Fluoropyrimidines form the mainstay in treatment of gastrointestinal
malignancies. For decades
5-fluorouracil (
5FU), was the major fluoropyrimidine. Currently it is usually given in a combination with
leucovorin and
oxaliplatin, i.e. FOLFOX, or
irinotecan, i.e. FOLFIRI, or all three, i.e.
FOLFIRINOX, but gradually it has been replaced by oral fluoropyrimidine
prodrug formulations, such as
tegafur-
uracil and S-1 (both contain
ftorafur), and
capecitabine (Xeloda®). Novel drugs such as the antivascular
endothelial growth factor antibody,
bevacizumab, and the anti-
epidermal growth factor receptor antibody,
cetuximab, are often combined with one of these treatment options. However, when resistance emerged, no alternatives were available.
TAS-102, a combination of
trifluorothymidine and the
thymidine phosphorylase inhibitor TPI in a 1:0.5 ratio, is a novel oral formulation, which is active in 5FU-resistant models, both in vitro and in xenograft models. In addition to inhibition of
thymidylate synthase, the major mechanism of action of classical fluoropyrimidines, TAS-102's major mechanism of action is incorporation into
DNA, thereby causing DNA damage.
TAS-102 also follows an alternative activation pathway via
thymidine kinase, and is not a substrate for
dihydropyrimidine dehydrogenase. All together this explains the efficacy in 5FU-resistant models. In early clinical studies, the twice-daily schedule (5 days on, 2 days rest) for 2 weeks every 4 weeks, led to a significant disease control rate in various
malignancies. This schedule showed consistent activity in two randomized trials on fluoropyrimidine refractory
colorectal cancer patients, reflected by an increase of 2-3 months in overall survival in the
TAS-102 group compared with placebo. Considering the impressive preclinical potential of various combinations
TAS-102 has the promise to become an alternative for 5FU-resistant
cancer.