Journal
BRITISH JOURNAL OF CANCER
Volume 110, Issue 6, Pages 1481-1487Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/bjc.2014.49
Keywords
gemcitabine; iRGD peptide; neuropilin-1; pancreatic cancer; tumour graft
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Funding
- Ministry of Education, Culture, Sports, Science, and Technology of Japan. [23300362, 23659635]
- Grants-in-Aid for Scientific Research [23659635, 23300362] Funding Source: KAKEN
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Background: Impaired drug transport is an important factor that reduces the efficacy of anticancer agents against pancreatic cancer. Here, we report a novel combination chemotherapy using gemcitabine (GEM) and internalised-RGD (iRGD) peptide, which enhances tumour-specific drug penetration by binding neuropilin-1 (NRP1) receptor. Methods: A total of five pancreatic cancer murine models (two cell line-based xenografts (CXs) and three tumour grafts (TGs)) were treated with either GEM (100mg kg(-1), q3d x 4) alone or GEM plus iRGD peptide (8 mu mol kg(-1)). Evaluation of NRP1 expression in xenografts and 48 clinical cancer specimens was performed by immunohistochemistry (IHC). Results: We identified a subset of pancreatic cancer models that showed NRP1 overexpression sensitive to iRGD coadministration. Treatment with GEM plus iRGD peptide resulted in a significant tumour reduction compared with GEM monotherapy in CXs, but not remarkable in TGs. Potential targets of iRGD were characterised as cases showing NRP1 overexpression (IHC-2 + /3+), and these accounted for 45.8% of the clinical specimens. Conclusions: Internalised RGD peptide enhances the effects of co-administered drugs in pancreatic cancer models, its efficacy is however only appreciable in those employing cell lines. Therefore, the clinical application needs to be given careful consideration.
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