Assessment of hypoxia-targeting therapy for gastrointestinal lymphoma in dogs: Preclinical test using murine models
Assessment of hypoxia-targeting therapy for gastrointestinal lymphoma in dogs: Preclinical test using murine models
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DOI：
10.1016/j.rvsc.2022.11.003
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发表时间：
2022-11-17
影响因子：
2.4
通讯作者：
Akiyoshi, Hideo
中科院分区：
文献类型：
--
作者：
Yamazaki, Hiroki;Tanaka, Toshiyuki;Akiyoshi, Hideo
转录因子缺氧诱导因子1 α (HIF-1 α)在几种肿瘤中表达，这种肿瘤在发病过程中出现肿瘤内缺氧应激，导致恶性进展。我们之前报道过缺氧刺激通过激活HIF-1 α信号通路来增强犬淋巴瘤细胞的生长潜力。相比之下，Evo在低氧肿瘤区域释放dna烷基化片段，提示Evo可作为犬淋巴瘤的低氧靶向药物。本研究旨在利用Evo评估低氧靶向治疗犬胃肠道淋巴瘤（GIL）的效果，并研究Evo如何影响三种t细胞GIL小鼠异种移植模型的抗肿瘤疗效和不良事件。在体外实验中，三种t细胞GIL细胞系在缺氧培养条件下对Evo的敏感性显著高于常氧培养条件下的敏感性。我们的代谢分析表明，这三种小鼠模型作为犬GIL的临床病例可能具有很高的再现性。我们的数据显示，与洛莫司汀相比，Evo在三种类型的小鼠模型中显示出更高的肿瘤生长潜力和更少的不良事件；CeeNu (CCNU)。此外，Evo还能抑制肿瘤组织中HIF-1 α蛋白的表达，提示其可能优先靶向并抑制低氧区肿瘤细胞。这里提出的证据支持有利的临床前评估，即Evo可能对狗的GIL有效。
The transcription factor hypoxia-inducible factor 1 alpha (HIF-1 alpha) is expressed in several cancers under intratumoral hypoxic stress that arises during pathogenic processes, resulting in malignant progression. We previously re -ported that hypoxic stimulation enhances the growth potential of canine lymphoma cells by activating the HIF-1 alpha signaling pathway. In contrast, evofosfamide (Evo) releases a DNA-alkylating moiety within hypoxic tumor re-gions, suggesting that Evo could serve as a hypoxia-targeting drug in canine lymphoma. This study aimed to use Evo to evaluate hypoxia-targeted therapy in dogs with gastrointestinal lymphoma (GIL) and investigate how Evo affects antitumor efficacy and adverse events in three type of murine xenograft models using T-cell GIL cells. In vitro tests, the sensitivity to Evo of three T-cell GIL cell lines under hypoxic culture was significantly higher than that under normoxic culture. Our metabolic analysis suggested that the three murine models might have high reproducibility as clinical cases in canine GIL. Our data showed that Evo showed significantly higher tumor growth potential and fewer adverse events in three type of murine models compared to lomustine; CeeNu (CCNU). Additionally, Evo suppressed the expression of HIF-1 alpha protein in tumor tissues, suggesting that it may preferentially target and inhibit tumor cells in a hypoxic region. The evidence presented here supports the favorable preclinical evaluation that Evo may be effective for GIL in dogs.