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ORIGINAL ARTICLE
Year : 2015  |  Volume : 11  |  Issue : 1  |  Page : 46-50

Significance of MDR-related proteins in the postoperative individualized chemotherapy of gastric cancer


Department of Abdominal Surgery, Zhejiang Cancer Hospital, Hangzhou, China

Date of Web Publication16-Apr-2015

Correspondence Address:
Yian Du
Department of Abdominal Surgery, Zhejiang Cancer Hospital, Hangzhou - 310022
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.147695

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 > Abstract 

Objectives: Post-operative adjuvant chemotherapy was beneficial for some patients; however, it may increase the treatment burden and reduce the immunity of other patients. Screening appropriate patients based on molecular markers for individualized adjuvant chemotherapy was necessary.
Materials and Methods: Between June 2002 and June 2004, 119 patients who underwent radical gastrectomy were retrospectively analyzed. Some patients had adjuvant chemotherapy based on platinum and 5-FU for four to six cycles. Topoisomerase II (ToPo II) negative, multidrug resistance protein (MRP) positive, and glutathione S-transferase π (GST-π) positive were regarded as three risk factors that may be associated with chemotherapy resistance and poor prognosis. Patients were divided into two groups: high-risk group (≥2 risk factors) and the low-risk group (<2 risk factors), and the tumor recurrence and patient survival time of the two groups were analyzed.
Results: The average recurrence time of the low-risk group was significantly longer than that of the high-risk group (21.29 ± 11.10 versus 15.16 ± 8.05 months, P < 0.01).The 3-year and 5-year survival rate of the high-risk group was 57.4% and 42.6%; however, it had no significant difference compared to 66.2% and 58.5% of the low-risk group (P > 0.05). In the high-risk group, the 3-year survival rate of patients with/without chemotherapy were 62.1% and 52.0%, 5-year survival rates were 44.8% and 40.0%, respectively, but the difference was not statistically significant (P > 0.05). In the low-risk group, the 3-year survival rate of patients with/without chemotherapy were 81.2% and 51.5%, and the 5-year survival rates were 71.9% and 45.5%, respectively, and the differences were statistically significant (P < 0.05).
Conclusions: Multidrug resistance (MDR)-related proteins ToPo II, MRP, and GST-ð had great significance for the individualized post-operative chemotherapy and prognosis of gastric cancer.

Keywords: Chemotherapy, multidrug resistance-associated proteins, prognosis, stomach neoplasms


How to cite this article:
Yu P, Cheng X, Du Y, Yang L, Huang L. Significance of MDR-related proteins in the postoperative individualized chemotherapy of gastric cancer. J Can Res Ther 2015;11:46-50

How to cite this URL:
Yu P, Cheng X, Du Y, Yang L, Huang L. Significance of MDR-related proteins in the postoperative individualized chemotherapy of gastric cancer. J Can Res Ther [serial online] 2015 [cited 2019 Sep 15];11:46-50. Available from: http://www.cancerjournal.net/text.asp?2015/11/1/46/147695


 > Background Top


There is still a higher risk of recurrence and metastasis after radical gastric surgery, and adjuvant chemotherapy may reduce post-operative residual tumor cells and prevent relapse. [1],[2] In recent years, new results of randomized controlled studies indicate that post-operative chemotherapy can improve the prognosis of the patients. [3],[4] These results have been accepted in the National Comprehensive Cancer Network (NCCN) Gastric Cancer Clinical Practice Guidelines and recommended as the basis of post-operative treatment programs. However, some issues still need to be addressed: (1) subgroup analysis indicates that some patients (female, node-negative, late stages, old patients, etc.) did not benefit from adjuvant therapy. (2) Another problem ischemotherapy toxicity and compliance, and some patients withdraw from treatment because of adverse events.

So post-operative adjuvant chemotherapy is beneficial for some patients; however, it may increase the treatment burden and reduce the immunity of other patients. Therefore, it is too early to determine a program as standard adjuvant chemotherapy for gastric cancer. There are still many issues that need high-quality research to answer for individualized adjuvant chemotherapy. What was particularly worth mentioning is that the ToGA study has confirmed the value of Herceptin in the treatment of advanced gastric cancer. [5] Recently, Deng and colleagues provide for the first time a detailed molecular map of genomic alterations in gastric cancer, which has revealed several promising targets for subtype-specific therapies. [6] Screening appropriate patients based on molecular markers will become a major research direction for individualized adjuvant chemotherapy.

Multidrug resistance gene related proteins topoisomerase II (ToPo II), multidrug resistance protein (MRP) and glutathione S-transferase π (GST-π) were the basis of multidrug resistance in malignant tumors. [7],[8] It had been confirmed that MRP and GST-π overexpression, and decreased expression of ToPo II were important mechanisms-mediated multidrug resistance. [9] So, we carried out the study of multidrug resistance (MDR) gene related proteins in post-operative individualized treatment of gastric cancer.


