title: Investigating the role of nucleoside transporters in the resistance of colorectal cancer to 5-fluorouracil therapy.
abstract: Resistance to 5-fluorouracil (5FU) poses a constant challenge to the management of colorectal cancer (CRC). Consistent efforts were called for to identify molecular markers that can effectively predict patients' response. This study investigated the role of nucleoside transporters, particularly human equilibrative nucleoside transporter 1 (hENT1), in predicting clinical treatment outcome with 5FU-based therapy. Expression of a panel of nucleoside transporters in biopsied tumors from 7 CRC patients was measured by real-time PCR prior to 5FU-based chemotherapy. To provide mechanistic support for the role of hENT1 in 5FU resistance, cell viability of Caco-2 cells was measured, following incubation with varying concentrations of 5FU and a hENT1 inhibitor. Biopsied tumors were further subjected to global metabonomic profiling using gas chromatography/mass spectrometry. High hENT1 levels in tumor tissue correlated with poor clinical response to 5FU. Corroborating with the clinical findings, chemical inhibition of hENT1 in Caco-2 cells resulted in an augmentation of 5FU efficacy. Metabonomic profiling revealed that the pretreatment metabotype associated with non-responders to 5FU therapy was distinct from metabotype of responders (partial least-squares discriminant analysis Q(2) (cumulative) = 0.898, R(2)X = 0.513, R(2)Y = 0.996). This is the first clinical report on the relationships of intratumoral expression of nucleoside transporters and tumor metabotype with response to 5FU among CRC patients. Coupled to the in vitro findings, our preliminary data suggested hENT1 to be a potential codeterminant of clinical response to 5FU.
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore.
authors.forename: Lee Cheng
authors.initials: LC
authors.lastname: Phua
authors.forename: Mainak
authors.initials: M
authors.lastname: Mal
authors.forename: Poh Koon
authors.initials: PK
authors.lastname: Koh
authors.forename: Peh Yean
authors.initials: PY
authors.lastname: Cheah
authors.forename: Eric Chun Yong
authors.initials: EC
authors.lastname: Chan
authors.forename: Han Kiat
authors.initials: HK
authors.lastname: Ho
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D033721:Equilibrative Nucleoside Transporter 1 / Q000235:genetics / Q000378:metabolism; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use*; D008401:Gas Chromatography-Mass Spectrometry; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D055432:Metabolomics; D008875:Middle Aged; D033703:Nucleoside Transport Proteins / Q000235:genetics / Q000378:metabolism*; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D000964:Antimetabolites, Antineoplastic; D033721:Equilibrative Nucleoside Transporter 1; D033703:Nucleoside Transport Proteins; D012334:RNA, Neoplasm; C438649:SLC29A1 protein, human; D005472:Fluorouracil