Noninvasive molecular imaging sheds light on the synergy between 5-fluorouracil and TRAIL/Apo2L for cancer therapy
Noninvasive molecular imaging sheds light on the synergy between 5-fluorouracil and TRAIL/Apo2L for cancer therapy
复制标题
DOI：
10.1158/1078-0432.ccr-06-1657
复制
发表时间：
2007-03-15
影响因子：
11.5
通讯作者：
Rehemtulla, Alnawaz
中科院分区：
文献类型：
--
作者：
Lee, Kuei C.;Hamstra, Daniel A.;Rehemtulla, Alnawaz
目的：在之前的报道中，通过caspase-3切割在细胞凋亡过程中激活的重组荧光素酶报告基因被开发出来，用于细胞凋亡的生物发光成像。在体内无创成像细胞凋亡的能力可以极大地促进针对细胞凋亡途径的治疗方法的临床前开发。在这项研究中，我们通过生物发光成像监测体内凋亡活性，研究了5-氟尿嘧啶（5-FU）对D54肿瘤对肿瘤坏死因子相关凋亡诱导配体（TRAIL）治疗的增敏作用。实验设计：利用我们的细胞凋亡成像平台和扩散磁共振成像（MRI），我们监测了5-FU、TRAIL和5-FU + TRAIL对D54异种移植物的抗肿瘤作用。此外，还进行了体积和组织学分析，以与生物发光成像和扩散MRI的结果相关联。结果：生物发光成像显示，单独使用TRAIL治疗可使凋亡活性增加400%，尽管继续治疗，但在10天的治疗期间，凋亡活性迅速下降。相比之下，5-FU和TRAIL联合治疗引起了整个治疗过程中持续的凋亡反应。使用弥散MRI，当联合治疗与单独治疗相比，检测到肿瘤反应增强。最后，与TRAIL单独治疗（类似4天）相比，联合治疗导致生长延迟延长（类似9天）。结论：我们发现5-FU和TRAIL联合治疗确实增强了体内细胞凋亡活性，这转化为更好的肿瘤控制。此外，这项技术揭示了5-FU和TRAIL的协同作用，不同治疗方案导致的caspase-3的时间激活差异证明了这一点。
Purpose: In a previous report, a recombinant luciferase reporter, activated during apoptosis via caspase-3 cleavage, was developed for imaging of apoptosis using bioluminescence. The ability to noninvasively image apoptosis in vivo could dramatically benefit the preclinical development of therapeutics targeting the apoptotic pathway. In this study, we examined the use of 5-fluorouracil (5-FU) for sensitizing D54 tumors to tumor necrosis factor alpha - related apoptosis - inducing ligand (TRAIL) therapy by monitoring apoptotic activity in vivo using bioluminescence imaging.Experimental Design: Using our apoptosis imaging platform and diffusion magnetic resonance imaging (MRI), we monitored the antitumor effects of 5-FU,TRAIL, and 5-FU + TRAIL using D54 xenografts. Additionally, volumetric and histologic analyses were done for correlation with findings from bioluminescence imaging and diffusion MRI.Results: Bioluminescence imaging showed that therapy with TRAIL alone produced an initial 400% increase in apoptotic activity that rapidly diminished during the 10-day treatment period despite continued therapy. In contrast, concomitant 5-FU and TRAIL therapy elicited an apoptotic response that was sustained throughout the entire therapeutic course. Using diffusion MRI, an enhanced tumor response was detected when concomitant therapy was given versus TRAIL-alone therapy. Last, concomitant therapy resulted in a prolonged growth delay (similar to 9 days) compared with TRAIL alone (similar to 4 days).Conclusion: We showed that concomitant 5-FU and TRAIL therapy indeed enhanced apoptotic activity in vivo, which translated into greater tumor control. Moreover, this technique sheds light on the synergy of 5-FU and TRAIL as evidenced by differences in the temporal activation of caspase-3 resulting from the different therapeutic regimens.