 > Materials and methods Top


Patients and tissue samples

Between June 2002 and June 2004, a total of 119 patients who underwent radical gastrectomy at the department of abdominal surgery, Zhejiang cancer hospital were retrospectively analyzed. Of these patients, 77 cases were males and 42 cases were females, aged 25-78 years (mean 57.3 ± 6.7 years), Phase I/II were 39 cases and Phase III/IV were 80 cases, lesions ≥5 cm were 76 cases and lesions <5 cm were 43 cases, patients with/without lymph nodes metastases were 93 cases and 26 cases, respectively. None of the patients received pre-operative chemotherapy or other treatment for the tumor, and some patients had adjuvant chemotherapy based on platinum and 5-FU for four to six cycles (cisplatin, 25mg/m 2 , d1 ~ 3 and 5-fluorouracil, 1000 mg/m 2 , d1 ~ 3, repeated every 3 weeks).

Immunohistochemical staining

The antibodies used in this study were purchased from GBI Company (Golden Bridge International, Inc., Mukilteo, Washington, USA). Immunohistochemical staining was carried out on the formalin-fixed, 4μm thick paraffin-embedded tissue specimens. Pancreas, colon samples were used as a positive control for Topo-II and MRP, and ovary samples for GST-π, respectively. The specimens were evaluated independently by two pathologists in a blind fashion. Only cells with brown-colored staining were considered as positive. The intensity of expression of MDR-related proteins were stratified into four categories scored as follows: (a) negative(-): no appreciable cytomembrane, nuclear, or cytoplasmic staining or staining in <10% of neoplastic cells; (b) 1+: appreciable staining in 10-25% of neoplastic cells; (c) 2+: appreciable staining in 25-75% of neoplastic cells; (d) 3+: appreciable staining in >75% of neoplastic cells.

Patients follow-up

Patients received routine follow-up after radical gastrectomy. Once every quarter for two years and thereafter, once every half year (patients received chemotherapy were followed-up with chemotherapy cycles). ToPo II negative, MRP positive, and GST- MRP positive ToPorapy were followed-up gastrectomy. Once every quarter independently by two pathologists in a blind fashion. Only cells with brown-colored staining were considered 2 risk factors) and the low-risk group (<2 risk factors), and the tumor recurrence and patients' survival time of the two groups were analyzed.

Statistical analysis

All the experiment data were integrated into a comprehensive data set. Numerical data were recorded directly and measurement data were described as median and range. Statistical analysis was performed on Statistical Package for the Social Sciences (SPSS) software version 16.0 (SPSS Inc. Chicago, IL), and P < 0.05 was considered as statistically significant.


 > Results Top


The positive staining of To Po II was recognized to be expressed in the cell nucleus [Figure 1], while MRP and GST-π were expressed in the cytoplasm of malignant cells [Figure 2] and [Figure 3].
Figure 1: Immunohistochemical staining of ToPo II was identified in the cell nucleus (original magnification ×400)

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Figure 2: Immunohistochemical staining of MRP was recognized to be expressed in the cytoplasm of malignant cells (original magnification ×400)

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Figure 3: Immunohistochemical staining of GST-π was recognized to be expressed in the cytoplasm of malignant cells (original magnification ×400)

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The positive rate of ToPo II was 73.9%. When comparing the well-, moderately and poorly differentiated degree, a significant correlation was shown between ToPo II expression and the level of differentiation (86.3%, 64.5%, and 64.9%, respectively, P < 0.05). As for MRP, the positive rate was 42.9%. No significant differences with MRP expression were found in relation to the clinicopathological factors. The positive rate of GST-π was 51.3%, and significant differences in GST-π expression were found in relation to sex (male versus female, 59.7% versus 35.7%, P < 0.05) and differentiation (the well, moderately, and poorly status, 40.5%, 41.9%, 64.7%, respectively, P < 0.05) [Table 1].
Table 1: The expression of ToPo II, MRP, GST-π, and their relationship with clinicopathological factors

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The 3-and 5-year survival rates of the total 119 patients were 57.3% and 49.2%, respectively. No statistical difference was observed between single protein (ToPo II, MRP, or GST-tistical difference was observed between single protein57.3% and 49.2%-π was 51.3n ToPo data were described as median and range. Statistical analysis was perf <2 risk factors), the average recurrence time of the low-risk group was 21.29 ± 11.10 months, and was significantly longer than 15.16 ± 8.05 months of the high-risk group (P < 0.01). The 3-year and 5-year survival rate of the high-risk group was 57.4% and 42.6%; however, it had no significant difference compared to 66.2% and 58.5% of the low-risk group (P > 0.05).

