title: Thymidylate synthase gene polymorphism determines response and toxicity of 5-FU chemotherapy.
abstract: Thymidylate synthase (TS) catalyses the conversion of deoxy-uridylate to deoxy-thymidylate and is essential for DNA synthesis. The human TS gene promoter is polymorphic, having either double or triple tandem repeats of a 28-bp sequence. Here we determined the significance of this polymorphism in humans and its prediction for clinical outcome of patients with metastatic colorectal cancer treated with 5-fluorouracil. The TS mRNA level was analyzed using RT-PCR. Individuals homozygous for the triple repeat variant (L/L) had 3.6 times higher TS mRNA levels compared to those homozygous for the double repeat variant (S/S) in tumor tissue (P = 0.004). We tested 50 patients with disseminated colorectal cancer who received 5-FU treatment to determine whether this TS polymorphism will predict clinical outcome. We found individuals with S/S genotype had a response rate of 50% (4/8) when compared to 9% (2/22) in those with L/L and 15% (3/20) in those with S/L genotype (P = 0.041). Patients with L/L had less severe side effects to 5-FU (P = 0.008). The data suggest that genotyping for the TS polymorphism may have the potential to identify patients more likely to respond to 5-FU based chemotherapy.
authors.affiliation: University of Southern California/Norris Comprehensive Cancer Center, Los Angeles 90033, USA.
authors.forename: S T
authors.initials: ST
authors.lastname: Pullarkat
authors.forename: J
authors.initials: J
authors.lastname: Stoehlmacher
authors.forename: V
authors.initials: V
authors.lastname: Ghaderi
authors.forename: Y P
authors.initials: YP
authors.lastname: Xiong
authors.forename: S A
authors.initials: SA
authors.lastname: Ingles
authors.forename: A
authors.initials: A
authors.lastname: Sherrod
authors.forename: R
authors.initials: R
authors.lastname: Warren
authors.forename: D
authors.initials: D
authors.lastname: Tsao-Wei
authors.forename: S
authors.initials: S
authors.lastname: Groshen
authors.forename: H J
authors.initials: HJ
authors.lastname: Lenz
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects*; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000032:analysis; D013940:Thymidylate Synthase / Q000235:genetics*
chemical_list: D000964:Antimetabolites, Antineoplastic; D012333:RNA, Messenger; D013940:Thymidylate Synthase; D005472:Fluorouracil