title: Thymidylate synthase gene polymorphism predicts response to capecitabine in advanced colorectal cancer.
abstract: Thymidylate synthase is a target enzyme for chemotherapeutic agents such as 5-fluorouracil and capecitabine, its oral prodrug. The human thymidylate synthase gene promoter is polymorphic, having either double or triple repeats of a 28-bp sequence. It has previously been shown that colorectal cancer patients who are homozygous for the triple tandem repeats (L/L) have significantly higher thymidylate synthase mRNA expression than those homozygous for the double repeat variant (S/S). Capecitabine is converted to 5-fluorouracil by a sequential triple enzyme pathway, with the last step catalyzed by the tumor-associated angiogenic factor thymidine phosphorylase. We have recently shown that individuals with metastatic colorectal cancer treated with 5-fluorouracil have a higher response rate if they are homozygous for the genotype S/S as opposed to S/L or L/L. Our hypothesis is that individuals homozygous for the double repeat variant (S/S) should have a better response to capecitabine than their counterparts with S/L or L/L. In this retrospective pilot study we assessed the thymidylate synthase polymorphic status of 24 patients with metastatic colorectal cancer and determined their response to capecitabine. We found that 75% (3/4) of individuals with the S/S variant responded to capecitabine, compared to 8% (1/12) and 25% (2/8) of those with the S/L and L/L variants, respectively. Our data suggest that genotyping patients for the thymidylate synthase polymorphism would be useful in identifying patients who are more likely to respond to capecitabine treatment for advanced colorectal cancer.
authors.affiliation: Department of Medical Oncology, Norris Cancer Center, University of Southern California, Los Angeles, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Park
authors.forename: Jan
authors.initials: J
authors.lastname: Stoehlmacher
authors.forename: Wu
authors.initials: W
authors.lastname: Zhang
authors.forename: Denice
authors.initials: D
authors.lastname: Tsao-Wei
authors.forename: Susan
authors.initials: S
authors.lastname: Groshen
authors.forename: Heinz-Josef
authors.initials: HJ
authors.lastname: Lenz
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D000069287:Capecitabine; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D005260:Female; D005472:Fluorouracil / Q000031:analogs & derivatives; D005838:Genotype; D006801:Humans; D008297:Male; D011110:Polymorphism, Genetic; D013940:Thymidylate Synthase / Q000235:genetics*
chemical_list: D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D000069287:Capecitabine; D013940:Thymidylate Synthase; D005472:Fluorouracil