Takami Haruna, Imura Yoshinori, Outani Hidetatsu, Nakai Sho, Inoue Akitomo, Kotani Yuki, Okada Seiji, Kaneda-Nakashima Kazuko
Department of Orthopaedic Surgery, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
Radiation Biological Chemistry, MS-CORE, FRC, Graduate School of Science, Osaka University, Osaka 560-0043, Japan.
Int J Mol Sci. 2025 Sep 4;26(17):8599. doi: 10.3390/ijms26178599.
Malignant bone and soft tissue tumors are often resistant to conventional treatment, and treatment options for unresectable and metastatic cases are limited. L-type amino acid transporter 1 (LAT1) is overexpressed in several malignancies, including sarcomas, making it an attractive target for targeted alpha therapy. In this study, we investigated the therapeutic efficacy of LAT1-targeted alpha therapy using a novel modified 3-astatin-211 Astato-α-methyl-L-tyrosine (At-AAMT) for bone and soft tissue sarcomas. LAT1 expression and the specificity of LAT1-mediated uptake of At-AAMT were evaluated in bone and soft tissue sarcoma cell lines. Antiproliferative effects were assessed using cell viability and colony formation assays. DNA damage was assessed using immunostaining with phosphorylated histone γH2AX. In vivo efficacy of At-AAMT, determined using xenograft mouse models, was compared with that of doxorubicin. LAT1 was highly expressed in all cell lines, especially MP-CCS-SY and MG-63 cells. At-AAMT uptake was LAT1-dependent and significant in all cell lines. It inhibited cell proliferation in a dose-dependent manner, comparable to that of doxorubicin. In xenograft models, a single administration of At-AAMT significantly inhibited tumor growth without systemic toxicity, whereas doxorubicin caused weight loss. Histopathological analysis showed reduced cell density, inhibited proliferation, and extensive DNA damage in tumors treated with At-AAMT, whereas LAT1 expression was maintained in residual tumor tissues. LAT1-targeted alpha therapy with At-AAMT demonstrated antitumor efficacy comparable to that of first-line chemotherapy for osteosarcoma and soft tissue sarcoma. Sustained LAT1 expression suggests the potential for repeated or combination treatments, highlighting its promise as a novel therapy for advanced, treatment-resistant sarcomas.
恶性骨和软组织肿瘤通常对传统治疗有抗性，对于不可切除和转移性病例的治疗选择有限。L型氨基酸转运体1（LAT1）在包括肉瘤在内的多种恶性肿瘤中过表达，使其成为靶向α治疗的一个有吸引力的靶点。在本研究中，我们使用新型修饰的3-他汀-211阿斯塔托-α-甲基-L-酪氨酸（At-AAMT）研究了针对骨和软组织肉瘤的LAT1靶向α治疗的疗效。在骨和软组织肉瘤细胞系中评估了LAT1表达以及LAT1介导的At-AAMT摄取的特异性。使用细胞活力和集落形成试验评估抗增殖作用。使用磷酸化组蛋白γH2AX免疫染色评估DNA损伤。使用异种移植小鼠模型确定的At-AAMT的体内疗效与多柔比星的疗效进行了比较。LAT1在所有细胞系中均高表达，尤其是MP-CCS-SY和MG-63细胞。At-AAMT摄取是LAT1依赖性的，并且在所有细胞系中均显著。它以剂量依赖性方式抑制细胞增殖，与多柔比星相当。在异种移植模型中，单次给予At-AAMT可显著抑制肿瘤生长且无全身毒性，而多柔比星导致体重减轻。组织病理学分析显示，At-AAMT治疗的肿瘤中细胞密度降低、增殖受抑制且有广泛的DNA损伤，而残余肿瘤组织中LAT1表达得以维持。用At-AAMT进行的LAT1靶向α治疗显示出与骨肉瘤和软组织肉瘤一线化疗相当的抗肿瘤疗效。持续的LAT1表达表明重复或联合治疗的潜力，突出了其作为晚期、难治性肉瘤新疗法的前景。
