Efficacy of dimethylaminoparthenolide and sulindac in combination with gemcitabine in a genetically engineered mouse model of pancreatic cancer.
OBJECTIVE
Pancreatic cancer remains one of the deadliest diseases, with limited surgical and treatment options. Two targets of interest include the transcription factor nuclear factor-κB and cyclooxygenase-2, which are constitutively activated and overexpressed, respectively, in human pancreatic adenocarcinoma. We have previously shown that dimethylaminoparthenolide (DMAPT), a bioavailable nuclear factor-κB inhibitor, and the cyclooxygenase inhibitors sulindac and celecoxib have potential chemotherapeutic efficacy. The current study evaluates the efficacy of intervention with DMAPT and sulindac in the LSL-Kras(G12D);Pdx-1-Cre genetically engineered mouse model. Gemcitabine, traditionally a chemotherapeutic agent, has relatively low toxicity; thus, combinations with low-dose gemcitabine were also explored.


METHODS
LSL-Kras(G12D);Pdx-1-Cre mice at 7 months of age were randomized into placebo, DMAPT (40 mg/kg per day), sulindac (20 mg/kg per day), gemcitabine (50 mg/kg twice weekly), and combination treatment groups. After 3 months of treatment, the mice were killed.


RESULTS
The percentage of normal pancreatic ducts was significantly increased by the combinations of DMAPT/sulindac, DMAPT/gemcitabine, sulindac/gemcitabine, and DMAPT/sulindac/gemcitabine compared to placebo. Additionally, the percentage of mouse pancreatic intraepithelial neoplasia-2 lesions was significantly decreased by DMAPT/gemcitabine.


CONCLUSIONS
Intervention with DMAPT and sulindac in combination with gemcitabine may delay or prevent progression of premalignant pancreatic lesions in the LSL-Kras(G12D);Pdx-1-Cre mouse model of pancreatic cancer.
Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA. myipschn@iupui.edu
Michele T
MT
Yip-Schneider
Huangbing
H
Wu
Ralph H
RH
Hruban
Andrew M
AM
Lowy
Peter A
PA
Crooks
Christian Max
CM
Schmidt
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002278:Carcinoma in Situ / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage; D016207:Cytokines / Q000097:blood; D018450:Disease Progression; D016158:Genes, p53; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D012717:Sesquiterpenes / Q000008:administration & dosage; D013467:Sulindac / Q000008:administration & dosage
D052246:Cyclooxygenase 2 Inhibitors; D016207:Cytokines; C524858:LC-1 compound; D016328:NF-kappa B; D012717:Sesquiterpenes; D013467:Sulindac; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)