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The novel Trk receptor tyrosine kinase inhibitor CEP-701 (KT-5555) exhibits antitumor efficacy against human pancreatic carcinoma (Panc1) xenograft growth and in vivo invasiveness
- Source :
- Annals of the New York Academy of Sciences. 880
- Publication Year :
- 1999
-
Abstract
- The survival rate for patients with pancreatic ductal adenocarcinoma (PDAC) is among the poorest for all cancers. The factors that contribute to this poor prognosis are lack of effective early detection, high rate of metastases and a generally refractory response to available treatment modalities. The most commonly used treatment methods--chemotherapy and radiation therapy--are mainly used for symptom palliation, with surgery being the only "curative" treatment option. The use of combinations of treatment modalities is the only therapy available to patients with locally advanced disease or that which is surgically unresectable. These options are still not sufficient to increase patient survival time significantly. The aggressive behavior and poor prognosis of this cancer is associated with an increased expression of many growth factors and their cognate receptors. We have demonstrated previously the aberrant expression of the Trk receptors (Trks A, B, and C) in PDAC specimens and human PDAC-derived cell lines and a biphasic, dose-dependent response of specific neurotrophic agents on the in vitro invasiveness of PDAC cells. Based on these data we have evaluated the therapeutic potential of inhibiting neurotrophin-Trk interactions using a selective Trk tyrosine kinase inhibitor (CEP-701) on subcutaneous (s.c.) and tracheal xenografts derived from the poorly differentiated PDAC cell line, Panc1. We demonstrate that CEP-701 administration at 10 mg/kg s.c. BID for 21 days inhibited tumor growth of the Panc1 s.c. xenografts in a statistically-significant manner (p < 0.01) compared to vehicle controls, in the absence of morbidity and mortality. A T/C value of 25% was observed for CEP-701-treated s.c. xenografts. In addition, CEP-701 administration inhibited tumor cell invasion in the s.c. tracheal xenograft model of in vivo invasiveness. Taken together, these data suggest that further studies are warranted to evaluate CEP-701 as a potential therapeutic agent in the treatment of PDAC.
- Subjects :
- Pathology
medicine.medical_specialty
Indoles
medicine.drug_class
Injections, Subcutaneous
Carbazoles
Mice, Nude
Antineoplastic Agents
Adenocarcinoma
General Biochemistry, Genetics and Molecular Biology
Tyrosine-kinase inhibitor
Mice
History and Philosophy of Science
In vivo
medicine
Animals
Humans
Neoplasm Invasiveness
Enzyme Inhibitors
Receptor
Furans
Survival rate
Mice, Inbred BALB C
biology
Molecular Structure
business.industry
General Neuroscience
Cancer
Receptor Protein-Tyrosine Kinases
medicine.disease
Rats
Pancreatic Neoplasms
Trachea
Cell culture
Trk receptor
Cancer research
biology.protein
Female
business
Neoplasm Transplantation
Neurotrophin
Subjects
Details
- ISSN :
- 00778923
- Volume :
- 880
- Database :
- OpenAIRE
- Journal :
- Annals of the New York Academy of Sciences
- Accession number :
- edsair.doi.dedup.....25da324a77faa0bfa5108f6905496d91