Radiation Therapy and Radiation Safety in Medicine
Suzanne Amador Kane, Boris A. Gelman in Introduction to Physics in Modern Medicine, 2020
Since only those direct or indirect interactions that affect DNA are thought to be important, most interactions between body chemicals and ionizing radiation are relatively innocuous. Cells appear perfectly able to function normally after sustaining damage to proteins, sugars, and fats, presumably because many copies of each of these molecules exist. Since only about 1% of the ionizations due to a 1-Gy dose happen in the genetic material, most radiation therefore has no lasting effect. Fortunately, even when a molecule of DNA interacts with ionizing radiation, almost all of the resulting chemical damage is quickly repaired. Genetic damage frequently occurs spontaneously from errors in cell metabolism, and to a much lesser extent from dangerous chemicals, ultraviolet light, and natural background radiation. Consequently, highly efficient natural mechanisms have evolved for repairing damaged DNA, using special-purpose proteins called repair enzymes. We will now consider how different types of DNA damage interacts with these natural DNA repair mechanisms.
Use of Spheroids in Hyperthermia Research
Rolf Bjerkvig in Spheroid Culture in Cancer Research, 2017
The cytotoxic effect of hyperthermia is probably caused by several mechanisms.3 The activation energy of hyperthermic cytotoxicity, analyzed by Arrhenius plots, is in the same range as that described for denaturation of proteins.4 Changes in protein structure will affect a large number of cellular functions, causing altered transport of ions and signal substances as well as modification of receptor functions.5 There are also reports indicating direct DNA damage probably caused by increased amounts of nuclear proteins and impaired DNA repair.3,6 The cell membrane structure may also be a target for hyperthermia, leading to alterations of endoplasmatic reticulum and destabilization of lysosomal membranes.7 Hyperthermia may also increase the speed of chemical reactions and thereby deplete the cellular energy reservoirs, resulting in activation of anaerobic glycolysis and reduced intracellular pH. The speed of chemical reactions with increased activation and decomposition of drugs, as well as reduced pH, are of interest when combining hyperthermia and cytotoxic drugs.6
Pharmacologic Ascorbate Influences Multiple Cellular Pathways Preferentially in Cancer Cells
Qi Chen, Margreet C.M. Vissers in Cancer and Vitamin C, 2020
A complex network of signaling pathways is altered when cells are exposed to DNA damaging agents [15]. Like other signaling pathways, a DNA damage response (DDR) signaling pathway consists of sensors, transducers, and effectors [16]. DNA damage sensors are the proteins that directly recognize aberrant DNA structures. Mre11-Rad50-Nbs1 (MRN) complex is the key sensor of DNA damage in mammalian cells; it activates ataxia-telangiectasia mutated (ATM) and ATM- and Rad3-related (ATR) kinases, two key transducers of the complex DDR network signaling. Pharmacologic ascorbate activates ATM in a concentration- and time-dependent manner by inducing ATM phosphorylation, and this phosphorylation can be rescued by catalase [4,13]. Following the initial activation, ATM triggers phosphorylation of histone 2Ax (H2Ax), which is a critical event for accumulation of numerous DNA repair proteins and chromatin-remodeling complexes around the DSBs [4,14]. Chk2, another downstream effector of ATM and ART, was also activated by ascorbate treatment [13]. It is also proposed that other downstream targets of ATM and ATR kinases (e.g., BRCA1/2, and p53) [17] are influenced by ascorbate treatment, which are primarily involved in a broad spectrum of cellular processes important for genomic stability and influence cell survival, cell cycle, apoptosis, and senescence [18,19].
Role of DNA damage and repair in radiation cancer therapy: a current update and a look to the future
Published in International Journal of Radiation Biology, 2020
Jingya Liu, Kun Bi, Run Yang, Hongxia Li, Zacharenia Nikitaki, Li Chang
Evolution equipped organisms, and mostly mammals, with an arsenal of enzymes and processes capable to defend their DNA damage integrity, by enormous probability of success. This is the DNA damage response, a network of interacting pathways which detects DNA lesions, sends the appropriate signals and ultimately repairs the damage. Upon damage induction, DDR begins with sensor proteins that recognize the damage, attract and activate signal transduction protein kinases (transducer kinases). Transducer kinases ‘alert’ the upstream effector kinases, which modificate the downstream effector kinases (Pateras et al. 2015). The later recruit the appropriate molecules to repair the damage. Depending on damage complexity level one or more of the following pathways are taking place.
Discovery of small-molecule ATR inhibitors for potential cancer treatment: a patent review from 2014 to present
Published in Expert Opinion on Therapeutic Patents, 2022
Suwen Hu, Zi Hui, Jilong Duan, Carmen Garrido, Tian Xie, Xiang-Yang Ye
DNA damage response (DDR) pathways are complex networks engaging in cellular DNA damage detection, cell-cycle adaptation, and damage repair process. Such networks play pivotal role in both the normal cells and the cancer cells in order to maintain their cell viability and to avoid genomic instability [1,2]. Impairing DDR networks of cancer cells using DNA-damaging agents is widely used as the strategy for cancer therapy. While such therapy approach is still in use, the anticancer efficacy is typically limited by the high toxicity of the DNA-damaging agents to the normal cells. Therefore, searching for compounds that could potentially exploit the presence of DNA damage in cancer cells utilizing the concept of synthetic lethality [3,4] has become the major ongoing focus in drug discovery.
Development of new TAK-285 derivatives as potent EGFR/HER2 inhibitors possessing antiproliferative effects against 22RV1 and PC3 prostate carcinoma cell lines
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Seohyun Son, Ahmed Elkamhawy, Anam Rana Gul, Ahmed A. Al‐Karmalawy, Radwan Alnajjar, Ahmed Abdeen, Samah F. Ibrahim, Saud O. Alshammari, Qamar A. Alshammari, Won Jun Choi, Tae Jung Park, Kyeong Lee
Cell cycle progression is responsible for normal cell growth and proliferation. DNA damage can result in apoptosis, which causes cell death, or DNA repair. At specific checkpoints that serve as control mechanisms to guarantee correct cell division, the state of the cells is evaluated. Checkpoints in the cell cycle include the G1 (restriction), S (metaphase), and G2/M29. Anticancer medications’ function is to halt cell division at these checkpoints. Treatment with potent cytotoxic (as an anticancer) agents can determine at which phase apoptosis occurs in the cell cycle. As a result, the most potent derivative, 9f, was chosen for testing its outcomes on the cell cycle profile and apoptosis. PC3 and 22RV1 cells were treated with compound 9f at its IC50. The comparison data in Table 6 and Figure 3 indicate that compound 9f (test 2) arrested the cell cycle of 22RV1 and PC3 cells at the G2/M phase by 62.74% and 49.43%, respectively (Figure 3). Also, the cell population in G1 and S phases decreases after treatment (test 2) compared to a negative control (test 1). The comparison data showed the control sample has arrested the cell cycle at G0/G1 phases while 9f treated sample has arrested it at G2/M phases as indicated by higher number of counts (%) in these phases of both cell cycle studies.