Division of Hematology, London Health Sciences Centre, London, Ontario, Canada.
Clin Cancer Res. 2011 Oct 15;17(20):6373-80. doi: 10.1158/1078-0432.CCR-10-2577. Epub 2011 Jul 12.
Over the past few decades, understanding of the physiologic function of erythropoietin (EPO) has evolved significantly. EPO binds to erythropoietin receptors (EPOR), initiating signaling that stimulates growth, inhibits apoptosis, and induces the differentiation of erythroid progenitors to increase red blood cell mass. EPO has additionally been shown to exert tissue-protective effects on multiple tissues, suggesting a pleiotropic mechanism of action. Erythropoiesis-stimulating agents (ESA) are used clinically for treating cancer-related anemia [chemotherapy-induced anemia (CIA)]. Recent clinical trials have reported increased adverse events and/or reduced survival in ESA-treated cancer patients receiving chemotherapy, potentially related to EPO-induced cancer progression. Signaling pathways downstream of EPO/EPOR have been shown to influence numerous cellular functions in both normal and tumor cells, including proliferation, apoptosis, and drug resistance. Some studies have reported effects on proliferation, reduced chemotherapy efficacy, reduction of apoptosis, and resistance to selective therapies on cancer cell lines, whereas others have shown null effects. In addition, newer targeted cancer therapies that are directed toward specific signaling pathways may be antagonized by ESAs. This molecular interplay between anticancer agents and potential survival signals triggered by ESAs may have been underestimated and may contribute toward decreased survival seen in certain trials. As more targeted anticancer therapies become available, these types of interactions may mitigate therapeutic efficacy by allowing tumor cells to acquire drug resistance. Therefore, a more complete understanding of the complex pathways involved will allow for the rational use of ESAs for the safe treatment of CIA in oncology patients.
在过去的几十年中，人们对促红细胞生成素（EPO）的生理功能的理解有了显著的发展。EPO 与促红细胞生成素受体（EPOR）结合，启动信号通路，刺激生长、抑制凋亡，并诱导红系祖细胞分化，以增加红细胞量。此外，EPO 还显示出对多种组织的组织保护作用，表明其具有多效性作用机制。促红细胞生成素刺激剂（ESA）临床上用于治疗癌症相关贫血（化疗引起的贫血，CIA）。最近的临床试验报告称，接受化疗的 ESA 治疗的癌症患者的不良反应增加和/或生存率降低，这可能与 EPO 诱导的癌症进展有关。EPO/EPOR 下游的信号通路已被证明会影响正常和肿瘤细胞中的许多细胞功能，包括增殖、凋亡和耐药性。一些研究报告称，ESA 对增殖有影响、降低化疗疗效、减少凋亡和对癌症细胞系的选择性治疗产生耐药性，而其他研究则显示无影响。此外，针对特定信号通路的新型靶向癌症疗法可能会被 ESAs 拮抗。抗癌药物与 ESAs 触发的潜在生存信号之间的这种分子相互作用可能被低估了，并且可能导致某些试验中生存率降低。随着更多的靶向抗癌疗法的出现，这些类型的相互作用可能会通过使肿瘤细胞获得耐药性来减轻治疗效果。因此，更全面地了解所涉及的复杂途径将允许合理使用 ESAs 来安全治疗肿瘤患者的 CIA。
