title: Evidence Implicating Immunological Host Effects in the Efficacy of Metronomic Low-Dose Chemotherapy.
abstract: Conventional chemotherapy drugs administered at a maximum tolerated dose (MTD) remains the backbone for treating most cancers. Low-dose metronomic (LDM) chemotherapy, which utilizes lower, less toxic, doses given on a close regular basis over prolonged periods, is an alternative and better tolerated potential strategy to improve chemotherapy. LDM chemotherapy has been evaluated preclinically and clinically and has shown therapeutic benefit, in both early and advanced stage metastatic disease, especially when used as a maintenance therapy. However, knowledge about the antitumor mechanisms by which LDM chemotherapy acts remain limited. Here we characterized the effects of LDM and MTD capecitabine therapy on tumor and host cells using high-throughput systems approaches involving mass spectrometry flow cytometry and automated cell imaging followed by in vivo analyses of such therapies. An increase in myeloid and T regulatory cells and a decrease in NK and T cytotoxic cells were found in MTD-capecitabine-treated tumors compared with LDM-capecitbine-treated tumors. Plasma from MTD capecitabine-treated mice induced a more tumorigenic and metastatic profile in both breast and colon carcinoma cells than plasma from mice treated with LDM capecitabine. These results correlated, in part, with in vivo studies using models of human or mouse advanced metastatic disease, where the therapeutic advantage of MTD capecitabine was limited despite a substantial initial antitumor activity found in the primary tumor setting. Overall these results implicate a possible contribution of immunologic host effects in accounting for the therapeutic limitations of MTD compared with LDM capecitabine. Cancer Res; 76(20); 5983-93. ©2016 AACR.
authors: Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion, Haifa, Israel. Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Canada. yshaked@tx.technion.ac.il robert.kerbel@sri.utoronto.ca.
authors: Yuval
authors: Y
authors: Shaked
authors: Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Canada.
authors: Elizabeth
authors: E
authors: Pham
authors: Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Canada. Department of Medical Biophysics, University of Toronto, Toronto, Canada.
authors: Santosh
authors: S
authors: Hariharan
authors: Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors: Ksenia
authors: K
authors: Magidey
authors: Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors: Ofrat
authors: O
authors: Beyar-Katz
authors: Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Canada.
authors: Ping
authors: P
authors: Xu
authors: Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Canada.
authors: Shan
authors: S
authors: Man
authors: Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Canada. Department of Medical Biophysics, University of Toronto, Toronto, Canada.
authors: Florence T H
authors: FT
authors: Wu
authors: Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors: Valeria
authors: V
authors: Miller
authors: Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Canada. Department of Medical Biophysics, University of Toronto, Toronto, Canada. Department of Biochemistry, University of Toronto, Toronto, Canada.
authors: David
authors: D
authors: Andrews
authors: Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Canada. Department of Medical Biophysics, University of Toronto, Toronto, Canada. yshaked@tx.technion.ac.il robert.kerbel@sri.utoronto.ca.
authors: Robert S
authors: RS
authors: Kerbel
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D001854:Bone Marrow Cells / Q000473:pathology; D000069287:Capecitabine / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D020714:Maximum Tolerated Dose; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality / Q000473:pathology
chemical_list: D000964:Antimetabolites, Antineoplastic; D000069287:Capecitabine