Nucleic Acids as Therapeutic Targets and Agents
David E. Thurston, Ilona Pysz in Chemistry and Pharmacology of Anticancer Drugs, 2021
A radiosensitizer is an agent that makes tumor cells more sensitive to radiation therapy and is sometimes known as a radio-enhancer. A true radiosensitizer should be relatively nontoxic itself, acting only as a potentiator of radiation therapy. Agents that show little or no differential effect between tumors and normal tissue do not improve the therapeutic ratio and are not of clinical benefit. Conventional chemotherapeutic agents are often used in conjunction with radiation therapy to increase their effectiveness. Examples include the antimetabolites (e.g., the fluoropyrimidines and gemcitabine) and DNA-interactive agents (e.g., platinum analogs). The fluoropyrimidines are thought to increase sensitivity by dysregulating the S-Phase cell-cycle checkpoints in tumor cells, while gemcitabine appears to inhibit the ability of cells in the S-Phase to repair DNA damage caused by the radiation. The DNA damage (e.g., cross-linking) caused by cisplatin appears to enhance the effects of DNA damage induced by radiation, possibly due to the inhibition of DNA-repair pathways.
Biologically Targeted Agents in Head and Neck Cancers
John C Watkinson, Raymond W Clarke, Terry M Jones, Vinidh Paleri, Nicholas White, Tim Woolford in Head & Neck Surgery Plastic Surgery, 2018
Other Chk1 inhibitors have been developed, including PF-00477736,84, 85 MK8776 (otherwise known as SCH900776)86 and SAR-020106.87 The latter agent, SAR-020106, was shown to be a potent radiosensitizer both in in vitro and in vivo models. The drug inhibited radiation-induced G2/M arrest and reduced clonogenic survival in p53-deficient, but not p53-competent, tumour cells. Importantly, SAR-020106 promoted mitotic entry after irradiation in all cell lines: p53-deficient cells were likely to undergo apoptosis or become aneuploid, while p53 wild-type cells experienced a post-mitotic G1 arrest followed by subsequent normal cell cycle re-entry. Following combined treatment with SAR-020106 and radiation, HR-mediated DNA damage repair was inhibited in all cell lines. However, a significant increase in pan-γH2AX-stained apoptotic cells was observed only in p53-deficient cell lines. Efficacy was confirmed in vivo in a clinically relevant human head and neck cancer xenograft model.87 The lack of oral bioavailability of this agent has arrested its clinical development. However, an orally bioavailable Chk1 inhibitor (CCT245737)88 is entering clinical studies in a range of solid cancers and it is hoped that its development will include combination studies with radiation in disease subtypes that will include head and neck cancers.
Carcinoma of the vagina and vulva
Pat Price, Karol Sikora in Treatment of Cancer, 2014
In recent years attention has focused on the use of neoadjuvant chemo-radiotherapy with the chemotherapy being used as a radiosensitizer rather than as a cytotoxic agent. Most of these studies have been carried out on only small numbers of patients. Koh et al.66 treated 20 patients with bulky cancers of the vulva with radiation doses to a maximum of 70.4 Gy to bulk disease and 54 Gy to areas at risk of microscopic spread combined with 5-FU (6 patients also received either cisplatin or Mitomycin C). A response rate of 90% was reported with 10 pathological complete responses and 8 pathological partial responses at viscera preserving surgery. Gerszten67 has reported treating 18 patients with a twice daily regime of radiotherapy cisplatin and 5FU followed by surgery with a complete response rate of 13 patients. Similarly, Geisler et al.68 treated 10 patients with advanced vulval carcinoma involving the anal sphincter or urethra cisplatin and 5-FU followed by radical surgery. They have reported conservation of the anus and the urethra in all the patients with a 100% response rate. It would therefore appear that pre-operative radiotherapy either alone or in combination with chemotherapy reported may be useful for advanced tumours to try to downsize the tumour in order to preserve urinary and anal sphincter control.
