Noninvasive molecular imaging sheds light on the synergy between 5-fluorouracil and TRAIL/Apo2L for cancer therapy.
OBJECTIVE
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.


METHODS
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 ( approximately 9 days) compared with TRAIL alone ( approximately 4 days).


CONCLUSIONS
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.
Lee
Kuei C
KC
Department of Biological Chemistry, The University of Michigan Medical Center, Ann Arbor, MI 48109-0582, USA.
Hamstra
Daniel A
DA
Bhojani
Mahaveer S
MS
Khan
Amjad P
AP
Ross
Brian D
BD
Rehemtulla
Alnawaz
A
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D038524:Diffusion Magnetic Resonance Imaging / Q000379:methods*; D004357:Drug Synergism; D005472:Fluorouracil / Q000008:administration & dosage*; D005910:Glioma / Q000175:diagnosis* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008164:Luminescent Proteins; D051379:Mice; D008819:Mice, Nude; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D008164:Luminescent Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; D016159:Tumor Suppressor Protein p53; D053148:Caspase 3; D005472:Fluorouracil