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Noninvasive Molecular Imaging Sheds Light on the Synergy between 5-Fluorouracil and TRAIL/Apo2L for Cancer Therapy

Authors' Affiliations: Departments of ¹ Biological Chemistry, ² Radiation Oncology, ³ Radiology, and ⁴ Center for Molecular Imaging, The University of Michigan Medical Center, Ann Arbor, Michigan

Requests for reprints: Alnawaz Rehemtulla, Center for Molecular Imaging, The University of Michigan Medical Center, 1331 East Ann Street, Room 4111, Ann Arbor, MI 48109-0582. Phone: 734-764-4209; Fax: 734-763-1581; E-mail: alnawaz{at}umich.edu.

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 –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 (9 days) compared with TRAIL alone (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.

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