tumor repopulation, and give patients undergoing radiotherapy an approving prognostic indicator with regard to tumor progression.
Topics: Humans; Prognosis; Radiation Tolerance; Cell Line, Tumor; Cell Death; Colorectal Neoplasms
PubMed: 37328854
DOI: 10.1186/s12967-023-04260-x -
The Journal of Pathology Apr 2020Normal tissue responses to ionizing radiation have been a major subject for study since the discovery of X-rays at the end of the 19th century. Shortly thereafter,... (Review)
Review
Normal tissue responses to ionizing radiation have been a major subject for study since the discovery of X-rays at the end of the 19th century. Shortly thereafter, time-dose relationships were established for some normal tissue endpoints that led to investigations into how the size of dose per fraction and the quality of radiation affected outcome. The assessment of the radiosensitivity of bone marrow stem cells using colony-forming assays by Till and McCulloch prompted the establishment of in situ clonogenic assays for other tissues that added to the radiobiology toolbox. These clonogenic and functional endpoints enabled mathematical modeling to be performed that elucidated how tissue structure, and in particular turnover time, impacted clinically relevant fractionated radiation schedules. More recently, lineage tracing technology, advanced imaging and single cell sequencing have shed further light on the behavior of cells within stem, and other, cellular compartments, both in homeostasis and after radiation damage. The discovery of heterogeneity within the stem cell compartment and plasticity in response to injury have added new dimensions to the consideration of radiation-induced tissue damage. Clinically, radiobiology of the 20th century garnered wisdom relevant to photon treatments delivered to a fairly wide field at around 2 Gy per fraction, 5 days per week, for 5-7 weeks. Recently, the scope of radiobiology has been extended by advances in technology, imaging and computing, as well as by the use of charged particles. These allow radiation to be delivered more precisely to tumors while minimizing the amount of normal tissue receiving high doses. One result has been an increase in the use of schedules with higher doses per fraction given in a shorter time frame (hypofractionation). We are unable to cover these new technologies in detail in this review, just as we must omit low-dose stochastic effects, and many aspects of dose, dose rate and radiation quality. We argue that structural diversity and plasticity within tissue compartments provides a general context for discussion of most radiation responses, while acknowledging many omissions. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Topics: Acute Radiation Syndrome; DNA Damage; Dose-Response Relationship, Radiation; Humans; Neoplasms; Radiation Tolerance; Time Factors
PubMed: 31990369
DOI: 10.1002/path.5389 -
Biochimica Et Biophysica Acta. Reviews... Aug 2017Despite recent advances in radiotherapy, a majority of patients diagnosed with pancreatic cancer (PC) do not achieve objective responses due to the existence of... (Review)
Review
Despite recent advances in radiotherapy, a majority of patients diagnosed with pancreatic cancer (PC) do not achieve objective responses due to the existence of intrinsic and acquired radioresistance. Identification of molecular mechanisms that compromise the efficacy of radiation therapy and targeting these pathways is paramount for improving radiation response in PC patients. In this review, we have summarized molecular mechanisms associated with the radio-resistant phenotype of PC. Briefly, we discuss the reversible and irreversible biological consequences of radiotherapy, such as DNA damage and DNA repair, mechanisms of cancer cell survival and radiation-induced apoptosis following radiotherapy. We further describe various small molecule inhibitors and molecular targeting agents currently being tested in preclinical and clinical studies as potential radiosensitizers for PC. Notably, we draw attention towards the confounding effects of cancer stem cells, immune system, and the tumor microenvironment in the context of PC radioresistance and radiosensitization. Finally, we discuss the need for examining selective radioprotectors in light of the emerging evidence on radiation toxicity to non-target tissue associated with PC radiotherapy.
Topics: Animals; Apoptosis; DNA Damage; DNA Repair; Humans; Pancreatic Neoplasms; Radiation Tolerance; Tumor Microenvironment
PubMed: 28249796
DOI: 10.1016/j.bbcan.2017.02.003 -
Radiotherapy and Oncology : Journal of... Dec 2023Radiotherapy is a widely used treatment modality against cancer, and although survival rates are increasing, radioresistant properties of tumours remain a significant... (Review)
Review
Radiotherapy is a widely used treatment modality against cancer, and although survival rates are increasing, radioresistant properties of tumours remain a significant barrier for curative treatment. Tumour hypoxia is one of the main contributors to radioresistance and is common in most solid tumours. Hypoxia is responsible for many molecular changes within the cell which helps tumours to survive under such challenging conditions. These hypoxia-induced molecular changes are predominantly coordinated by the hypoxia inducible factor (HIF) and have been linked with the ability to confer resistance to radiation-induced cell death. To overcome this obstacle research has been directed towards autophagy, a cellular process involved in self degradation and recycling of macromolecules, as HIF plays a large role in its coordination under hypoxic conditions. The role that autophagy has following radiotherapy treatment is conflicted with evidence of both cytoprotective and cytotoxic effects. This literature review aims to explore the intricate relationship between radiotherapy, hypoxia, and autophagy in the context of cancer treatment. It provides valuable insights into the potential of targeting autophagy as a therapeutic strategy to improve the response of hypoxic tumours to radiotherapy.
