Failure of detection of the tyrosine to histidine substitution at the residue 33 of thymidylate synthase in human colorectal cancer. A preliminary study

Structural changes in the macromolecular targets of pharmacological agents can result in alterations in the efficacy of these agents. In previous stud ies Berger et al. (1) identified a variant structural form of thymidylate s ynthase (TS) that is associated with relative resistance to 5-fluoro-2'-deo xyuridine, in a human colonic tumor cell line. They observed that expressio n of the variant TS, which differs from the normal form by a tyrosine to hi stidine substitution at residue 33, confers a 4-fold level of drug resistan ce in mammalian cells, as well as in bacteria. Now we report on the use of RT-PCR techniques to see if that valiant TS form could be present in human samples from patients who underwent surgery for primary colorectal cancer a nd been previously untreated and to try to find relationships between that hypothetical variant TS form and the 5-Fluorouracil treatment. The possible role of Tyr 33 in 5-fluoropyrimidine-mediated inhibition of TS is discusse d.