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Anti-Bv8 antibody and metronomic gemcitabine improve pancreatic adenocarcinoma treatment outcome following weekly gemcitabine therapy.
- Source :
-
Neoplasia (New York, N.Y.) [Neoplasia] 2014 Jun; Vol. 16 (6), pp. 501-10. Date of Electronic Publication: 2014 Jun 20. - Publication Year :
- 2014
-
Abstract
- Weekly gemcitabine therapy is the major treatment offered for patients with pancreatic adenocarcinoma cancer; however, relative resistance of tumor cells to chemotherapy, rapid regrowth, and metastasis are the main causes of death within a year. Recently, the daily continuous administration of chemotherapy in low doses--called metronomic chemotherapy (MC)--has been shown to inhibit primary tumor growth and delay metastases in several tumor types; however, its use as a single therapy is still in question due to its moderate therapeutic benefit. Here, we show that the combination of weekly gemcitabine with MC of the same drug delays tumor regrowth and inhibits metastasis in mice implanted orthotopically with pancreatic tumors. We further demonstrate that weekly gemcitabine, but not continuous MC gemcitabine or the combination of the two drug regimens, promotes rebound myeloid-derived suppressor cell (MDSC) mobilization and increases angiogenesis in this tumor model. Furthermore, Bv8 is highly expressed in MDSCs colonizing pancreatic tumors in mice treated with weekly gemcitabine compared to MC gemcitabine or the combination of the two regimens. Blocking Bv8 with antibodies in weekly gemcitabine-treated mice results in a significant reduction in tumor regrowth, angiogenesis, and metastasis. Overall, our results suggest that pro-tumorigenic effects induced by weekly gemcitabine are mediated in part by MDSCs expressing Bv8. Therefore, both Bv8 inhibition and MC can be used as legitimate 'add-on' treatments for preventing post-chemotherapy pancreatic cancer recurrence, progression, and metastasis following weekly gemcitabine therapy.<br /> (Copyright © 2014 Neoplasia Press, Inc. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Adenocarcinoma mortality
Adenocarcinoma pathology
Administration, Metronomic
Animals
Cell Line, Tumor
Cell Movement drug effects
Deoxycytidine administration & dosage
Disease Models, Animal
Female
Gastrointestinal Hormones metabolism
Humans
Mice
Neoplasm Metastasis
Neuropeptides metabolism
Pancreatic Neoplasms mortality
Pancreatic Neoplasms pathology
Treatment Outcome
Tumor Burden drug effects
Xenograft Model Antitumor Assays
Gemcitabine
Adenocarcinoma drug therapy
Antibodies, Monoclonal administration & dosage
Antimetabolites, Antineoplastic administration & dosage
Deoxycytidine analogs & derivatives
Gastrointestinal Hormones antagonists & inhibitors
Neuropeptides antagonists & inhibitors
Pancreatic Neoplasms drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5586
- Volume :
- 16
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Neoplasia (New York, N.Y.)
- Publication Type :
- Academic Journal
- Accession number :
- 24957319
- Full Text :
- https://doi.org/10.1016/j.neo.2014.05.011