PMID- 17426706
OWN - NLM
STAT- MEDLINE
DCOM- 20070912
LR  - 20181201
IS  - 0007-0920 (Print)
IS  - 1532-1827 (Electronic)
IS  - 0007-0920 (Linking)
VI  - 96
IP  - 9
DP  - 2007 May 7
TI  - A preclinical evaluation of pemetrexed and irinotecan combination as second-line 
      chemotherapy in pancreatic cancer.
PG  - 1358-67
AB  - 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.
FAU - Mercalli, A
AU  - Mercalli A
AD  - Laboratory of Experimental Surgery, San Raffaele Scientific Institute, Via 
      Olgettina 60, Milan 20132, Italy.
FAU - Sordi, V
AU  - Sordi V
FAU - Formicola, R
AU  - Formicola R
FAU - Dandrea, M
AU  - Dandrea M
FAU - Beghelli, S
AU  - Beghelli S
FAU - Scarpa, A
AU  - Scarpa A
FAU - Di Carlo, V
AU  - Di Carlo V
FAU - Reni, M
AU  - Reni M
FAU - Piemonti, L
AU  - Piemonti L
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20070410
PL  - England
TA  - Br J Cancer
JT  - British journal of cancer
JID - 0370635
RN  - 0 (Glutamates)
RN  - 04Q9AIZ7NO (Pemetrexed)
RN  - 5Z93L87A1R (Guanine)
RN  - 7673326042 (Irinotecan)
RN  - XT3Z54Z28A (Camptothecin)
SB  - IM
MH  - Animals
MH  - Antineoplastic Combined Chemotherapy 
      Protocols/*pharmacokinetics/pharmacology/therapeutic use
MH  - Apoptosis/drug effects
MH  - Camptothecin/*analogs & derivatives/pharmacokinetics/pharmacology/toxicity
MH  - Cell Cycle/drug effects
MH  - Cell Line, Tumor
MH  - Drug Administration Schedule
MH  - Female
MH  - Glutamates/pharmacokinetics/*pharmacology/toxicity
MH  - Guanine/*analogs & derivatives/pharmacokinetics/pharmacology/toxicity
MH  - Humans
MH  - Irinotecan
MH  - Mice
MH  - Mice, Nude
MH  - Pancreatic Neoplasms/*drug therapy/pathology
MH  - Pemetrexed
MH  - Transplantation, Heterologous
PMC - PMC2360188
EDAT- 2007/04/12 09:00
MHDA- 2007/09/13 09:00
PMCR- 2008/05/07
CRDT- 2007/04/12 09:00
PHST- 2007/04/12 09:00 [pubmed]
PHST- 2007/09/13 09:00 [medline]
PHST- 2007/04/12 09:00 [entrez]
PHST- 2008/05/07 00:00 [pmc-release]
AID - 6603726 [pii]
AID - 10.1038/sj.bjc.6603726 [doi]
PST - ppublish
SO  - Br J Cancer. 2007 May 7;96(9):1358-67. doi: 10.1038/sj.bjc.6603726. Epub 2007 Apr 
      10.