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利用FLT-PET成像早期检测非小细胞肺癌中的胸苷酸合成酶耐药性。

Early detection of thymidylate synthase resistance in non-small cell lung cancer with FLT-PET imaging.

作者信息

Chen Xiao, Yang Yizeng, Katz Sharyn

机构信息

Department of Radiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

Department of Radiology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, China.

出版信息

Oncotarget. 2017 Jul 31;8(47):82705-82713. doi: 10.18632/oncotarget.19751. eCollection 2017 Oct 10.

DOI:10.18632/oncotarget.19751
PMID:29137296
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5669922/
Abstract

INTRODUCTION

Inhibition of thymidylate synthase (TS) results in a transient compensatory "flare" in thymidine salvage pathway activity measureable with F-thymidine (FLT)- positron emission tomography (PET) at 2hrs. of therapy which may predict non-small cell lung cancer (NSCLC) sensitivity to TS inhibition.

MATERIALS AND METHODS

Resistance to TS inhibition by pemetrexed was induced in NSCLC cell lines H460 and H1299 through TS overexpression. TS overexpression was confirmed with RT-PCR and Western blotting and pemetrexed resistance confirmed with IC assays. The presence of a pemetrexed-induced thymidine salvage pathway "flare" was then measured using H-thymidine in both pemetrexed sensitive (H460 and H1299) and resistant (H460R, H1299R, CALU-6, H522, H650, H661, H820, H1838) lines , and validated with FLT-PET using H460 and H460R xenografts.

RESULTS

Overexpression of TS induced pemetrexed resistance with IC for H460, H1299, H460R and H1299R measured as 0.141 μM, 0.656 μM, 22.842 μM, 213.120 μM, respectively. Thymidine salvage pathway H-thymidine "flare" was observed following pemetrexed in H460 and H1299 but not H460R, H1299R, CALU-6, H522, H650, H661, H820 or H1838 . Similarly, a FLT "flare" was observed following pemetrexed therapy in H460 but not H460R tumor-bearing xenografts.

CONCLUSIONS

Imaging of TS inhibition is predictive of NSCLC sensitivity to pemetrexed.

摘要

引言

胸苷酸合成酶（TS）的抑制会导致在治疗2小时时，用氟代胸苷（FLT）-正电子发射断层扫描（PET）可测量到胸苷补救途径活性出现短暂的代偿性“激增”，这可能预示着非小细胞肺癌（NSCLC）对TS抑制的敏感性。

材料与方法

通过TS过表达在NSCLC细胞系H460和H1299中诱导对培美曲塞TS抑制的耐药性。通过逆转录聚合酶链反应（RT-PCR）和蛋白质免疫印迹法确认TS过表达，并通过IC测定法确认培美曲塞耐药性。然后在培美曲塞敏感（H460和H1299）和耐药（H460R、H1299R、CALU-6、H522、H650、H661、H820、H1838）细胞系中使用氚代胸苷测量培美曲塞诱导的胸苷补救途径“激增”，并使用H460和H460R异种移植瘤通过FLT-PET进行验证。

结果

TS过表达诱导了对培美曲塞的耐药性，H460、H1299、H460R和H1299R的IC50分别测定为0.141μM、0.656μM、22.842μM、213.120μM。在H460和H1299中，培美曲塞治疗后观察到胸苷补救途径的氚代胸苷“激增”，但在H460R、H1299R、CALU-6、H522、H650、H661、H820或H1838中未观察到。同样，在H460荷瘤异种移植瘤中，培美曲塞治疗后观察到FLT“激增”，但在H460R中未观察到。

结论

TS抑制的成像可预测NSCLC对培美曲塞的敏感性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe9b/5669922/cd6e1297e058/oncotarget-08-82705-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe9b/5669922/c65ba16f3ab7/oncotarget-08-82705-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe9b/5669922/c90d2a7bbdf5/oncotarget-08-82705-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe9b/5669922/72de11cc860d/oncotarget-08-82705-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe9b/5669922/cd6e1297e058/oncotarget-08-82705-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe9b/5669922/c65ba16f3ab7/oncotarget-08-82705-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe9b/5669922/c90d2a7bbdf5/oncotarget-08-82705-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe9b/5669922/72de11cc860d/oncotarget-08-82705-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe9b/5669922/cd6e1297e058/oncotarget-08-82705-g004.jpg

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