Why Levamisole Appears to Improve the Efficacy of 5-FU

British researchers reporting in a recent issue of the Journalof the National Cancer Institute offer a study-based explanationof why levamisole and fluorouracil (5-FU), used together, canlengthen survival for certain colon cancer patients, while neitherdrug alone has consistently been shown to make a difference.

The combination of these two drugs, used as a postoperative treatmentfor Dukes' stage C colon cancer, reduces the risk of dying within3 years by about one third.

On the basis of laboratory experiments with colon cancer cells,investigators at the University of Leeds (England) propose thatlevamisole and fluorouracil have complementary effects at thelevel of RNA activity. Specifically, levamisole offsets 5-FU'sgeneral suppression of RNA synthesis, and both have a role inthe increase and accumulation of the messenger RNAs responsiblefor producing a particular class of immune system proteins: ClassI Human Leukocyte Antigens.

The findings suggest, the investigators say, that levamisole bothreduces the toxicity that fluorouracil would otherwise exhibitbecause of its general suppression of RNA synthesis, and at thesame time augments the therapeutic benefit of 5-FU through selectiveeffects on certain messenger RNAs.

In an accompanying editorial, Chris H. Takimoto, MD,PhD, NationalCancer Institute, notes that "this study reports the firstbiochemical 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 ofthe two drugs differed markedly from typical clinical drug administrationschedules, which may affect the applicability of these in vitrotests to the clinical setting. Dr. Takimoto recommends validationof these results in additional laboratory research with differentcolon cancer cell lines and actual tumor specimens.