The Evaluative Roles Of Some Clinical And Pathological Parameters In Multidrug Resistance Of Colorectal Cancer

Objective: Colorectal cancer is one of the common malignant tumors, itsincidence in the worldwide malignant tumors located in the third top. In China, recently,due to some changes of living habits and social structure of the aging tendencies etc, theincidence of colorectal cancer is increasing obviously. Surgical resection withchemotherapy as a main method is still used commonly in treatment of the cancer. Thechemotherapy is one of the important treatment methods, particularly for some patientswho have lost a chance to receive surgical operation. Over the last decade, adjuvantchemotherapy is changed from single chemotherapy after operation to the chemotherapybefore and/or in operation looked as "sandwich". There are many chemotherapyregimens clinically, but so far the effect of chemotherapy is still far from satisfactory.Tumor multidrug resistance including primary and acquired drug resistances is the mostimportant reason for the failure of chemotherapy. If the clinical and pathologicalparameters would be used as soon as possible to make a correct assessment of theresistance state of the tumor which is about to be removed, it maybe help us to decidethe operation and chemotherapy program.Multidrug resistance of tumors can be divided into primary and acquired drugresistance. There many factors relating to multidrug resistance, of which TopoisomeraseⅡ (TopoⅡ) and P-glycoprotein (P-gp) are the most representative, about them there aremany researches and the clinical applications. TopoⅡ is the key enzyme, which coulddirectly affect cell DNA replication, repair, transcription, and play an important role inDNA metabolic processes. If TopoⅡ was decreased in content or inactivated, it wasunable to form the drug-TopoⅡ-DNA complexes after the chemotherapy drugs entered into cancer cells, then TopoⅡ-DNA complexes would dissociate faster, therefore thedissociated DNA would join replication and transcription in cancer cells, so cancer cellswould be free from death. P-gp as an energy-dependent protein has ability to protectcells to avoid the harm from toxins or exogenous chemicals. Some of cancer cells couldexpress P-gp when they were attacked by chemotherapy drugs. P-gp could identify andbind drug molecules, at the same time, ATP could also bind to nucleotide binding siteson P-gp. P-gp would pump drugs out of the cells directly or indirectly with the energyreleased by ATP hydrolysis, moreover some drugs would swim out of cells throughchannels of P-gp, finally the concentration of drugs in the cancer cells would be reduced.In this study, TopoⅡ and P-gp were used as the primary drug resistance marks, wedetected their expressions in colorectal cancer and analyzed the correlation of theseprotein expressions to the clinical pathological parameters of the patients with colorectalcancer, explored the feasibility to assess of multidrug resistance of colorectal cancerwith clinical and pathological parameters.Methods: Three hundred and six surgical resection cases of colorectal cancerwere selected from January2011to December2011in Dalian University AffiliatedXinhua Hospital. The patients included168males and138females, their ages werefrom32to89years old with the average age of63.18years old. The expressions ofTopoⅡ and P-gp proteins in the tumor tissues were detected by immunohistochemistry.The expression of Ki67protein was also detected and then used as the marker for cellproliferation. We analyzed the correlations of the expressions of TopoⅡ, P-gp proteinsto the patients’ gender, age and tumor’s growth position, differentiation, infiltratingdepth, lymph node metastases and the expression of Ki67protein.These findings wereanalyzed by using the SPSSl3.0software package.Results:1.There was144cancers with high expression and162with low expression ofKi67protein, so the cancers were divided into high and low Ki67expression groupsaccording to the expression of Ki67protein. The expression of Ki67protein wasnegatively significant correlation to the degree of differentiation (P=0.016＜0.05), butnot significant correlation to patients’ gender, age and tumor’s site, infiltrating depth andlymph node metastases(P＞0.05). Therefore, in this research Ki67protein could be usedas a marker of cell proliferation.2. The positive rate of TopoⅡ protein expression in colorectal cancer was82.68%.The positive rates of TopoⅡ protein expression were96.53%and70.37%in the high and low Ki67expression groups respectively, there was positively significantcorrelation (P=0.000＜0.05), but the expression of TopoⅡ protein had no significantcorrelations to patients’ gender, age and tumor’s site, differentiation, infiltrating depthand lymph node metastases (P＞0.05).3. The positive rate of P-gp protein expression in colorectal cancer was77.12%.Its positive rates in stage T1,T2,T3and T4were42.86%,70.49%,78.90%and90.00%respectively, the expression of P-gp protein was positively significant correlation toinfiltrating depth of the tumor (P=0.038＜0.05). The positive rates in cancers without(stage N0) and with (stage N1/N2) lymph node metastases were72.19%and83.21%respectively, there was significant difference (P=0.022＜0.05).The positive rates ofP-gp protein expression were84.03%and70.99%in the high and low Ki67expressiongroups respectively, there was significant difference (P=0.007＜0.05), but theexpression of P-gp protein had no significant correlation to patients’ gender, age andtumor’s site, differentiation (P＞0.05).Conclusion:1. TopoⅡ protein is expressed in majority of colorectal cancers, we should selectchemotherapy drugs as the target of TopoⅡ.2. The common clinical and pathological parameters are not be used to judge thesensitivity of colorectal cancer to the drugs which target is TopoⅡ.3. Colorectal cancer with high expression of Ki67protein often expresses Topo Ⅱ,this finding indicates that the patients with colorectal cancer having high expression ofKi67protein may be benefit from the TopoⅡ inhibitors.4. P-gp protein is expressed in majority of colorectal cancers, therefore enoughattention should be paid in treating colorectal cancer with P-gp-mediated anti-cancerdrugs.5. The positive expression of P-gp protein would be used as a marker to representmalignant behaviors of the colorectal cancer.6. The common pathological parameters would not be used to judge the patientssensitivity to chemotherapy related to the expression of P-gp protein.7. Colorectal cancer with high expression of Ki67protein often expresses P-gpprotein, the finding suggests that colorectal cancer patients with high expression of Ki67protein might have the primary drug resistance.