| Multidrug resistance (MDR) is a main phenomenon observed within tumor cells which is a major obstacle to failure of chemotherapy. MDR is a cross-resistance induced by one anticancer but it can resistance to different form and different action mechanism drug . In vitro MDR1 gene expression is activated following exposure to multiple agents including anticancer drug ,carcinogen, ultraviolet radiation, the ras oncogene and p53 tumor suppressor gene can modulate the activity of the MDR1 gene. Although there is much shortcoming in chemotherapy, it is an important mean to therapy tumor. So it is very important to overcome tumor multidrug resistance. The multidrug resistance of tumor is the focus of studying anticancer at present. Tumor suppressor P53 function loss is one of common genetic mutations during tumor progression,and it is mutated in 50% of all tumors. Much evidence indicates that mutant P53 plays a role not only in the process of tumorigenesis but also in determining the sensitivity or resistance of cancer cells to chemotherapeutic agents.Some studies demonstrated that mutant P53 increase MDR-1 mRNA which decrease chemotherapeutic sensitivity. To study the possibility of P53 approach to prevent and cure tumor multidrug resistance, this study was designed to examine the level of P53 protein and MDR-1 gene product using immunohistochemical techinques and examinedMDR-1 mRNA using RT-PCR to explore the relationship between mutant P53 and MDR-1 gene; at the same time ,the difference in chemotherapeutic sensitivity of cancer cells with mutant P53 was compared with those with mP53+sv40Tag and control by MTT.Methods1. Examining the level of P53 protein and MDR-1 gene product using immunohistochemical techniques to explore the relationship between mutant P53 and MDR-1 gene2. Construction of mutant P53(mP53) and SV40Tag recombinant;mP53 and mP53+sv40Tag was transferred to gastric cancer cell line singly,then examined MDR-1 mRNA using RT-PCR; At the same time ,the difference in chemotherapeutic sensitivity of cancer cells with mutant P53 was compared with those with mP53+ sv40Tag and control by MTT.Results1. 28(60.87%) of 46 samples examined were positive for P53, and 34(73.91%) of 46 were positive for PgP. Pgp expression were detected in 23 of 28 that were positive for P53, and in 9 of 18 that were negative for P53. We found that P53 and PgP co-expression was significant (P<0.05). There was relationship between PgP or P53 protein accumulation and histologic differentiation.2. Cancer cell line with mutant P53 showed higher MDR-1 mRNA than others .3. Cancer cell line with mutant P53 showed higher Chemotherapeutic sensitivity to 5-Fu than those with mP53+sv40Tag and control(P<0.05), but no difference between those with mP53+sv40Tag and control (P>0.05). Cancer cells with mutant P53 and those with mP53+sv40Tag showed higher Chemotherapeutic sensitivity to ADM than control(P<0.05), but no difference between those with mP53 and those with mP53+sv40Tag(P>0.05). There is no difference in chemotherapeutic sensitivityof cancer cells with mutant P53 compared with those with mP53+sv40Tag and control to CDDP(P>0.05). It showed that it is easy to induce multidrug resistance if it lies mutant P53, especially to 5-Fu and ADM, but not to CDDP.ConclusionThe results demonstrate that Mutant P53 may regulate the MDR-1 gene expression by several mechanism, it has close relation to tumor cells MDR. On one hand, PgP expression is closely associated with P53 protein accummulation in human gastric cancer which result in multidrug resistance. On the other hand , mP53 activate MDR1 gene that increase MDR-1 gene mRNA. The functional status of P53 in human gastric cancer cell lines directly affects their sensitivity to chemotherapeutic agents.. It showed that it is easy to induce multidrug resistance if it lies mutant p53.
|
PDF Full Text Request