[Thymidylate synthase gene promoter polymorphism in patients with advanced head and neck cancer treated by radio- and 5-fluorouracil chemotherapy].
OBJECTIVE
Thymidylate synthase (TS) is a rate-limiting enzyme in the DNA synthetic pathway, and represents a cellular target of antimetabolite drug 5-fluorouracil. It catalyzes the reductive methylation of deoxyuridine-5'-monophosphate to deoxythymidine-5'-monophosphate. Inhibition of TS will result in depletion of both dTMP and, subsequently, dTTP. As a consequence, dUTP is misincorporated into DNA, resulting in DNA breakage and cell death. Developing resistance against 5-fluorouracil (FURA) based drugs might be due to the failure of inhibition of thymidylate synthase enzyme function. In the promoter region of the TS gene there is a tandem repeat sequence (2R or 3R), which was found to be polymorphic and influences the gene expression. Effectiveness and tolerability of Tegafur treatment might be influenced by expression of the TS gene. Our purpose was to determine the effectiveness and tolerability of concomitant radiotherapy and low-dose chemotherapy using Tegafur in respect of promoter polymorphism of thymidilate synthase gene.


METHODS
TS promoter polymorphism (2R/2R, 2R/3R, 3R/3R) was determined by polymerase chain reaction using genomic DNA, in 47 patients with advanced head and neck cancer.


RESULTS
Thirty patients out of 47 showed complete response, and genotyping of these patients revealed 2R/2R in 22 (73.3%), 2R/3R in 2 (6.7%) and 3R/3R in 6 (20%). Seventeen out of 47 patients reacted with partial response, and 2R/2R or 2R/3R were revealed in 5 (29.4%) and 3 (17.6%) patients, respectively, and 3R/3R genotype was identified in 9 patients (53%).


CONCLUSIONS
We did not find any correlation between patient's data and response to therapy, but strong correlation was found between the latter and the patient's genotype. This facts indicate that the analysis of promoter polymorphism of thymidylate synthase gene might be a useful target to examine before FURA-based chemotherapy, and might allow to go into the direction of individualized treatment of head and neck cancer. We suppose that tumor response depends on genomic features of the patients.
Kiss-László
Zsuzsanna
Z
Orvosi Genetikai Intézet, Szegedi Tudományegyetem, Altalános Orvostudományi Kar, Szent-Györgyi Albert Orvos- és Gyógyszerésztudományi Centrum, Szeged 6720, Hungary.
Nagy
Beatrix
B
Thurzó
László
L
Szabó
János
J
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017024:Chemotherapy, Adjuvant; D016009:Chi-Square Distribution; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000532:radiotherapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests; D011401:Promoter Regions, Genetic; D018714:Radiotherapy, Adjuvant; D013940:Thymidylate Synthase / Q000235:genetics* / Q000378:metabolism; D016896:Treatment Outcome
D013940:Thymidylate Synthase; D005472:Fluorouracil