Ono Takahiro, Sasajima Toshio, Doi Yoshihiro, Oka Shuntaro, Ono Masahiro, Kanagawa Masaru, Baden Atsumi, Mizoi Kazuo, Shimizu Hiroaki
Department of Neurosurgery, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan.
Department of Neurosurgery, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan.
Nucl Med Biol. 2015 Jul;42(7):598-607. doi: 10.1016/j.nucmedbio.2015.01.008. Epub 2015 Jan 31.
We examined whether the amino acid PET tracers, trans-1-amino-3-(18)F-fluorocyclobutanecarboxylic acid (anti-(18)F-FACBC) and (11)C-methyl-l-methionine ((11)C-Met), are suitable for detecting early responses to combination therapies including temozolomide (TMZ), interferon-β (IFN), and bevacizumab (Bev) in glioblastoma.
Human glioblastoma U87MG (U87) cells were incubated with low dose TMZ to induce chemoresistance. Both trans-1-amino-3-fluoro-1-(14)C-cyclobutanecarboxylic acid (anti-(14)C-FACBC) and (3)H-methyl-l-methionine ((3)H-Met) uptake were quantified using triple-label accumulation assays to examine the relationship between tracer uptake and proliferation ((3)H-thymidine (TdR) accumulation) in vitro. U87 and U87R (TMZ-resistant subculture) cells were inoculated into the right and left basal ganglia, respectively, of F344/N-rnu rats. The efficacy of single-agent (TMZ, Bev) and combination therapy (TMZ/IFN, TMZ/Bev, TMZ/IFN/Bev) was examined in orthotopic gliomas using MRI, Evans blue extravasation, anti-(14)C-FACBC, and (3)H-Met autoradiography, and MIB-1 immunostaining.
TMZ treatment decreased (3)H-TdR accumulation and the volume distribution of anti-(14)C-FACBC and (3)H-Met in U87 but not U87R cells. TMZ/IFN combination therapy significantly decreased these parameters in U87R cells; however, Bev had no additional effect in vitro. In vivo, U87R-derived gliomas were observed as equivocal tumors on MRI and T2-high intensity lesions. Bev treatment, either alone or in combination, markedly decreased U87 enhancing lesions. By contrast, autoradiographic images using anti-(14)C-FACBC and (3)H-Met clearly delineated tumor extent, which spread widely beyond T2-high intensity lesions and enhancing lesions. TMZ therapy significantly decreased tracer accumulation and proliferation of U87- but not U87R-derived tumors. TMZ/IFN combination treatment significantly decreased these parameters in U87R tumors, which were further reduced (in both tumor types) by Bev addition. Tracer uptake correlated with the MIB-1 proliferation index. However, MRI was unsuitable for tumor delineation and assessment of Bev treatment response.
Triple-agent therapy (TMZ/IFN/Bev) was effective against even TMZ-resistant glioblastomas. PET with amino acid tracers provides useful information on the early response of glioblastomas to single-agent and combination therapy.
我们研究了氨基酸正电子发射断层显像（PET）示踪剂反式-1-氨基-3-（18）F-氟环丁烷羧酸（anti-（18）F-FACBC）和（11）C-甲基-L-蛋氨酸（（11）C-Met）是否适用于检测胶质母细胞瘤中对包括替莫唑胺（TMZ）、干扰素-β（IFN）和贝伐单抗（Bev）在内的联合治疗的早期反应。
用人胶质母细胞瘤U87MG（U87）细胞与低剂量TMZ孵育以诱导化学抗性。使用三标记积累测定法定量反式-1-氨基-3-氟-1-（14）C-环丁烷羧酸（anti-（14）C-FACBC）和（3）H-甲基-L-蛋氨酸（（3）H-Met）的摄取，以检查体外示踪剂摄取与增殖（（3）H-胸腺嘧啶核苷（TdR）积累）之间的关系。将U87和U87R（TMZ抗性亚培养物）细胞分别接种到F344/N-rnu大鼠的右侧和左侧基底神经节中。使用磁共振成像（MRI）、伊文思蓝外渗、anti-（14）C-FACBC和（3）H-Met放射自显影以及MIB-1免疫染色，在原位胶质瘤中检查单药治疗（TMZ、Bev）和联合治疗（TMZ/IFN、TMZ/Bev、TMZ/IFN/Bev）的疗效。
TMZ治疗降低了U87细胞中（3）H-TdR积累以及anti-（14）C-FACBC和（3）H-Met的体积分布，但对U87R细胞没有影响。TMZ/IFN联合治疗显著降低了U87R细胞中的这些参数；然而，Bev在体外没有额外作用。在体内，U87R衍生的胶质瘤在MRI上表现为可疑肿瘤，T2加权像上呈高信号病变。单独或联合使用Bev治疗均显著减少了U87增强病变。相比之下，使用anti-（14）C-FACBC和（3）H-Met的放射自显影图像清楚地描绘了肿瘤范围，其广泛超出T2加权像高信号病变和增强病变。TMZ治疗显著降低了U87衍生肿瘤而非U87R衍生肿瘤的示踪剂积累和增殖。TMZ/IFN联合治疗显著降低了U87R肿瘤中的这些参数，添加Bev后（两种肿瘤类型）这些参数进一步降低。示踪剂摄取与MIB-1增殖指数相关。然而，MRI不适用于肿瘤描绘和评估Bev治疗反应。
三联疗法（TMZ/IFN/Bev）即使对TMZ抗性胶质母细胞瘤也有效。使用氨基酸示踪剂的PET可为胶质母细胞瘤对单药治疗和联合治疗的早期反应提供有用信息。
