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1. A preclinical evaluation of pemetrexed and irinotecan combination as second-line chemotherapy in pancreatic cancer.

Author

Mercalli, A., Sordi, V., Formicola, R., Dandrea, M., Beghelli, S., Scarpa, A., Di Carlo, V., Reni, M., and Piemonti, L.

Subjects
CANCER relapse, DRUG side effects, ANTINEOPLASTIC agents, DRUG therapy, PANCREATIC cancer, CANCER cells, CELL lines, ANIMAL experimentation, APOPTOSIS, CAMPTOTHECIN, CELL cycle, COMPARATIVE studies, DRUG administration, GLUTAMIC acid, RESEARCH methodology, MEDICAL cooperation, MICE, PANCREATIC tumors, PURINES, RESEARCH, XENOGRAFTS, EVALUATION research, PHARMACODYNAMICS
Abstract

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 IC50s under the Cmax 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.British Journal of Cancer (2007) 96, 1358–1367. doi:10.1038/sj.bjc.6603726 www.bjcancer.com Published online 10 April 2007 [ABSTRACT FROM AUTHOR]

Published
2007
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2. A preclinical evaluation of pemetrexed and irinotecan combination as second-line chemotherapy in pancreatic cancer

Author

Stefania Beghelli, Lorenzo Piemonti, Michele Reni, V. Di Carlo, Alessia Mercalli, Roberta Formicola, Mario D'Andrea, Valeria Sordi, Aldo Scarpa, Mercalli, A, Sordi, V, Formicola, R, Dandrea, M, Beghelli, S, Scarpa, A, Di Carlo, V, Reni, M, and Piemonti, Lorenzo

Subjects
Cancer Research, Guanine, endocrine system diseases, medicine.medical_treatment, pancreatic cancer, Transplantation, Heterologous, Mice, Nude, Apoptosis, Pemetrexed, Irinotecan, Drug Administration Schedule, Mice, Glutamates, Cell Line, Tumor, Pancreatic cancer, Antineoplastic Combined Chemotherapy Protocols, medicine, Animals, Humans, human, Chemotherapy, business.industry, Cell Cycle, chemiosensitivity, medicine.disease, digestive system diseases, Gemcitabine, Oxaliplatin, Pancreatic Neoplasms, Oncology, Docetaxel, Immunology, Cancer research, Camptothecin, Female, Translational Therapeutics, business, Raltitrexed, medicine.drug
Abstract

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 IC50s under the Cmax 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 microM; CPT-11 1 microm). 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.

Published
2007

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