British researchers reporting in a recent issue of the Journal
of the National Cancer Institute offer a study-based explanation
of why levamisole and fluorouracil (5-FU), used together, can
lengthen survival for certain colon cancer patients, while neither
drug alone has consistently been shown to make a difference.
The combination of these two drugs, used as a postoperative treatment
for Dukes' stage C colon cancer, reduces the risk of dying within
3 years by about one third.
On the basis of laboratory experiments with colon cancer cells,
investigators at the University of Leeds (England) propose that
levamisole and fluorouracil have complementary effects at the
level of RNA activity. Specifically, levamisole offsets 5-FU's
general suppression of RNA synthesis, and both have a role in
the increase and accumulation of the messenger RNAs responsible
for producing a particular class of immune system proteins: Class
I Human Leukocyte Antigens.
The findings suggest, the investigators say, that levamisole both
reduces the toxicity that fluorouracil would otherwise exhibit
because of its general suppression of RNA synthesis, and at the
same time augments the therapeutic benefit of 5-FU through selective
effects on certain messenger RNAs.
In an accompanying editorial, Chris H. Takimoto, MD,PhD, National
Cancer Institute, notes that "this study reports the first
biochemical or molecular interaction between [levamisole and 5-FU]
to be demonstrated at pharmacologically relevant levamisole concentrations."
He also notes, however, that the patterns of administration of
the two drugs differed markedly from typical clinical drug administration
schedules, which may affect the applicability of these in vitro
tests to the clinical setting. Dr. Takimoto recommends validation
of these results in additional laboratory research with different
colon cancer cell lines and actual tumor specimens.