HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

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

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.
AuthorsA Mercalli, V Sordi, R Formicola, M Dandrea, S Beghelli, A Scarpa, V Di Carlo, M Reni, L Piemonti
JournalBritish journal of cancer (Br J Cancer) Vol. 96 Issue 9 Pg. 1358-67 (May 07 2007) ISSN: 0007-0920 [Print] England
PMID17426706 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Glutamates
  • Pemetrexed
  • Guanine
  • Irinotecan
  • Camptothecin
Topics
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols (pharmacokinetics, pharmacology, therapeutic use)
  • Apoptosis (drug effects)
  • Camptothecin (analogs & derivatives, pharmacokinetics, pharmacology, toxicity)
  • Cell Cycle (drug effects)
  • Cell Line, Tumor
  • Drug Administration Schedule
  • Female
  • Glutamates (pharmacokinetics, pharmacology, toxicity)
  • Guanine (analogs & derivatives, pharmacokinetics, pharmacology, toxicity)
  • Humans
  • Irinotecan
  • Mice
  • Mice, Nude
  • Pancreatic Neoplasms (drug therapy, pathology)
  • Pemetrexed
  • Transplantation, Heterologous

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: