Department of Medical Oncology Center, Bayi Affiliated Hospital of Nanjing University of Chinese Medicine; Yanggongjing 34 Biao No. 34, Qinhuai Distrct, Nanjing City, Jiangsu Province, 210002, China.
Nanjing University of Chinese Medicine; No. 138 Xianlin Road, Qixia District, Nanjing City, Jiangsu Province, 210023, China.
J Pharmacol Sci. 2023 Jun;152(2):69-75. doi: 10.1016/j.jphs.2023.03.004. Epub 2023 Mar 30.
AST-3424 is a novel specific aldo-keto reductase 1C3 (AKR1C3) prodrug that releases a DNA alkylating reagent upon reduction by AKR1C3. This study aimed to evaluate the efficacy and safety of AST-3424 in patient-derived tumor xenograft (PDTX) model and orthotopic model against hepatocellular carcinoma (HCC).
PDTX models derived from three HCC patients and orthotopic mice models using HepG2 cells were developed. The mice were treated with AST-3424 alone or combined with other drugs (oxaliplatin, apatinib, sorafenib and elemene in PDTX models, oxaliplatin and 5- fluorouracil in orthotopic models). The tumor volume and weight, as well as the mice weight were assessed. The liver tumor and transplanted tumor were removed for histological, immunohistochemical and Western blot detection in orthotopic model experiments.
AST-3424 could inhibit tumor growth in HCC PDTX models and orthotopic models, with no difference in safety compared with other marketed drugs, and the drug combination did not increase toxicity. The inhibitory effect of combination treatment was more obvious than which used alone. The reduction of AKR1C3 expression was negatively correlated with AST-3424 dose.
AST-3424 had a promising effect against HCC in PDTX model and orthotopic model with good safety. It could promote the sensitivity of other drugs without increasing toxicity. Clinical trials are warranted to further certify its antitumor effect and safety.
AST-3424 是一种新型的特异性醛酮还原酶 1C3（AKR1C3）前药，在被 AKR1C3 还原后释放出一种 DNA 烷化试剂。本研究旨在评估 AST-3424 在肝癌患者来源肿瘤异种移植（PDTX）模型和原位模型中的疗效和安全性。
建立了源自三名肝癌患者的 PDTX 模型和使用 HepG2 细胞的原位小鼠模型。小鼠单独或联合其他药物（奥沙利铂、阿帕替尼、索拉非尼和艾素在 PDTX 模型中，奥沙利铂和 5-氟尿嘧啶在原位模型中）接受 AST-3424 治疗。评估肿瘤体积和重量以及小鼠体重。在原位模型实验中，切除肝肿瘤和移植瘤，进行组织学、免疫组织化学和 Western blot 检测。
AST-3424 可抑制 HCC PDTX 模型和原位模型中的肿瘤生长，与其他市售药物相比安全性无差异，且药物联合并未增加毒性。联合治疗的抑制效果比单独使用更为明显。AKR1C3 表达的减少与 AST-3424 剂量呈负相关。
AST-3424 在 PDTX 模型和原位模型中对 HCC 具有良好的安全性和有前景的疗效。它可以提高其他药物的敏感性而不增加毒性。需要进行临床试验以进一步证实其抗肿瘤作用和安全性。
