Background/aims: Multidrug resistance (MDR) is closely correlated to an unfavorable prognosis in various human cancers. However, the clinical significance of the expression of MDR-related proteins p-glycoprotein (PGP), glutathione-s-transferases (GST-pi), topoisomerase-II (Topo-II) and lung resistance protein (LRP) in primary gastric cardiac adenocarcinoma (PGCA) remains unclear. In this study, the total of the four kinds of MDR-related proteins mentioned above were detected by using immunohistochemistry and their clinical significance in chemoresistance were also investigated.
Methodology: This retrospective study included 69 resected specimens from patients with PGCA. The expression of PGP, GST-pi, Topo-II and LRP in formalin-fixed paraffin-embedded tissue sections was determined by a labelled streptavidin-biotin immunohistochemical technique, and the results were analyzed in correlation with clinicopathological data. None of these patients received chemotherapy prior to surgery.
Results: The positive rates of expression of PGP, GST-pi, Topo-II and LRP in malignant tissues (49.2%, 75.4%, 68.1% and 58%, respectively) were all higher than that of the normal tissues (0, 30%, 20% and 0, respectively, P<0.01). PGP expression in tumors that had metastasized was significantly more frequent than in tumors that had not metastasized (67.5% vs. 24.1%, P<0.01).The expression of PGP was closely related with clinicopathologic staging (staging 1/2 vs. 3/4, 28.6% vs. 58.3%, P<0.05). No significant correlation was shown between PGP and increasing differentiated degree (40%, 42.4% and 61.5%, P>0.05). GST-pi expression status progressively increased with increasing differentiated degree (40%, 75.8% and 88.5%, P<0.05) and clinico pathologic stage (staging 1/2 vs. 3/4, 57.1% vs. 83.3%, P<0.05). In addition, a significant positive correlation was also observed between GST-pi and lymphatic metastasis (with vs. without metastasis, 87.5% vs. 58.6%, P<0.05). The expression of Topo-II was associated with increasing differentiated degree (33.3%, 69.7% and 80.7%, P<0.01). No significant differences with Topo-II expression was found in relation to the clinicopathologic stage (staging 1/2 vs. 3/4, 57.1% vs. 72.9%, P>0.05) and lymphatic metastasis (with vs. without metastasis, 65.0% vs. 72.4%, P>0.05). Moreover, a significant difference with the expression of LRP was found in relation to the clinicopathologic stage (staging 1/2 vs. 3/4, 38% vs. 66.6%, P<0.05), and lymphatic metastasis (with vs. without metastasis, 70.0% vs. 41.4%, P<0.05). Comparing the well, moderately and poorly differentiated cohort, a non-statistical increasing trend towards LRP expression status was noted (50.0%, 54.5% and 65.3%, respectively, P>0.05). Besides, the co-expression of all four tested MDR-related proteins also existed. The positive rates of co-expression of PGP and GST-pi, PGP and Topo-II, PGP and LRP, GST-pi and Topo-II, LRP and GST-pi, LRP and Topo-II, PGP, GST-pi, Topo-II and LRP in malignant cells were 23.2%, 15.9%, 11.6%, 13.0%, 26.1%, 7.24%, 5.8%, respectively.
Conclusions: MDR-related proteins PGP, GST-pi, Topo-II and LRP are involved in multiple mechanisms of drug resistance in PGCA. Combined determination of PGP, GST-pi, Topo-II and LRP may be prospectively valuable for optimizing the chemotherapy regimes, developing high quality anti-cancer drugs, and further predicting the outcomes of those patients with PGCA.