Yoshioka Koki, Furuta Taisuke, Sakuda Tomohiko, Oda Akihiro, Ikeda Yutaka, Miyaki Shigeru, Nagasaki Yukio, Adachi Nobuo
Department of Orthopaedic Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
Department of Orthopaedic Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
Anticancer Res. 2025 Jul;45(7):2905-2916. doi: 10.21873/anticanres.17658.
BACKGROUND/AIM: Doxorubicin (DOX) is the most impactful drug developed for osteosarcoma. However, despite its therapeutic effects, it also causes serious side effects, such as cardiotoxicity and hemotoxicity. To address this, we developed a novel DOX prodrug that exhibits high antitumor activity specifically in hypoxic regions while demonstrating low toxicity in normal organs. Based on these properties, we evaluated its efficacy against osteosarcoma with the aim of significantly reducing side effects while maintaining therapeutic efficacy.
To evaluate antitumor effects, tumor diameter changes were measured in osteosarcoma cell line-bearing mice divided into the following groups: control, DOX 8 mg/kg, DOX prodrug 8 mg/kg, and 5 doses of DOX prodrug 16 mg/kg every other day. To evaluate side effects, blood samples were collected 2 weeks after treatment in all groups to determine the complete blood count and aspartate aminotransferase, alanine aminotransferase, creatinine, and blood urea nitrogen levels. After the mice were sacrificed, sections of the liver, kidney, heart, and testes were prepared for histological evaluation.
Regarding antitumor effects, the DOX and DOX prodrug groups showed comparable reductions in tumor size when compared to the control group. Blood test results showed that mice in the DOX prodrug group had no leukopenia or liver dysfunction. Histological evaluation revealed that the DOX prodrug group showed significantly less myocardial damage and gonadal toxicity compared to the DOX group.
The DOX prodrug developed by our group showed tumor-suppressive effects comparable to those of DOX while being able to suppress blood toxicity, cardiotoxicity, as well as liver and testicular dysfunction.
背景/目的：阿霉素（DOX）是开发用于骨肉瘤的最具影响力的药物。然而，尽管它具有治疗效果，但也会引起严重的副作用，如心脏毒性和血液毒性。为了解决这个问题，我们开发了一种新型的阿霉素前药，它在缺氧区域具有高抗肿瘤活性，而在正常器官中表现出低毒性。基于这些特性，我们评估了其对骨肉瘤的疗效，目的是在保持治疗效果的同时显著减少副作用。
为了评估抗肿瘤效果，在分为以下几组的荷骨肉瘤细胞系小鼠中测量肿瘤直径变化：对照组、8mg/kg阿霉素组、8mg/kg阿霉素前药组以及每隔一天给予5剂16mg/kg阿霉素前药组。为了评估副作用，在治疗2周后收集所有组的血样以测定全血细胞计数以及天冬氨酸转氨酶、丙氨酸转氨酶、肌酐和血尿素氮水平。在处死小鼠后，制备肝脏、肾脏、心脏和睾丸切片用于组织学评估。
关于抗肿瘤效果，与对照组相比，阿霉素组和阿霉素前药组的肿瘤大小均有类似程度的减小。血液检测结果显示，阿霉素前药组的小鼠没有白细胞减少或肝功能障碍。组织学评估显示，与阿霉素组相比，阿霉素前药组的心肌损伤和性腺毒性明显更小。
我们小组开发的阿霉素前药显示出与阿霉素相当的肿瘤抑制作用，同时能够抑制血液毒性、心脏毒性以及肝脏和睾丸功能障碍。
