[18F]fluorothymidine PET Informs the Synergistic Efficacy of Capecitabine and Trifluridine/Tipiracil in Colon Cancer

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'-[F]fluorothymidine ([F]FLT) PET as a means to predict therapeutic response to a sequential combination of capecitabine and trifluridine/tipiracil. [H]FLT uptake after 5-fluorouracil treatment and [F]FLT uptake after capecitabine (360 mg/kg/day) in athymic nude mice (Balb/c-nu) with xenografts ( = 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 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 ( = 6-10 per group). We observed significant increases in [H]FLT uptake in all cell lines and [F]FLT uptake in five xenograft models after 5-fluorouracil and capecitabine treatment, respectively. Increased [F]FLT uptake after capecitabine followed by extinction of uptake correlated strongly with tumor growth inhibition ( = -0.81, = 0.02). The effects of these combinations were synergistic A synergy for sequential capecitabine and trifluridine/tipiracil was found only in mouse xenograft models showing increased [F]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 [F]FLT PET imaging may predict the response to capecitabine and the synergistic antitumor efficacy of a sequential combination of capecitabine and trifluridine/tipiracil. .

Precision treatment in colorectal cancer: Now and the future

“…Based on the RECOURSE group’s phase III randomized trial, which included nearly 800 participants from three different geographical areas, lonsurf results in a 1.8‐month improvement in median OS compared with the placebo group . Methods for optimizing lonsurf treatment are currently under investigation, including the development of a CRC xenograft experimental model that predicts treatment outcome; the use of 3′‐Deoxy‐3′‐18F‐fluorothymidine positron emission tomography ([ 18 F]FLT‐PET) as a noninvasive radio‐traceable substitute for thymidine; and using the MSI status as an indicator for the use of lonsurf in combination with nivolumab, a PD‐1 inhibitor, in refractory mCRC patients (NCT02860546).…”

The mechanism and tumor inhibitory study of Lagopsis supine ethanol extract on colorectal cancer in nude mice

“…The colorectal cancer cells of HCT116 were digested and adjusted to 1 × 10 7 /mL, the counted cells in cell medium were mixed with matrigel with the ratio of 1:1 on ice, and then take 200 μL of the cell mixture seeded into the right axilla in Balb/c-nude mice with the cell numbers of 1 × 10 6 /mice. The xenograft mice were randomly divided into five groups (n = 12): model group, Capecitabine (Cap) 300 mg/kg group [28], Ls 75 mg/kg group, Ls 150 mg/kg group and Ls 300 mg/kg group, when the volume of the tumor growth to 100 mm 3 , which need about two weeks from the initial inoculation. The selected dosage of Ls was calculated from human to mice according to Chinese pharmacopoeia of 2010.…”