Cellular Basis of Antiproliferative and Antitumor Activity of the Novel Camptothecin Derivative, Gimatecan, in Bladder Carcinoma Models
To investigate the cellular/molecular basis of the activity of a novel lipophilic camptothecin, gimatecan (ST1481), against slowly proliferating cells, we performed a comparative study of topotecan and gimatecan in human bladder cancer models (HT1376 and MCR). Gimatecan was significantly more effect...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2005-02-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558605800168 |
| _version_ | 1828948534975528960 |
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| author | Paola Ulivi Wainer Zoli Francesco Fabbri Giovanni Brigliadori Luca Ricotti Anna Tesei Marco Rosetti Michelandrea De Cesare Giovanni L. Beretta Elisabetta Corna Rosanna Supino Franco Zunino |
| author_facet | Paola Ulivi Wainer Zoli Francesco Fabbri Giovanni Brigliadori Luca Ricotti Anna Tesei Marco Rosetti Michelandrea De Cesare Giovanni L. Beretta Elisabetta Corna Rosanna Supino Franco Zunino |
| author_sort | Paola Ulivi |
| collection | DOAJ |
| description | To investigate the cellular/molecular basis of the activity of a novel lipophilic camptothecin, gimatecan (ST1481), against slowly proliferating cells, we performed a comparative study of topotecan and gimatecan in human bladder cancer models (HT1376 and MCR). Gimatecan was significantly more effective than topotecan in inhibiting the growth of HT1376 tumor, thus reflecting anti proliferative potency. In both HT1376 and MCR cells, gimatecan caused a persistent S-phase arrest, indicating an efficient DNA damage checkpoint. This response was consistent with a cytostatic effect, because no evidence of apoptosis was detected. In contrast to gimatecan, topotecan at equitoxic concentrations caused an early and persistent downregulation of topoisomerase I. Modulation of protein level could not be solely ascribed to the proteasome-mediated degradation of the enzyme because the proteasome inhibitor PS341 sensitized MCR but not HT1376 cells to camptothecins, suggesting alternative mechanisms of drug-induced topoisomerase I downregulation. Indeed, the two camptothecins caused a differential inhibition of topoisomerase I transcription, which is more marked in topotecan-treated cells. The HT1376 model was more sensitive to this immediate decrease of mRNA level. Our data document a marked antitumor activity of gimatecan against a bladder carcinoma model. A limited downregulation of topoisomerase I by gimatecan provides additional insights into the cellular basis of drug potency. |
| first_indexed | 2024-12-14T05:49:45Z |
| format | Article |
| id | doaj.art-d60ba5e4abc447279cd7c7c59c5c5d12 |
| institution | Directory Open Access Journal |
| issn | 1476-5586 1522-8002 |
| language | English |
| last_indexed | 2024-12-14T05:49:45Z |
| publishDate | 2005-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj.art-d60ba5e4abc447279cd7c7c59c5c5d122022-12-21T23:14:47ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55861522-80022005-02-017215216110.1593/neo.04397Cellular Basis of Antiproliferative and Antitumor Activity of the Novel Camptothecin Derivative, Gimatecan, in Bladder Carcinoma ModelsPaola Ulivi0Wainer Zoli1Francesco Fabbri2Giovanni Brigliadori3Luca Ricotti4Anna Tesei5Marco Rosetti6Michelandrea De Cesare7Giovanni L. Beretta8Elisabetta Corna9Rosanna Supino10Franco Zunino11Istituto Oncologico Romagnolo, Forlì, ItalyIstituto Oncologico Romagnolo, Forlì, ItalyIstituto Oncologico Romagnolo, Forlì, ItalyIstituto Oncologico Romagnolo, Forlì, ItalyIstituto Oncologico Romagnolo, Forlì, ItalyIstituto Oncologico Romagnolo, Forlì, ItalyIstituto Oncologico Romagnolo, Forlì, ItalyIstituto Nazionale per to Studio e la Cura dei Tumori, Milan, ItalyIstituto Nazionale per to Studio e la Cura dei Tumori, Milan, ItalyIstituto Nazionale per to Studio e la Cura dei Tumori, Milan, ItalyIstituto Nazionale per to Studio e la Cura dei Tumori, Milan, ItalyIstituto Nazionale per to Studio e la Cura dei Tumori, Milan, ItalyTo investigate the cellular/molecular basis of the activity of a novel lipophilic camptothecin, gimatecan (ST1481), against slowly proliferating cells, we performed a comparative study of topotecan and gimatecan in human bladder cancer models (HT1376 and MCR). Gimatecan was significantly more effective than topotecan in inhibiting the growth of HT1376 tumor, thus reflecting anti proliferative potency. In both HT1376 and MCR cells, gimatecan caused a persistent S-phase arrest, indicating an efficient DNA damage checkpoint. This response was consistent with a cytostatic effect, because no evidence of apoptosis was detected. In contrast to gimatecan, topotecan at equitoxic concentrations caused an early and persistent downregulation of topoisomerase I. Modulation of protein level could not be solely ascribed to the proteasome-mediated degradation of the enzyme because the proteasome inhibitor PS341 sensitized MCR but not HT1376 cells to camptothecins, suggesting alternative mechanisms of drug-induced topoisomerase I downregulation. Indeed, the two camptothecins caused a differential inhibition of topoisomerase I transcription, which is more marked in topotecan-treated cells. The HT1376 model was more sensitive to this immediate decrease of mRNA level. Our data document a marked antitumor activity of gimatecan against a bladder carcinoma model. A limited downregulation of topoisomerase I by gimatecan provides additional insights into the cellular basis of drug potency.http://www.sciencedirect.com/science/article/pii/S1476558605800168Bladder carcinomaDNA topoisomerase Igimatecancamptothecinsantitumor activity |
| spellingShingle | Paola Ulivi Wainer Zoli Francesco Fabbri Giovanni Brigliadori Luca Ricotti Anna Tesei Marco Rosetti Michelandrea De Cesare Giovanni L. Beretta Elisabetta Corna Rosanna Supino Franco Zunino Cellular Basis of Antiproliferative and Antitumor Activity of the Novel Camptothecin Derivative, Gimatecan, in Bladder Carcinoma Models Neoplasia: An International Journal for Oncology Research Bladder carcinoma DNA topoisomerase I gimatecan camptothecins antitumor activity |
| title | Cellular Basis of Antiproliferative and Antitumor Activity of the Novel Camptothecin Derivative, Gimatecan, in Bladder Carcinoma Models |
| title_full | Cellular Basis of Antiproliferative and Antitumor Activity of the Novel Camptothecin Derivative, Gimatecan, in Bladder Carcinoma Models |
| title_fullStr | Cellular Basis of Antiproliferative and Antitumor Activity of the Novel Camptothecin Derivative, Gimatecan, in Bladder Carcinoma Models |
| title_full_unstemmed | Cellular Basis of Antiproliferative and Antitumor Activity of the Novel Camptothecin Derivative, Gimatecan, in Bladder Carcinoma Models |
| title_short | Cellular Basis of Antiproliferative and Antitumor Activity of the Novel Camptothecin Derivative, Gimatecan, in Bladder Carcinoma Models |
| title_sort | cellular basis of antiproliferative and antitumor activity of the novel camptothecin derivative gimatecan in bladder carcinoma models |
| topic | Bladder carcinoma DNA topoisomerase I gimatecan camptothecins antitumor activity |
| url | http://www.sciencedirect.com/science/article/pii/S1476558605800168 |
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