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A preclinical evaluation of pemetrexed and irinotecan combination as second-line chemotherapy in pancreatic cancer
Gemcitabine (GEM)-based chemotherapy is regarded as the standard treatment of pancreatic adenocarcinoma, but yields a very limited disease control. Very few studies have investigated salvage chemotherapy after failure of GEM or GEM-containing chemotherapy and preclinical studies attempting to widen...
Autores principales: | , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Nature Publishing Group
2007
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2360188/ https://www.ncbi.nlm.nih.gov/pubmed/17426706 http://dx.doi.org/10.1038/sj.bjc.6603726 |
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author | Mercalli, A Sordi, V Formicola, R Dandrea, M Beghelli, S Scarpa, A Di Carlo, V Reni, M Piemonti, L |
author_facet | Mercalli, A Sordi, V Formicola, R Dandrea, M Beghelli, S Scarpa, A Di Carlo, V Reni, M Piemonti, L |
author_sort | Mercalli, A |
collection | PubMed |
description | Gemcitabine (GEM)-based chemotherapy is regarded as the standard treatment of pancreatic adenocarcinoma, but yields a very limited disease control. Very few studies have investigated salvage chemotherapy after failure of GEM or GEM-containing chemotherapy and preclinical studies attempting to widen the therapeutic armamentarium, not including GEM, are warranted. MIA PaCa2, CFPAC-1 and Capan-1 pancreatic cancer cell lines were treated with GEM, fluouracil (5-FU), docetaxel (DCT), oxaliplatin (OXP), irinotecan (CPT-11), pemetrexed (PMX) and raltitrexed (RTX) as single agent. Pemetrexed, inducing apoptosis with IC(50)s under the C(max) in the three lines tested, appeared the most effective drug as single agent. Based on these results, schedule- and concentration-dependent drug interactions (assessed using the combination index) of PMX/GEM, PMX/DCT and PMX–CPT-11 were evaluated. The combinatory study clearly indicated the PMX and CPT-11 combination as the most active against pancreatic cancer. To confirm the efficacy of PMX–CPT-11 combination, we extended the study to a panel of 10 pancreatic cancer cell lines using clinically relevant concentrations (PMX 10 μM; CPT-11 1 μm). In eight of 10 lines, the PMX–CPT-11 treatment significantly reduced cell recovery and increased both the subG1 and caspase 3/7 fraction. After a 5-day wash out period, an increased fraction of subG1 and caspase3/7 persisted in PMX–CPT-11-pretreated cell lines and a significant reduction in the clonogenicity capacity was evident. Finally, in vivo, the PMX/CPT-11 combination showed the ability to inhibit xenograft tumours growth as second-line therapy after GEM treatment. The PMX and CPT-11 combination displays a strong schedule-independent synergistic cytotoxic activity against pancreatic cancer, providing experimental basis for its clinical testing as salvage chemotherapy in pancreatic cancer patients. |
format | Text |
id | pubmed-2360188 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2007 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-23601882009-09-10 A preclinical evaluation of pemetrexed and irinotecan combination as second-line chemotherapy in pancreatic cancer Mercalli, A Sordi, V Formicola, R Dandrea, M Beghelli, S Scarpa, A Di Carlo, V Reni, M Piemonti, L Br J Cancer Translational Therapeutics Gemcitabine (GEM)-based chemotherapy is regarded as the standard treatment of pancreatic adenocarcinoma, but yields a very limited disease control. Very few studies have investigated salvage chemotherapy after failure of GEM or GEM-containing chemotherapy and preclinical studies attempting to widen the therapeutic armamentarium, not including GEM, are warranted. MIA PaCa2, CFPAC-1 and Capan-1 pancreatic cancer cell lines were treated with GEM, fluouracil (5-FU), docetaxel (DCT), oxaliplatin (OXP), irinotecan (CPT-11), pemetrexed (PMX) and raltitrexed (RTX) as single agent. Pemetrexed, inducing apoptosis with IC(50)s under the C(max) in the three lines tested, appeared the most effective drug as single agent. Based on these results, schedule- and concentration-dependent drug interactions (assessed using the combination index) of PMX/GEM, PMX/DCT and PMX–CPT-11 were evaluated. The combinatory study clearly indicated the PMX and CPT-11 combination as the most active against pancreatic cancer. To confirm the efficacy of PMX–CPT-11 combination, we extended the study to a panel of 10 pancreatic cancer cell lines using clinically relevant concentrations (PMX 10 μM; CPT-11 1 μm). In eight of 10 lines, the PMX–CPT-11 treatment significantly reduced cell recovery and increased both the subG1 and caspase 3/7 fraction. After a 5-day wash out period, an increased fraction of subG1 and caspase3/7 persisted in PMX–CPT-11-pretreated cell lines and a significant reduction in the clonogenicity capacity was evident. Finally, in vivo, the PMX/CPT-11 combination showed the ability to inhibit xenograft tumours growth as second-line therapy after GEM treatment. The PMX and CPT-11 combination displays a strong schedule-independent synergistic cytotoxic activity against pancreatic cancer, providing experimental basis for its clinical testing as salvage chemotherapy in pancreatic cancer patients. Nature Publishing Group 2007-05-07 2007-04-10 /pmc/articles/PMC2360188/ /pubmed/17426706 http://dx.doi.org/10.1038/sj.bjc.6603726 Text en Copyright © 2007 Cancer Research UK https://creativecommons.org/licenses/by/4.0/This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material.If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Translational Therapeutics Mercalli, A Sordi, V Formicola, R Dandrea, M Beghelli, S Scarpa, A Di Carlo, V Reni, M Piemonti, L A preclinical evaluation of pemetrexed and irinotecan combination as second-line chemotherapy in pancreatic cancer |
title | A preclinical evaluation of pemetrexed and irinotecan combination as second-line chemotherapy in pancreatic cancer |
title_full | A preclinical evaluation of pemetrexed and irinotecan combination as second-line chemotherapy in pancreatic cancer |
title_fullStr | A preclinical evaluation of pemetrexed and irinotecan combination as second-line chemotherapy in pancreatic cancer |
title_full_unstemmed | A preclinical evaluation of pemetrexed and irinotecan combination as second-line chemotherapy in pancreatic cancer |
title_short | A preclinical evaluation of pemetrexed and irinotecan combination as second-line chemotherapy in pancreatic cancer |
title_sort | preclinical evaluation of pemetrexed and irinotecan combination as second-line chemotherapy in pancreatic cancer |
topic | Translational Therapeutics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2360188/ https://www.ncbi.nlm.nih.gov/pubmed/17426706 http://dx.doi.org/10.1038/sj.bjc.6603726 |
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