Effects of a combined treatment regimen consisting of Hsp90 inhibitor DS-2248 and radiation in vitro and in a tumor mouse model.
Effects of a combined treatment regimen consisting of Hsp90 inhibitor DS-2248 and radiation in vitro and in a tumor mouse model.
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由Hsp 90抑制剂DS-2248和辐射组成的联合治疗方案在体外和肿瘤小鼠模型中的作用。
DOI：
10.21037/tcr-21-71
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发表时间：
2021-06
影响因子：
0.9
通讯作者：
Matsuo M
中科院分区：
文献类型：
--
作者：
Kondo T;Shibamoto Y;Kawai T;Sugie C;Wang Z;Nakamura K;Murai T;Manabe Y;Nakashima M;Matsuo M
热休克蛋白 90 (HSP90) 是一种分子伴侣，负责多种客户蛋白的构象维持，这些蛋白在 DNA 损伤修复、辐射后细胞凋亡和放射治疗抵抗中发挥重要作用。 DS-2248（三环吡唑并嘧啶衍生物）是一种新开发的口服HSP90抑制剂，不良反应低。我们研究了辐射和 DS-2248 在体外和体内的综合影响。使用SCCVII鳞状细胞癌细胞和移植到C3H/HeN小鼠中的肿瘤。使用菌落测定研究了 X 射线辐射和 DS-2248 的体外联合效应。磷酸化组蛋白 H2AX (γH2AX) 在 2 Gy 照射后进行定量，无论是否经过 DS-2248 24 小时预处理。携带 SCCVII 肿瘤的小鼠在 2 周内接受 10 次口服 DS-2248，并在 2 周内接受 6 次剂量为 1、2、3 和 4 Gy 的局部照射。然后，测量肿瘤体积。放射加 50 nM DS-2248 预处理 24 小时对 SCCVII 细胞产生协同作用。与对照细胞相比，DS-2248 处理的细胞中的 γH2AX 病灶在辐射后持续存在的时间更长（6 小时和 24 小时）。在体内，当 5 或 10 mg/kg DS-2248 与 6-18 Gy 的总辐射剂量组合时，组合效应似乎是相加的，但当 15 mg/kg DS-2248 与 24 Gy 的总辐射剂量组合时，该效应被认为是超相加的。 DS-2248 和辐射的联合作用在低药物和辐射剂量下是相加的，但在较高剂量下可能是超相加的。抑制 DNA 双链断裂的缓慢修复（即同源重组）被认为有助于这种综合效应。
Heat shock protein 90 (HSP90) is a molecular chaperone that is responsible for the conformational maintenance of several client proteins that play important roles in DNA damage repair, apoptosis following radiation, and resistance to radiation therapy. DS-2248 (tricyclic pyrazolopyrimidine derivative) is a newly-developed, orally available inhibitor of HSP90 with low adverse effects. We investigated the combined effects of radiation and DS-2248 in vitro and in vivo. SCCVII squamous cell carcinoma cells and tumors transplanted in C3H/HeN mice were used. In vitro combined effects of X-ray radiation and DS-2248 were investigated using a colony assay. Phosphorylated histone H2AX (γH2AX) was quantified after 2-Gy irradiation with or without 24-hour pretreatment with DS-2248. The mice bearing SCCVII tumors received oral DS-2248 10 times over 2 weeks and received local irradiation with doses of 1, 2, 3, and 4 Gy delivered 6 times over 2 weeks. Then, tumor volumes were measured. Radiation plus pretreatment with 50 nM DS-2248 for 24 hours produced synergistic effects on SCCVII cells. γH2AX foci persisted after radiation for longer periods (6 and 24 hours) in DS-2248-treated cells than in control cells. In vivo, the combined effects appeared to be additive when 5 or 10 mg/kg DS-2248 was combined with total radiation doses of 6–18 Gy, but the effect was considered supra-additive when 15 mg/kg of DS-2248 was combined with a total dose of 24 Gy. The combined effects of DS-2248 and radiation were additive at low drug and radiation doses, but may have been supra-additive at higher doses. Inhibition of slow repair of DNA double strand breaks (i.e., homologous recombination) was considered to contribute to this combined effect.
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影响因子：
4
作者：
Hirakawa, Hirokazu;Fujisawa, Hiroshi;Masaoka, Aya;Noguchi, Miho;Hirayama, Ryoichi;Takahashi, Momoko;Fujimori, Akira;Okayasu, Ryuichi
通讯作者：
Okayasu, Ryuichi
影响因子：
3.6
作者：
Chettiar ST;Malek R;Annadanam A;Nugent KM;Kato Y;Wang H;Cades JA;Taparra K;Belcaid Z;Ballew M;Manmiller S;Proia D;Lim M;Anders RA;Herman JM;Tran PT
通讯作者：
Tran PT
影响因子：
4.6
作者：
Spiegelberg, Diana;Abramenkovs, Andris;Stenerlow, Bo
通讯作者：
Stenerlow, Bo
影响因子：
3.4
作者：
SHIBAMOTO, Y;STREFFER, C;BUDACH, V
通讯作者：
BUDACH, V
影响因子：
45.3
作者：
Sequist, Lecia V.;Gettinger, Scott;Natale, Ronald
通讯作者：
Natale, Ronald