In the high-risk group, the 3-year survival rate of patients with chemotherapy and patients without chemotherapy were 62.1% and 52.0%, 5-year survival rates were 44.8% and 40.0%, but the difference was not statistically significant (P > 0.05) [Figure 4]. In the low-risk group, the 3-year survival rate of patients with chemotherapy and patients without chemotherapy were 81.2% and 51.5%, 5-year survival rates were 71.9% and 45.5%, and the difference was statistically significant (P < 0.05) [Figure 5].
Figure 4: Overall survival of patients with or without chemotherapy in the high-risk group

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Figure 5: Overall survival of patients with or without chemotherapy in the low-risk group

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 > Discussion Top


Adjuvant chemotherapy after operation has been considered as necessary to eliminate systemic micrometastases and remanent malignant cells to the fullest extent possible, ultimately improving survival. [10],[11] Unfortunately, so far, this kind of adjuvant treatment strategy has been disappointing as a result of MDR of malignant cells to different chemotherapeutic agents. [12],[13] Therefore, detection and evaluation of MDR genes or proteins may help guide adjuvant chemotherapy in gastric cancer and determine the prognosis of patients.

MRP, one of the most studied mechanisms of MDR, acts as an adenosine triphosphate (ATP)-dependent outward transport pump and decreases intracellular accumulation of drugs by reducing the co-transport mechanism of glutathione. [14] Several previous studies have also indicated that overexpression of MRP most frequently predicts MDR. MRP confers resistance to alkylating agents, cyclophosphamide, and other drugs. [15] GST-π is a multifunctional enzyme that plays a critical role in cellular detoxification by catalyzing the conjugation of reduced glutathione to hydrophobic and electrophilic compounds. [16] GST-π is considered to be associated with the efflux of cis-diaminodichloroplatin (CDDP), flurouracil, and doxorubicin (DOX) through ATP-binding cassette transporters. [17] Topo-II is the target of several anticancer agents, such as doxorubicin, VM26, VP16, and mitoxantrone. [18] The decreased expression of ToPo II and changes of enzyme activity result in the dissociation of cleavable complex and reduced deoxyribonucleic acid (DNA) damage, and finally cause the drug resistance. [19]

In our study, statistical analysis indicates that none of the three proteins were significantly correlated with the recurrence and survival rates, so the determination of a single indicator is difficult to judge the effectiveness of adjuvant chemotherapy. Then, ToPo II negative, MRP positive, and GST- MRP positivefficult to judge the effectiveness of adjuvant chemotherapy. Then, ToPoof cleavable complex and reduced ced glutathione to hydrophobic and electrophilic compoundsidered 2 risk factors) and the low-risk group (<2 risk factors). The recurrence time of the low-risk group was significantly longer than that of the high-risk group, suggesting that the decreased expression of ToPo II and high expression of MRP and GST-π was associated with tumor invasion, recurrence, and poor prognosis, and this conclusion had been confirmed in the ovarian cancer. [20] In the low-risk group, the 3-year and 5-year survival rate of patients with chemotherapy was higher than that of the patients without chemotherapy. This result indicated that 5-Fu and platinum-based post-operative chemotherapy can increase survival benefits for patients in the low-risk group. Chemotherapy resistance was rare in these patients, and in theory, post-operative chemotherapy can be done fully fit and the prognosis of the patient will be significantly improved. In the high-risk group, the 3-year and 5-year survival rate of patients with chemotherapy was higher than that of the patients without chemotherapy, but the difference was not statistically significant. Therefore, the 5-Fu and platinum-based adjuvant chemotherapy did not improve the prognosis of the high-risk group, and for such patients, post-operative chemotherapy needs to be carefully discussed and selected.

Cisplatin combined with 5-FU was a classic chemotherapy regimen for gastric cancer [21] , but it did not get good effect in the high-risk group. Therefore, these conventional chemotherapy program (non-adaptation program) is in need of improvement, choosing other types of chemotherapy drugs (such as paclitaxel) [22] , or in combination with chemotherapy sensitizer or resistance reversal agents are better alternatives for the high-risk patients. [23]

These conclusions were based on a small number of cases and may have some limitations. Large sample of patients is being followed-up in our center, and the detailed results including the subgroup analysis (gender, lymph node metastasis, staging, etc.) will be reported in the near future.


 > Conclusions Top


Therefore, combined determination of MDR-related proteins ToPo II, MRP and GST-ππ may be prospectively valuable for optimizing chemotherapy regimes, and further predicting the outcomes of those patients. Further research should focus on the combined detection of molecular markers for individualized chemotherapy, and carry out a multi-center clinical trials, the results may be exciting.

 
 > References Top

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