Department of Biochemistry and Molecular Biology, Omaha, NE, United States.
Fred & Pamela Buffett Cancer Center, Omaha, NE, United States; Department of Radiation Oncology, Omaha, NE, United States.
Biochim Biophys Acta Rev Cancer. 2017 Aug;1868(1):69-92. doi: 10.1016/j.bbcan.2017.02.003. Epub 2017 Feb 27.
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.
尽管放疗技术最近取得了进展，但由于存在内在和获得性放射抵抗，大多数被诊断为胰腺癌 (PC) 的患者并未获得客观反应。鉴定影响放疗疗效的分子机制并针对这些途径进行靶向治疗对于改善 PC 患者的放疗反应至关重要。在这篇综述中，我们总结了与 PC 放射抵抗表型相关的分子机制。简而言之，我们讨论了放疗的可逆和不可逆生物学后果，如 DNA 损伤和 DNA 修复、放疗后癌细胞存活和辐射诱导细胞凋亡的机制。我们进一步描述了目前在临床前和临床研究中作为 PC 潜在放射增敏剂测试的各种小分子抑制剂和分子靶向药物。值得注意的是，我们提请注意在 PC 放射抵抗和放射增敏的背景下，癌症干细胞、免疫系统和肿瘤微环境的混杂影响。最后，我们讨论了根据与 PC 放疗相关的非靶向组织辐射毒性的新出现证据，检查选择性放射保护剂的必要性。
