BIRMINGHAM, AlaNew oral agents being tested in clinical trials
for the treatment of colorectal cancer show promise of improving the
efficacy of 5-fluorouracil (5-FU) in combination regimens. A review
of several agents under studycapecitabine (Xeloda), UFT (a
combination of uracil plus ftorafur [Tegafur]), and S-1was
presented by Robert B. Diasio, MD, at a clinical investigators workshop.
Dr. Diasio is a member of the Department of Medicine and
Pharmacology/Toxicology at the University of Alabama Comprehensive
Cancer Center in Birmingham, Alabama. The workshop was sponsored by
the University of Texas M. D. Anderson Cancer Center and Pharmacia Oncology.
Capecitabine has been approved for chemotherapy-resistant breast
cancer and is awaiting approval for use in colorectal cancer. It is
an oral prodrug that is converted to 5-fluorouracil by thymidine
phosphorylase, which is present in higher concentrations in tumors
than in normal tissue. Toxicity is less severe than the Mayo Clinic
intravenous 5-FU/leucovorin regimen, but hand-foot syndrome occurs in
about 42% of patients.
How DPD Inhibitors Act
Dihydropyrimidine dehydrogenase (DPD) inhibitors decrease the
variability of 5-FU bioavailability and have the effect of increasing
exposure to 5-FU. The DPD inhibitors UFT, eniluracil, and S-1 are all
in clinical trials. Dr. Diasio warned that preliminary data suggest
that using another fluoropyrimidine within 8 weeks of eniluracil (and
possibly other DPD inhibitors) can increase the risk of late 5-FU
Some of these new agents, including capecitabine and UFT, have
shown antitumor activity at least equal to 5-FU, Dr. Diasio
said. They also offer quality of life and economic benefits, as
well as less toxicity. There may also be selective biochemical
effects such as selective activation within tumors for capecitabine
and the ability to overcome 5-FU resistance caused by increased tumor
DPD with eniluracil, he added.