| Summary: | 碩士 === 中山醫學大學 === 醫學分子毒理學研究所 === 96 === Lung cancer is the leading cause of cancer deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for about 85 %, while SCLC accounts for the rest 15 %. The tubulin-binding agents (TBAs) are used extensively in the treatment of cancer. However, the prognosis for patients remains dismal due to the emergence of drug-resistant tumors which significantly limits the clinical utility of these drugs in the treatment of NSCLC. Therefore, we study the TBAs resistant mechanisms on the TBAs-resistant cell lines. We established A549 taxotere resistant cell lines and vincristine resistant cell lines and analyzed their drug resistance by MTT assay. The obtained results from A549 taxotere- resistant cell lines showed 700-fold resistance against taxotere and ＞400-fold resistance against vincristine when compared with the parental A549 cell.. The A549 vincristine-resistant cell line showed 200-fold resistance against taxotere and 250-fold resistance against vincristine .
There are two drug-resistant mechanisms associated with TBAs. One is the tumor cells expressed multi-drug resistant (MDR; ABCB1) phenotype. The phosphoglycoproteins on the cell membrane are the pumps for exporting drugs. Taxanes and Vinca alkaloids are the ligands of the pumps. So the drug could be exported out of cells and reduced the drugs efficiency by the pumps. The other mechanism is the tubulin gene alteration. We found ATP-binding cassette (ABC) transporter isotypes, especially ABCB1 expression were upregulated in A549 taxotere-resistant cells analyzed by microarray and real-time PCR. Then we found that A549 taxotere-resistant cell survival rate was obviously decreased after treating with the ABCB1 inhibitor Verapamil. Interestingly, the ABC transporter isotypes mRNA and tubulin expression of A549 vincristine-resistant cell line was not different when compared to A549. cells. Since the A549 vincristine-resistant cell lines still resisted to taxotere treatment, therefore, we presume that other drug-resistant mechanism may exist in the vincristine-resistant cells. In the future, we want to search those drug-resistant mechanisms in addition to ABC, and find out inhibitors to cooperate with chemotherapy drugs to induce sensitivity of drug-resistant cancer cells.
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