Topics: Humans; Radiation Tolerance; Neoplasms; Hypoxia; Cell Hypoxia; Autophagy; Cell Line, Tumor; Hypoxia-Inducible Factor 1, alpha Subunit
PubMed: 37838322
DOI: 10.1016/j.radonc.2023.109951 -
Cancer Gene Therapy Mar 2015Radiation therapy is a critical component of cancer treatment with over half of patients receiving radiation during their treatment. Despite advances in image-guided... (Review)
Review
Radiation therapy is a critical component of cancer treatment with over half of patients receiving radiation during their treatment. Despite advances in image-guided therapy and dose fractionation, patients receiving radiation therapy are still at risk for side effects due to off-target radiation damage of normal tissues. To reduce normal tissue damage, researchers have sought radioprotectors, which are agents capable of protecting tissue against radiation by preventing radiation damage from occurring or by decreasing cell death in the presence of radiation damage. Although much early research focused on small-molecule radioprotectors, there has been a growing interest in gene therapy for radioprotection. The amenability of gene therapy vectors to targeting, as well as the flexibility of gene therapy to accomplish ablation or augmentation of biologically relevant genes, makes gene therapy an excellent strategy for radioprotection. Future improvements to vector targeting and delivery should greatly enhance radioprotection through gene therapy.
Topics: Animals; Gene Expression; Genetic Therapy; Humans; Neoplasms; Radiation Injuries; Radiation Tolerance; Transgenes
PubMed: 25721205
DOI: 10.1038/cgt.2015.8 -
The British Journal of Radiology Jan 2019A summary of the key aspects of radiobiological modelling is provided, based on the theoretical and practical concepts of the linear quadratic model, which gradually... (Review)
Review
A summary of the key aspects of radiobiological modelling is provided, based on the theoretical and practical concepts of the linear quadratic model, which gradually replaced other numerical approaches. The closely related biological effective dose concept is useful in many clinical applications. Biological effective dose formulations in conventional photon-based radiotherapy continue to be developed, and can be extended to the now increasingly used proton and ion-beam therapy, to very low or high dose ranges, the dose rate effect, hypoxia and repopulation. Such established and new research developments will be of interest to clinicians, physicists and biologists to better understand the processes underlying radiotherapy and assist their collaborative efforts to make radiotherapy safer and more effective.
Topics: Dose-Response Relationship, Radiation; Forecasting; Humans; Models, Biological; Patient Safety; Proton Therapy; Radiation Injuries; Radiation Tolerance; Radiobiology; Radiotherapy Dosage; Relative Biological Effectiveness
PubMed: 29557215
DOI: 10.1259/bjr.20180097 -
Trends in Genetics : TIG Aug 2018High-throughput sequencing can be used to measure changes in tumor composition across space and time. Specifically, comparisons of pre- and post-treatment samples can... (Review)
Review
High-throughput sequencing can be used to measure changes in tumor composition across space and time. Specifically, comparisons of pre- and post-treatment samples can reveal the underlying clonal dynamics and resistance mechanisms. Here, we discuss evidence for distinct modes of tumor evolution and their implications for therapeutic strategies. In addition, we consider the utility of spatial tissue sampling schemes, single-cell analysis, and circulating tumor DNA to track tumor evolution and the emergence of resistance, as well as approaches that seek to forestall resistance by targeting tumor evolution. Ultimately, characterization of the (epi)genomic, transcriptomic, and phenotypic changes that occur during tumor progression coupled with computational and mathematical modeling of tumor evolutionary dynamics may inform personalized treatment strategies.
Topics: Animals; Biomarkers, Tumor; Cell Transformation, Neoplastic; Clonal Evolution; Computer Simulation; Disease Progression; Drug Resistance, Neoplasm; Genetic Heterogeneity; Humans; Models, Biological; Molecular Targeted Therapy; Neoplasms; Radiation Tolerance
PubMed: 29903534
DOI: 10.1016/j.tig.2018.05.007