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Abstract：
BACKGROUND: Renal cell carcinoma (RCC) was historically considered to be less responsive to radiation therapy (RT) compared to other cancer indications. However, advancements in precision high-dose radiation delivery through single-fraction and multi-fraction stereotactic ablative radiotherapy (SABR) have led to better outcomes and reduced treatment-related toxicities, sparking renewed interest in using RT to treat RCC. Moreover, numerous studies have revealed that certain therapeutic agents including chemotherapies can increase the sensitivity of tumors to RT, leading to a growing interest in combining these treatments. Here, we developed a rational combination of two radiosensitizers in a tumor-targeted liposomal formulation for augmenting RT in RCC. The objective of this study is to assess the efficacy of a tumor-targeted liposomal formulation combining the mTOR inhibitor everolimus (E) with the survivin inhibitor YM155 (Y) in enhancing the sensitivity of RCC tumors to radiation.
METHODS: We slightly modified our previously published tumor-targeted liposomal formulation to develop a rational combination of E and Y in a single liposomal formulation (EY-L) and assessed its efficacy in RCC cell lines in vitro and in RCC tumors in vivo. We further investigated how well EY-L sensitizes RCC cell lines and tumors toward radiation and explored the underlying mechanism of radiosensitization.
RESULTS: EY-L outperformed the corresponding single drug-loaded formulations E-L and Y-L in terms of containing primary tumor growth and improving survival in an immunocompetent syngeneic mouse model of RCC. EY-L also exhibited significantly higher sensitization of RCC cells towards radiation in vitro than E-L and Y-L. Additionally, EY-L sensitized RCC tumors towards radiation therapy in xenograft and murine RCC models. EY-L mediated induction of mitotic catastrophe via downregulation of multiple cell cycle checkpoints and DNA damage repair pathways could be responsible for the augmentation of radiation therapy.
CONCLUSIONS: Taken together, our study demonstrated the efficacy of a strategic combination therapy in sensitizing RCC to radiation therapy via inhibition of DNA damage repair and a substantial increase in mitotic catastrophe. This combination therapy may find its use in the augmentation of radiation therapy during the treatment of RCC patients.
METHODS: We slightly modified our previously published tumor-targeted liposomal formulation to develop a rational combination of E and Y in a single liposomal formulation (EY-L) and assessed its efficacy in RCC cell lines in vitro and in RCC tumors in vivo. We further investigated how well EY-L sensitizes RCC cell lines and tumors toward radiation and explored the underlying mechanism of radiosensitization.
RESULTS: EY-L outperformed the corresponding single drug-loaded formulations E-L and Y-L in terms of containing primary tumor growth and improving survival in an immunocompetent syngeneic mouse model of RCC. EY-L also exhibited significantly higher sensitization of RCC cells towards radiation in vitro than E-L and Y-L. Additionally, EY-L sensitized RCC tumors towards radiation therapy in xenograft and murine RCC models. EY-L mediated induction of mitotic catastrophe via downregulation of multiple cell cycle checkpoints and DNA damage repair pathways could be responsible for the augmentation of radiation therapy.
CONCLUSIONS: Taken together, our study demonstrated the efficacy of a strategic combination therapy in sensitizing RCC to radiation therapy via inhibition of DNA damage repair and a substantial increase in mitotic catastrophe. This combination therapy may find its use in the augmentation of radiation therapy during the treatment of RCC patients.
摘要：
背景：历史上认为与其他癌症适应症相比，肾细胞癌（RCC）对放射疗法（RT）的反应较低。然而,通过单部分和多部分立体定向消融放射治疗（SABR）的精确高剂量辐射输送的进步导致了更好的结果和减少治疗相关的毒性，引发了人们对使用RT治疗RCC的新兴趣。此外，许多研究表明，包括化疗在内的某些治疗剂可以增加肿瘤对RT的敏感性，导致对结合这些治疗的兴趣越来越大。这里,我们在肿瘤靶向脂质体制剂中开发了两种放射增敏剂的合理组合,用于增强RCC的RT.本研究的目的是评估结合mTOR抑制剂依维莫司(E)和生存素抑制剂YM155(Y)的肿瘤靶向脂质体制剂在增强RCC肿瘤对放射的敏感性中的功效。
方法:我们稍微修改了我们先前公开的肿瘤靶向脂质体制剂,以开发E和Y在单一脂质体制剂(EY-L)中的合理组合,并评估其在体外RCC细胞系和体内RCC肿瘤中的功效。我们进一步研究了EY-L对RCC细胞系和肿瘤的放射敏感性，并探索了放射增敏的潜在机制。
结果：在具有免疫活性的同基因RCC小鼠模型中，EY-L在包含原发性肿瘤生长和改善存活率方面优于相应的单一载药制剂E-L和Y-L。与E-L和Y-L相比，EY-L还表现出明显更高的体外RCC细胞对辐射的敏感性。此外,在异种移植物和鼠RCC模型中，EY-L对放射治疗敏感的RCC肿瘤。EY-L通过下调多个细胞周期检查点和DNA损伤修复途径介导的有丝分裂突变的诱导可能是增强放射治疗的原因。
结论：综合来看，我们的研究证明了战略性联合治疗通过抑制DNA损伤修复和显著增加有丝分裂突变,使RCC对放射治疗敏感的疗效.这种联合疗法可能会在RCC患者治疗期间用于增强放射疗法。
方法:我们稍微修改了我们先前公开的肿瘤靶向脂质体制剂,以开发E和Y在单一脂质体制剂(EY-L)中的合理组合,并评估其在体外RCC细胞系和体内RCC肿瘤中的功效。我们进一步研究了EY-L对RCC细胞系和肿瘤的放射敏感性，并探索了放射增敏的潜在机制。
结果：在具有免疫活性的同基因RCC小鼠模型中，EY-L在包含原发性肿瘤生长和改善存活率方面优于相应的单一载药制剂E-L和Y-L。与E-L和Y-L相比，EY-L还表现出明显更高的体外RCC细胞对辐射的敏感性。此外,在异种移植物和鼠RCC模型中，EY-L对放射治疗敏感的RCC肿瘤。EY-L通过下调多个细胞周期检查点和DNA损伤修复途径介导的有丝分裂突变的诱导可能是增强放射治疗的原因。
结论：综合来看，我们的研究证明了战略性联合治疗通过抑制DNA损伤修复和显著增加有丝分裂突变,使RCC对放射治疗敏感的疗效.这种联合疗法可能会在RCC患者治疗期间用于增强放射疗法。
