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 (55% 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 (525% of tumour cells positive) of thymidylate synthase. There was a significant association between multidrug resistance-associated protein1 and Pglycoprotein expression (P50.0001) as well as P-glycoprotein and thymidylate synthase expression (P50.0001). High multidrug resistance-associated protein1 and P-glycoprotein expressions were associated with well and moderately differentiated histology (P50.0001 and P=0.03, respectively) and intestinal type (P50.0001 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), Pglycoprotein (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 resistanceassociated 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 doxorubicinbased adjuvant chemotherapy. A larger study including patients treated with surgical resection alone would be necessary.

The association of P‐glycoprotein with response to chemotherapy and clinical outcome in patients with osteosarcoma

“…42,43 However, several studies also failed to find an association with prognosis of specific malignancies, such as rhabdomyosarcoma 44 and Ewing sarcoma, 45 as well as types of lymphomas, 46 gastric carcinoma, 47 and mesothelioma. 48 Thus, the literature on a potential prognostic role of Pgp in sarcomas in particular has been ambivalent.…”

ΔNp73α regulates MDR1 expression by inhibiting p53 function

“…A product of the mdr1 gene, p-glycoprotein (p-gp), is a 170-kDa transmembrane protein that functions as an energy-dependent drug efflux pump, the substrates of which include a wide range of anticancer drugs. MDR1 is often overexpressed in primary gastric adenocarcinoma and its precursor lesions (Vollrath et al, 1991;Wallner et al, 1993;Lacueva et al, 1998;Choi et al, 2002). This increase in p-gp levels correlates with an increased resistance to the chemotherapeutic drug, doxorubicin, in primary gastric cancer cells (Hotta et al, 1999).…”

Association between ABCB1 Immunohistochemical Expression and Overall Survival in Gastric Cancer Patients

“…Choi et al (2002) found higher expression of ABCB1 protein in moderately differentiated tumors and especially in intestinal-type GC of Lauren's classification. Similarly, we found increased expression of ABCB1 protein in moderately differentiated tumors and intestinaltype of Lauren.…”