Abstract
In cancer therapy, enhanced thymidine uptake by the salvage pathway can bypass dTMP depletion, thereby conferring resistance to thymidylate synthase inhibition. We investigated whether sequential combination therapy of capecitabine and trifluridine/tipiracil (TAS-102) could synergistically enhance antitumor efficacy in colon cancer xenograft models. We also examined 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT) PET as a means to predict therapeutic response to a sequential combination of capecitabine and trifluridine/tipiracil. [3H]FLT uptake after 5-fluorouracil treatment in vitro and [18F]FLT uptake after capecitabine (360 mg/kg/day) in athymic nude mice (Balb/c-nu) with xenografts (n = 10-12 per group) were measured using eight human colon cancer cell lines. We determined the synergistic effects of sequential combinations of 5-fluorouracil and trifluridine in vitro as well as the sequential combination of oral capecitabine (30-360 mg/kg) and trifluridine/tipiracil (trifluridine 75 or 150 mg/kg with tipiracil) in six xenograft models (n = 6-10 per group). We observed significant increases in [3H]FLT uptake in all cell lines and [18F]FLT uptake in five xenograft models after 5-fluorouracil and capecitabine treatment, respectively. Increased [18F]FLT uptake after capecitabine followed by extinction of uptake correlated strongly with tumor growth inhibition (ρ = -0.81, P = 0.02). The effects of these combinations were synergistic in vitro A synergy for sequential capecitabine and trifluridine/tipiracil was found only in mouse xenograft models showing increased [18F]FLT uptake after capecitabine. Our results suggest that the sequential combination of capecitabine and trifluridine/tipiracil is synergistic in tumors with an activated salvage pathway after capecitabine treatment in mice, and [18F]FLT PET imaging may predict the response to capecitabine and the synergistic antitumor efficacy of a sequential combination of capecitabine and trifluridine/tipiracil. Cancer Res; 77(24); 7120-30. ©2017 AACR.
Highlights
Capecitabine is an orally administered prodrug of 5-fluorouracil [1]
These results indicate that our colon cancer cell lines had varying sensitivity to 5-fluorouracil, and were suitable for studying the response to 5-fluorouracil or capecitabine
We found synergistic antitumor efficacy for a sequential combination of 5-fluorouracil and trifluridine in all cell lines
Summary
Capecitabine is an orally administered prodrug of 5-fluorouracil [1]. Capecitabine is sequentially converted to 5-fluorouracil by enzymatic processes and yields a substantially higher concentration of 5-fluorouracil in tumors than in normal tissues. Capecitabine is recommended as one of the initial che-. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Motherapy regimens for advanced or metastatic colon cancer. Responses to capecitabine remain mostly in the form of a partial response and stable disease, with only a modest impact on survival [2, 3]. Frequent treatmentlimiting adverse effects are typically managed by dosage reduction, despite a lack of relevant evidence from well-designed randomized trials [4]
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