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 studies Berger et al. (1) identified a variant structural form of thymidylate synthase (TS) that is associated with relative resistance to 5-fluoro-2'-deoxyuridine, in a human colonic tumor cell line. They observed that expression of the variant TS, which differs from the normal form by a tyrosine to histidine substitution at residue 33, confers a 4-fold level of drug resistance in mammalian cells, as well as in bacteria. Now we report on the use of RT-PCR techniques to see if that variant TS form could be present in human samples from patients who underwent surgery for primary colorectal cancer and 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 discussed.
Sanguedolce
R
R
Dipartmenti di Scienze Farmacologiche, Policlinico Via Del Vespro N. 127, Palermo, Italy. sanguedolce@unipa.it
Alessandro
R
R
De Leo
G
G
Gullotti
L
L
Sanguedolce
F
F
Vultaggio
G
G
Diana
G
G
Cirello
B
B
Rausa
L
L
D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D000368:Aged; D003110:Colonic Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D005260:Female; D006639:Histidine; D006801:Humans; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics*; D009367:Neoplasm Staging; D017354:Point Mutation; D012004:Rectal Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013940:Thymidylate Synthase / Q000235:genetics*; D014443:Tyrosine
D009363:Neoplasm Proteins; D014443:Tyrosine; D006639:Histidine; D013940:Thymidylate Synthase