Radiosensitivity enhancement of Fe3O4@Ag nanoparticles on human glioblastoma cells
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2018
Xiaohong Zhang, Zhujun Liu, Zhichao Lou, Feng Chen, Shuquan Chang, Yuji Miao, Zhuo Zhou, Xiaodan Hu, Jundong Feng, Qi Ding, Peidang Liu, Ning Gu, Haiqian Zhang
The radiosensitizer is synergistic with radiation to increase the lethal effect of cancer cells. Although the cell death induced by radiation combined with the radiosensitizer may differ from that by radiation alone, the former is commonly categorized as the ionizing radiation-induced cell death [19]. The ionizing radiation-induced cell death includes necrosis, apoptosis and autophagy [20]. Recent studies demonstrated that apoptosis and autophagy can interconvert into each other [21], which makes the mechanisms of the ionizing radiation-induced cell death more complicated. In this paper, we explored the function of Fe3O4@Ag nanoparticles as a highly efficient radiosensitizer and the corresponding mechanisms for Fe3O4@Ag nanoparticles to enhance radiosensitivity of cancer cells. Firstly, the radiosensitizing effects of Fe3O4-OA nanoparticles, Ag nanoparticles and Fe3O4@Ag nanoparticles on human glioblastoma U251 cells was studied. Then, the models of cell death at different intervals induced by X-rays combined with nanoparticles were examined. Finally, the mechanisms of cell death were explored.
Sulfonyl chromen-4-ones (CHW09) shows an additive effect to inhibit cell growth of X-ray irradiated oral cancer cells, involving apoptosis and ROS generation
Published in International Journal of Radiation Biology, 2019
Jen-Yang Tang, Chih-Wen Shu, Chun-Lin Wang, Sheng-Chieh Wang, Meng-Yang Chang, Li-Ching Lin, Hsueh-Wei Chang
Radiotherapy is one of the common treatments for cancer. According to the complex causation, etiology and proliferation of cancer, multiple therapeutic treatments including combinations of radiation and anticancer drugs have been developed, for example in oral cancer therapy (Hartner 2018; Lin 2018). Several synthetic or natural chemical agents are used to sensitize cancer tissues for subsequent radiotherapeutic treatment (Yang et al. 2011; Bigdeli et al. 2016; Chang et al. 2016; Cheng et al. 2018; Choi et al. 2018; da Costa Araldi et al. 2018; Gong et al. 2018; Park et al. 2018). An ideal radiosensitizer can enhance the efficiency of radiotherapy against cancerogenic tissues and is tolerated by normal tissues. Drug discovery for suitable radiosensitizers in cancer therapy remains a challenge.
Evaluation of combined effect of hyperthermia and ionizing radiation on cytotoxic damages induced by IUdR-loaded PCL-PEG-coated magnetic nanoparticles in spheroid culture of U87MG glioblastoma cell line
Published in International Journal of Radiation Biology, 2018
Parisa Rezaie, Samideh Khoei, Sepideh Khoee, Sakine Shirvalilou, Seied Rabi Mahdavi
Thus, to avoid such undesirable outcomes, strategies that sensitize the tumor cells to ionizing radiation (IR) are used. Use of the radiosensitizer caused increased tumor radiosensitivity or diminished ionizing radiation side effects (Khoei et al. 2011). IUdR is a known radiosensitizer. These halogenated thymidine analogues are incorporated into DNA instead of thymidine during replication in the synthetic phase and increase the radiosensitization of tumor cells (Aziz et al. 2009). The degree of cell sensitization reflects the amount of thymidine replacement in the replicating DNA (Williams et al. 2008). IUdR reaction with hydrated electrons caused by ionized rays creates reacting uracil free radicals and halide ions, and finally induces formation of single strand break (SSB) and double strand break (DSB) and leads to cell death (Kinsella et al. 2007). However, extremely rapid degradation of these compounds with the short biological half-life (only 5–7 min) and nonselective uptake by all proliferating cells (whether normal or tumour cells) such as bone marrow, have constituted the serious drawbacks to use of IUdR for tumor targeting after systemic administration (Mariani et al. 1996). Nanoparticles can be used to overcome these restrictions. Therefore, an exciting potential solution for this problem is incorporating the drug into biocompatible and biodegradable nanoparticles (Meidanchi et al. 2015).
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