Yanazume Shintaro, Fang Jun, Islam Rayhanul, Gao Shanghui, Kobayashi Hiroaki
Department of Obstetrics & Gynecology, Faculty of Medicine, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan.
Faculty of Pharmaceutical Sciences, Sojo University, Ikeda 4-22-1, Nishi-ku, Kumamoto 860-0082, Japan.
J Pers Med. 2022 May 18;12(5):814. doi: 10.3390/jpm12050814.
Anthracyclines are important for the treatment of gynecological malignancies, but their effects are modest, and one of the major reasons is the lack of a tumor-targeting property. To overcome this drawback, a poly (hydroxypropyl meta-acrylamide) conjugated with tetrahydropyraryl doxorubicin (P-THP) has been developed, which exhibits a highly tumor-specific accumulation owing to the enhanced permeability and retention effect. The effect of P-THP has been confirmed by using various cell lines and solid tumor models, while its effect on gynecological malignancies have not been investigated. In this regard, human uterine sarcoma cell line with metastatic potential MEA-SA C9 high, epithelial ovarian cancer cell line A2780 and its cisplatin-resistant line A2780cis, and DOX-resistant line A2780ADR were used in this study, and the therapeutic effect as well as the safety profiles of P-THP were investigated compared to native THP, cisplatin, and paclitaxel, which are commonly used for gynecological malignancies, both in vitro and in vivo. Similar to native THP, a dose-dependent toxicity of P-THP was identified in all cell lines. Moreover, the IC50 values in the 3 h following P-THP were 1.5-10 times higher than those at 72 h, though the intracellular uptake of P-THP in all cells were 2-10-fold less than THP. In vivo studies using xenograft tumor models revealed that P-THP significantly suppressed the MES-SA C9 high, A2780, and A2780cis tumor growth at the dose of 15 mg/kg (THP equivalent), which is three times above the maximal tolerance dose of native THP, while no body weight loss or acute death occurred. However, in A2780ADR cells and the xenograft model, no significant difference in the therapeutic effect was observed between THP and P-THP, suggesting that P-THP exhibits its effect depending on the release of the active free THP in tumor tissues, and thus the internalization into tumor cells. These findings indicates that P-THP has the potential as a therapeutic for gynecological malignancies to improve the therapeutic outcomes and survival rates of patients, even in refractory patients.
蒽环类药物对妇科恶性肿瘤的治疗很重要，但其效果一般，主要原因之一是缺乏肿瘤靶向性。为克服这一缺点，已开发出一种与四氢吡喃基阿霉素共轭的聚（羟丙基间丙烯酰胺）（P - THP），由于增强的渗透和滞留效应，它表现出高度的肿瘤特异性蓄积。P - THP的效果已通过多种细胞系和实体瘤模型得到证实，但其对妇科恶性肿瘤的影响尚未研究。在这方面，本研究使用了具有转移潜能的人子宫肉瘤细胞系MEA - SA C9 high、上皮性卵巢癌细胞系A2780及其顺铂耐药系A2780cis以及阿霉素耐药系A2780ADR，并在体外和体内研究了P - THP与常用于妇科恶性肿瘤的天然THP、顺铂和紫杉醇相比的治疗效果及安全性。与天然THP类似，在所有细胞系中均发现P - THP具有剂量依赖性毒性。此外，P - THP作用3小时后的IC50值比72小时时高1.5至10倍，尽管所有细胞中P - THP的细胞内摄取量比THP少2至10倍。使用异种移植肿瘤模型的体内研究表明，P - THP以15 mg/kg（THP等效剂量）的剂量可显著抑制MES - SA C9 high、A2780和A2780cis肿瘤生长，该剂量是天然THP最大耐受剂量的三倍，且未发生体重减轻或急性死亡。然而，在A2780ADR细胞和异种移植模型中，THP和P - THP之间未观察到治疗效果的显著差异，这表明P - THP的作用取决于肿瘤组织中活性游离THP的释放以及因此进入肿瘤细胞的内化过程。这些发现表明，P - THP有潜力作为妇科恶性肿瘤的治疗药物，以改善患者的治疗效果和生存率，即使是难治性患者。
