Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Clin Cancer Res. 2011 Mar 1;17(5):1099-110. doi: 10.1158/1078-0432.CCR-10-1430. Epub 2011 Jan 18.
To determine whether treatment response to the Aurora B kinase inhibitor, AZD1152, could be monitored early in the course of therapy by noninvasive [(18)F]-labeled fluoro-2-deoxyglucose, [(18)F]FDG, and/or 3'-deoxy-3'-[(18)F]fluorothymidine, [(18)F]FLT, PET imaging.
AZD1152-treated and control HCT116 and SW620 xenograft-bearing animals were monitored for tumor size and by [(18)F]FDG, and [(18)F]FLT PET imaging. Additional studies assessed the endogenous and exogenous contributions of thymidine synthesis in the two cell lines.
Both xenografts showed a significant volume-reduction to AZD1152. In contrast, [(18)F]FDG uptake did not demonstrate a treatment response. [(18)F]FLT uptake decreased to less than 20% of control values in AZD1152-treated HCT116 xenografts, whereas [(18)F]FLT uptake was near background levels in both treated and untreated SW620 xenografts. The EC(50) for AZD1152-HQPA was approximately 10 nmol/L in both SW620 and HCT116 cells; in contrast, SW620 cells were much more sensitive to methotrexate (MTX) and 5-Fluorouracil (5FU) than HCT116 cells. Immunoblot analysis demonstrated marginally lower expression of thymidine kinase in SW620 compared with HCT116 cells. The aforementioned results suggest that SW620 xenografts have a higher dependency on the de novo pathway of thymidine utilization than HCT116 xenografts.
AZD1152 treatment showed antitumor efficacy in both colon cancer xenografts. Although [(18)F]FDG PET was inadequate in monitoring treatment response, [(18)F]FLT PET was very effective in monitoring response in HCT116 xenografts, but not in SW620 xenografts. These observations suggest that de novo thymidine synthesis could be a limitation and confounding factor for [(18)F]FLT PET imaging and quantification of tumor proliferation, and this may apply to some clinical studies as well.
通过非侵入性[(18)F]-标记氟代-2-脱氧葡萄糖、[(18)F]FDG 和/或 3'-脱氧-3'-[(18)F]氟胸苷、[(18)F]FLT PET 成像，确定 Aurora B 激酶抑制剂 AZD1152 的治疗反应是否可以在治疗过程的早期进行监测。
监测 AZD1152 治疗和对照 HCT116 和 SW620 异种移植荷瘤动物的肿瘤大小，并进行[(18)F]FDG 和[(18)F]FLT PET 成像。其他研究评估了这两种细胞系中胸苷合成的内源性和外源性贡献。
两种异种移植瘤均显示出对 AZD1152 的显著体积减小。相比之下，[(18)F]FDG 摄取并未显示出治疗反应。AZD1152 治疗的 HCT116 异种移植瘤中，[(18)F]FLT 摄取减少到对照值的 20%以下，而在治疗和未治疗的 SW620 异种移植瘤中，[(18)F]FLT 摄取接近背景水平。AZD1152-HQPA 的 EC(50)在 SW620 和 HCT116 细胞中约为 10 nmol/L；相比之下，SW620 细胞对甲氨蝶呤（MTX）和 5-氟尿嘧啶（5FU）的敏感性比 HCT116 细胞高得多。免疫印迹分析表明，SW620 细胞中胸苷激酶的表达略低于 HCT116 细胞。上述结果表明，SW620 异种移植瘤比 HCT116 异种移植瘤对胸苷利用的从头途径依赖性更高。
AZD1152 治疗在两种结肠癌异种移植瘤中均显示出抗肿瘤疗效。尽管[(18)F]FDG PET 不足以监测治疗反应，但[(18)F]FLT PET 非常有效地监测 HCT116 异种移植瘤的反应，但不能监测 SW620 异种移植瘤的反应。这些观察结果表明，从头胸苷合成可能是[(18)F]FLT PET 成像和肿瘤增殖定量的限制和混杂因素，这可能也适用于一些临床研究。
