title: Expression of multidrug resistance-associated protein1,P-glycoprotein, and thymidylate synthase in gastric cancer patients treated with 5-fluorouracil and doxorubicin-based adjuvant chemotherapy after curative resection.
abstract: Both 5-fluorouracil and doxorubicin are commonly used agents in chemotherapy of gastric cancer in adjuvant setting as well as metastatic disease. In a variety of malignancies, high expression of multidrug resistance-associated protein1 and P-glycoprotein has been associated with resistance to doxorubicin, whereas 5-fluorouracil resistance has correlated with the level of thymidylate synthase expression. We evaluated the expression of multidrug resistance-associated protein1, P-glycoprotein, and thymidylate synthase using immunohistochemistry in 103 locally advanced gastric cancer patients (stage IB-IV) who underwent 5-fluorouracil and doxorubicin-based adjuvant chemotherapy after curative resection and investigated the association between their expression and clinicopathologic characteristics including prognosis of the patients. While high expression (> or =5% of tumour cells positive) of multidrug resistance-associated protein1 and P-glycoprotein was observed in 70 patients (68%) and 42 patients (41%), respectively, 65 patients (63%) had primary tumours with high expression (> or =25% of tumour cells positive) of thymidylate synthase. There was a significant association between multidrug resistance-associated protein1 and P-glycoprotein expression (P<0.0001) as well as P-glycoprotein and thymidylate synthase expression (P<0.0001). High multidrug resistance-associated protein1 and P-glycoprotein expressions were associated with well and moderately differentiated histology (P<0.0001 and P=0.03, respectively) and intestinal type (P<0.0001 and P=0.009, respectively). High multidrug resistance-associated protein1 expression correlated with lymph node metastasis (P=0.037), advanced stage (P=0.015), and older age (P=0.021). Five-year disease-free survival and overall survival of total patients were 55.2% and 56.2%, respectively, with a median follow-up of 68 months. There were no significant differences in disease-free survival and overall survival according to the expression of multidrug resistance-associated protein1 (P=0.902 and P=0.975, respectively), P-glycoprotein (P=0.987 and P=0.955, respectively), and thymidylate synthase (P=0.604 and P=0.802, respectively). Concurrent high expression of these proteins (high multidrug resistance-associated protein1/P-glycoprotein, high multidrug resistance-associated protein1/thymidylate synthase, high P-glycoprotein/thymidylate synthase) did not correlate with disease-free survival or overall survival. Even high expression of all three proteins was not associated with poor disease-free survival (P=0.919) and overall survival (P=0.852). In conclusion, high expression of multidrug resistance-associated protein1, P-glycoprotein, and thymidylate synthase did not predict poor prognosis of gastric cancer patients treated with 5-fluorouracil and doxorubicin-based adjuvant chemotherapy. A larger study including patients treated with surgical resection alone would be necessary.
authors.affiliation: Department of Hematology-Oncology, Ajou University School of Medicine, Suwon, 442-721, Korea (Rep.).
authors.forename: J-H
authors.initials: JH
authors.lastname: Choi
authors.forename: H-Y
authors.initials: HY
authors.lastname: Lim
authors.forename: H J
authors.initials: HJ
authors.lastname: Joo
authors.forename: H S
authors.initials: HS
authors.lastname: Kim
authors.forename: J W
authors.initials: JW
authors.lastname: Yi
authors.forename: H C
authors.initials: HC
authors.lastname: Kim
authors.forename: Y K
authors.initials: YK
authors.lastname: Cho
authors.forename: M W
authors.initials: MW
authors.lastname: Kim
authors.forename: K B
authors.initials: KB
authors.lastname: Lee
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis*; D000230:Adenocarcinoma / Q000737:chemistry* / Q000188:drug therapy / Q000401:mortality / Q000601:surgery / Q000628:therapy; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017024:Chemotherapy, Adjuvant; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005743:Gastrectomy; D006801:Humans; D007167:Immunotherapy; D007912:Lentinan / Q000008:administration & dosage; D015993:Life Tables; D008297:Male; D008875:Middle Aged; D016685:Mitomycin / Q000008:administration & dosage; D009363:Neoplasm Proteins / Q000032:analysis*; D010844:Picibanil / Q000008:administration & dosage; D013274:Stomach Neoplasms / Q000737:chemistry* / Q000188:drug therapy / Q000401:mortality / Q000601:surgery / Q000628:therapy; D016019:Survival Analysis; D013940:Thymidylate Synthase / Q000032:analysis*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D009363:Neoplasm Proteins; D007912:Lentinan; D010844:Picibanil; D016685:Mitomycin; D004317:Doxorubicin; D013940:Thymidylate Synthase; D005472:Fluorouracil