Thymidylate synthase gene polymorphism determines response and toxicity of 5-FU chemotherapy.
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.
Pullarkat
S T
ST
University of Southern California/Norris Comprehensive Cancer Center, Los Angeles 90033, USA.
Stoehlmacher
J
J
Ghaderi
V
V
Xiong
Y P
YP
Ingles
S A
SA
Sherrod
A
A
Warren
R
R
Tsao-Wei
D
D
Groshen
S
S
Lenz
H J
HJ
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*
D000964:Antimetabolites, Antineoplastic; D012333:RNA, Messenger; D013940:Thymidylate Synthase; D005472:Fluorouracil