title: Anti-Bv8 antibody and metronomic gemcitabine improve pancreatic adenocarcinoma treatment outcome following weekly gemcitabine therapy.
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.
authors: Department of Molecular Pharmacology, Rappaport Faculty of Medicine, Technion, Haifa, Israel; Department of Internal Medicine C, Rambam Health Care Campus, Haifa, Israel.
authors: Erez
authors: E
authors: Hasnis
authors: Department of Molecular Pharmacology, Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors: Dror
authors: D
authors: Alishekevitz
authors: Department of Molecular Pharmacology, Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors: Svetlana
authors: S
authors: Gingis-Veltski
authors: Department of Molecular Pharmacology, Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors: Rotem
authors: R
authors: Bril
authors: Department of Molecular Pharmacology, Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors: Ella
authors: E
authors: Fremder
authors: Department of Molecular Pharmacology, Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors: Tali
authors: T
authors: Voloshin
authors: Department of Molecular Pharmacology, Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors: Ziv
authors: Z
authors: Raviv
authors: Department of Internal Medicine C, Rambam Health Care Campus, Haifa, Israel.
authors: Amir
authors: A
authors: Karban
authors: Department of Molecular Pharmacology, Rappaport Faculty of Medicine, Technion, Haifa, Israel. Electronic address: yshaked@tx.technion.ac.il.
authors: Yuval
authors: Y
authors: Shaked
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D059250:Administration, Metronomic; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004195:Disease Models, Animal; D005260:Female; D005768:Gastrointestinal Hormones / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D051379:Mice; D009362:Neoplasm Metastasis; D009479:Neuropeptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000911:Antibodies, Monoclonal; D000964:Antimetabolites, Antineoplastic; D005768:Gastrointestinal Hormones; D009479:Neuropeptides; C423608:PROK2 protein, human; D003841:Deoxycytidine; D000093542:Gemcitabine