Expression of multidrug resistance-associated protein 1, P-glycoprotein, and thymidylate synthase in gastric cancer patients treated with 5-fluorouracil and doxorubicin-based adjuvant chemotherapy after curative resection

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 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-glycolprotein, and thymidylate synthase using immunohistochemistry in 103 locally advanced gastric cancer patients (stage IB-lV) 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 (->5% of tumour cells positive) of multidrug resistance-associated protein I and P-glycoprotein was observed in 70 patients (68%) and 42 patients (41%), respectively, 65 patients (63%) had primary tumours with high expression (greater than or equal to25% 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 b multidrug resistance-associated proteinl1 and P-glycoprotein expressions were associated with well and moderately differentiated histology (P < 0.0001 and P = 0.03, respectively) and intestinal type (P < 00001 and P = 0.009, respectively), High multidrug resistance-associated protein1 expression correlated with lymph node metastasis (P = 0.037), advanced stage b (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 doxorubcin-based adjuvant chemotherapy A larger study including patients treated with surgical resection alone would be necessary.