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Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, 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
Published in John C Watkinson, Raymond W Clarke, Terry M Jones, Vinidh Paleri, Nicholas White, Tim Woolford, Head & Neck Surgery Plastic Surgery, 2018
Kevin J. Harrington, Magnus T. Dillon
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.
Gastrinoma (Zollinger–Ellison syndrome) and rare neuroendocrine tumors
Published in Demetrius Pertsemlidis, William B. Inabnet III, Michel Gagner, Endocrine Surgery, 2017
Other TMZ-based combination regimens have been studied in small cohorts in single-arm studies, but also look promising. TMZ with 177Lu-octreotate and capecitabine resulted in an overall radiological response rate or objective response rate (ORR) of 82% [145]. In this regimen, the tumor response determined by RECIST was thought to be due to the 177Lu-octreotate and the PFS due to the capecitabine and TMZ combination therapy. In addition, the chemotherapy acted as a radiosensitizer. TMZ combined with antiangiogenic compounds shows efficacy: TMZ with bevacizumab, TMZ with bevacizumab and long-acting octreotide, and TMZ with thalidomide [142–144].
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.
Capecitabine for the treatment of pancreatic cancer
Published in Expert Opinion on Pharmacotherapy, 2019
Nauman S. Siddiqui, Amandeep Godara, Margaret M. Byrne, Muhammad Wasif Saif
The convenience of oral administration cannot be more emphasized in the palliative setting and that the fact that myelosuppression is relatively less common with capecitabine compared to intravenous 5-FU. However, the known toxicities of capecitabine such as diarrhea and HFS may compromise its efficacy [56,57]. In the U.S.A., it is difficult to administer capecitabine 1250mg/m2 twice daily for 14 days without experiencing toxicities requiring dose reduction [27]. Though many factors have been postulated include folate fortification in food in U.S.A., pharmacogenetics or BSA. To aid this matter, we have evaluated two different strategies, including addition of PHY-906 (herbal medicine) to mitigate toxicity [60] and 7/7 schedule, similar to a study by investigators from Germany [39]. Moreover, to define its role as a radiosensitizer, we developed a dose of 800mg/m2 to be administered only Monday-through-Friday with concurrent radiotherapy and no capecitabine during the weekend, something that allowed dose intensity to be maintained and less toxicity.
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).