吉西他滨
核苷酸还原酶
抗代谢物
胸苷酸合酶
癌症研究
DNA修复
核苷类似物
放射增敏剂
医学
化疗
核苷
放射治疗
氟尿嘧啶
DNA
生物
内科学
生物化学
蛋白质亚单位
基因
作者
Donna S. Shewach,Theodore S. Lawrence
标识
DOI:10.1200/jco.2007.11.5287
摘要
Radiosensitization with antimetabolites has improved clinical outcome for patients with solid malignancies, especially cancers of the GI tract, cervix, and head and neck. Fluorouracil (FU) and hydroxyurea have been widely used clinically during the last four decades, and promising results have been observed more recently with gemcitabine. Although the antimetabolites all target DNA replication, they differ with respect to the mechanisms by which they produce radiosensitization. The antimetabolite radiosensitizers may inhibit thymidylate synthase (TS) or ribonucleotide reductase, and the nucleoside/nucleobase analogs can be incorporated into DNA. Radiosensitization can result from chemotherapy-induced increase in DNA double-strand breaks or inhibition of their repair. Studies of repair pathways involved in radiosensitization with antimetabolites implicate base excision repair with the TS inhibitors, homologous recombination with gemcitabine, and mismatch repair with FU and gemcitabine. Gemcitabine can also stimulate epidermal growth factor receptor (EGFR) phosphorylation; inhibiting this effect with EGFR inhibitors can potentiate cytotoxicity and radiosensitization. Additional work is necessary to determine more precisely the processes by which antimetabolites act as radiation sensitizers and to define the optimal sequencing of these agents with EGFR inhibitors to provide better guidance for clinical protocols combining these drugs with radiotherapy.
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