Topotecan (Hycamtin) responsiveness in human renal carcinoma cell lines of the clear cell and papillary types.
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.


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.


CONCLUSIONS
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.
Ramp
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U
Institute of Pathology, Heinrich Heine University, Duesseldorf, Germany.
Mahotka
C
C
Kalinski
T
T
Ebel
E
E
Gabbert
H E
HE
Gerharz
C D
CD
D018262:Adenocarcinoma, Clear Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001761:Bleomycin / Q000494:pharmacology; D002291:Carcinoma, Papillary / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D019772:Topotecan / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D051028:bcl-2-Associated X Protein
D000970:Antineoplastic Agents; C494826:BAX protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D001761:Bleomycin; D019772:Topotecan; D005472:Fluorouracil