| Mutation of DNA Mismatch Repair Genes and its Relation to Taxol and Topotecan Chemosensitivity in the Clones from the Cisplatin-Resistant Ovarian Cancer Cell Lines. |
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Heung Ki Kim, Woo Seok Son, Tae Chul Park, Tae Eung Kim, Young Me Koh, Ji Min Song, Ki Young Park, Jae Hoon Kim, Ki Seong Ryu, Jin Woo Kim, Sung Eun NamKoong, Soo Pyung Kim |
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| Abstract |
OBJECTIVE
Ovarian cancer represents a relatively chemosensitive solid tumor, with responsiveness to a range of agents. Cisplatin is the mainstay of drug treatment and is one of the most active single agent. However, the overall outcome for patients remains unsatisfactory and the emergence of drug resistance is a major factor in treatment failure. Loss of DNA mismatch repair is a common finding in many types of sporadic cancer as well as in patients with hereditary nonpolyposis colon cancer. Cells that lack DNA mismatch repair are resistant to commonly used chemotherapeutic agents. Selection of cells for resistance to cisplatin, a well-recognized mutagen, could result in mutation in genes involved in DNA mismatch repair. METHODS: This study evaluated the mutation of hMLH1 and hMSH2, and its relation to the Taxol and Topotecan chemosensitivity in the clones from the ovarian cancer cell line 2008 and cisplatin-resistant cell line 2008/ C13*5.25. RESULTS: 1. Cells from 2008 and 2008/C13*5.25 expressed both hMLH1 and hMSH2 when analysed with immunoblotting. 2. Twenty two out of 100 single-cell clones from 2008 and 27 of clones from 2008/C13*5.25 expressed no hMLH1. hMSH2 was expressed in all clones. 3. There was no difference of Taxol chemosensitivity between 2008 and 2008/C13*5.25 cell lines. In the 2008/C13*5.25 cell line, the hMLH1-deficient clones were more sensitive to Taxol than the hMLH1-proficient clones(P=0.049), but in 2008 cell lines hMLH1-proficient clones were more sesitive to Taxol(P=0.003). 4. There was no difference in Topotecan chemosensitivity between 2008 and 2008/C13*5.25 cell lines. In the 2008/C13*5.25 cell line, the hMLH1- deficient clones were not more sensitive to Topotecan than the hMLH1-proficient clones. In the 2008 cell lines hMLH1-deficient clones were more sesitive to Topotecan(P=0.001). Overall, hMLH1-deficient clones from both 2008 and 2008/C13*5.25 cell lines were significantly more sensitive to Topotecan(P=0.001). 5. Microsatellite instability was not demonstrated in all 4 types of single-cell clones from 2008 and 2008/C13*5.25 cell lines. CONCLUSIONS: The present results indicate that there is no relation between mutation of mismatch repair gene and cisplatin resistance. But hMLH1-deficient ovarian cancer cells are more sensitive to Taxol or Topotecan in this study. The latter finding mandates the examination to assess the mutation of hMLH1 in tumor cells before treatment or at the time clinical resistance to cisplatin develops in ovarian cancer. |
| Key Words:
Ovarian cancer, Cisplatin, Drug resistance, Mismatch repair, Taxol, Topotecan, Single cell clone |
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