Effect of celecoxib and the novel anti-cancer agent, dimethylamino-parthenolide, in a developmental model of pancreatic cancer.
OBJECTIVE
Cancer of the exocrine pancreas is the fourth leading cause of cancer-related deaths in the United States. The efficacy of a novel bioavailable anticancer agent, dimethylamino-parthenolide (DMAPT), and the cyclooxygenase 2 inhibitor, celecoxib, was evaluated in a carcinogen-induced developmental model of pancreatic cancer.


METHODS
Syrian golden hamsters were injected with N-nitrosobis(2-oxopropyl)amine, once weekly for 6 weeks. Upon the first injection, hamsters were randomized as follows: placebo, low-/high-dose DMAPT (20 and 40 mg/kg per day), low-/high-dose celecoxib (10and 50 mg/kg per day), or combination DMAPT/celecoxib (low/low, high/high).


RESULTS
The 32-week trial showed that 40 mg/kg DMAPT alone significantly decreased the size of gross pancreatic cancers relative to placebo. No significant difference in gross tumor number was observed between the treatment groups and placebo with the exception of 50 mg/kg celecoxib with a higher tumor incidence; this group also exhibited lower lymphotactin levels suggestive of decreased immune surveillance. Tumor invasion into adjacent organs and metastasis were not observed in the DMAPT/celecoxib treatment groups. Drug targets including prostaglandin E2, prostaglandin E2 metabolite and activated nuclear factor kappaB were significantly decreased.


CONCLUSIONS
Dimethylamino-parthenolide and celecoxib have the potential to be novel chemotherapeutic agents for pancreatic cancer; however, further optimization or the use of other modalities may be required for chemoprevention.
Yip-Schneider
Michele T
MT
Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA. myipschn@iupui.edu
Wu
Huangbing
H
Njoku
Victor
V
Ralstin
Matthew
M
Holcomb
Bryan
B
Crooks
Peter A
PA
Neelakantan
Sundar
S
Sweeney
Christopher J
CJ
Schmidt
C Max
CM
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D000068579:Celecoxib; D049109:Cell Proliferation / Q000187:drug effects; D019744:Chemokines, C / Q000378:metabolism; D006224:Cricetinae; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D019394:Ki-67 Antigen / Q000378:metabolism; D008647:Mesocricetus; D009077:Mucins / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009602:Nitrosamines; D010190:Pancreatic Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D011720:Pyrazoles / Q000008:administration & dosage; D012717:Sesquiterpenes / Q000008:administration & dosage; D013449:Sulfonamides / Q000008:administration & dosage; D013997:Time Factors
D019744:Chemokines, C; D052246:Cyclooxygenase 2 Inhibitors; D019394:Ki-67 Antigen; C524858:LC-1 compound; D009077:Mucins; D016328:NF-kappa B; D009602:Nitrosamines; D011720:Pyrazoles; D012717:Sesquiterpenes; D013449:Sulfonamides; C486249:Xcl1 protein, mouse; C013622:nitrosobis(2-oxopropyl)amine; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D000068579:Celecoxib; D015232:Dinoprostone