BACKGROUND: Since no effective therapeutic approach is yet known for metastatic renal cell carcinoma (RCC), we analyzed the effects of topotecan (Hycamtin), a novel topoisomerase I-inhibitor, in RCC cell lines of the clear cell and papillary/chromophilic types. MATERIALS AND METHODS: The anti-proliferative and apoptosis-inducing effects of topotecan were analyzed in 20 RCC cell lines by MTT-assay and light microscopic apoptosis counting. Moreover, Bcl-2 and Bax expression was investigated by Northern blot and immunocytochemistry while the p53 mutation status was analyzed by DNA sequencing. RESULTS: Exposure to clinically relevant concentrations of topotecan (i.e. < or = 1 microg/ml) resulted in a significant (p<0.05) dose-dependent reduction of cell number in 17 out of 20 RCC cell lines. The reduction of cell number was paralleled by an increase in apoptotic cell death. Papillary/chromophilic RCCs exhibited a significantly (p<0.05) more pronounced responsiveness to topotecan than clear cell RCCs. Moreover, the effects of topotecan proved to be superior to those of 5-fluorouracil (5-FU), an anticancer drug currently used in the therapy of RCCs. No correlation became evident between responsiveness to topotecan and the expression levels of Bcl-2 and Bax. Moreover, the response to topotecan could not be correlated with the p53 mutation status of our RCC cell lines. CONCLUSION: Clinically relevant concentrations of topotecan induced apoptosis in RCC cell lines more effectively than 5-FU. Further testing will show whether topotecan-induced apoptosis can be exploited for the treatment of RCCs in vivo as well.
BACKGROUND: Since no effective therapeutic approach is yet known for metastatic renal cell carcinoma (RCC), we analyzed the effects of topotecan (Hycamtin), a novel topoisomerase I-inhibitor, in RCC cell lines of the clear cell and papillary/chromophilic types. MATERIALS AND METHODS: The anti-proliferative and apoptosis-inducing effects of topotecan were analyzed in 20 RCC cell lines by MTT-assay and light microscopic apoptosis counting. Moreover, Bcl-2 and Bax expression was investigated by Northern blot and immunocytochemistry while the p53 mutation status was analyzed by DNA sequencing. RESULTS: Exposure to clinically relevant concentrations of topotecan (i.e. < or = 1 microg/ml) resulted in a significant (p<0.05) dose-dependent reduction of cell number in 17 out of 20 RCC cell lines. The reduction of cell number was paralleled by an increase in apoptotic cell death. Papillary/chromophilic RCCs exhibited a significantly (p<0.05) more pronounced responsiveness to topotecan than clear cell RCCs. Moreover, the effects of topotecan proved to be superior to those of 5-fluorouracil (5-FU), an anticancer drug currently used in the therapy of RCCs. No correlation became evident between responsiveness to topotecan and the expression levels of Bcl-2 and Bax. Moreover, the response to topotecan could not be correlated with the p53 mutation status of our RCC cell lines. CONCLUSION: Clinically relevant concentrations of topotecan induced apoptosis in RCC cell lines more effectively than 5-FU. Further testing will show whether topotecan-induced apoptosis can be exploited for the treatment of RCCs in vivo as well.
Authors: Yi Zhi; Jin Yang; Shengchao Tian; Fang Yuan; Yang Liu; Yi Zhang; Pinghua Sun; Bo Song; Zhiwen Chen Journal: Int J Mol Sci Date: 2012-05-18 Impact factor: 6.208