title: Low-dose metronomic oral dosing of a prodrug of gemcitabine (LY2334737) causes antitumor effects in the absence of inhibition of systemic vasculogenesis.
abstract: Metronomic chemotherapy refers to the close, regular administration of conventional chemotherapy drugs at relatively low, minimally toxic doses, with no prolonged break periods; it is now showing encouraging results in various phase II clinical trials and is currently undergoing phase III trial evaluation. It is thought to cause antitumor effects primarily by antiangiogenic mechanisms, both locally by targeting endothelial cells of the tumor neovasculature and systemically by effects on bone marrow-derived cells, including circulating endothelial progenitor cells (CEP). Previous studies have shown reduction of CEPs by metronomic administration of a number of different chemotherapeutic drugs, including vinblastine, cyclophosphamide, paclitaxel, topotecan, and tegafur plus uracil (UFT). However in addition to, or even instead of, antiangiogenic effects, metronomic chemotherapy may cause suppression of tumor growth by other mechanisms such as stimulating cytotoxic T-cell responses or by direct antitumor effects. Here we report results evaluating the properties of metronomic administration of an oral prodrug of gemcitabine LY2334737 in nontumor-bearing mice and in preclinical models of human ovarian (SKOV3-13) and breast cancer (LM2-4) xenografts. Through daily gavage (at 6 mg/kg/d), the schedules tested were devoid of toxicity and caused antitumor effects; however, a suppressive effect on CEPs was not detected. Unexpectedly, metronomic LY2334737 administration caused increased blood flow in luciferase-tagged LM2-4 tumor xenografts, and this effect, readily measured using contrast micro-ultrasound, coincided with a relative increase in tumor bioluminescence. These results highlight the possibility of significant antitumor effects mediated by metronomic administration of some chemotherapy drugs without a concomitant inhibition of systemic angiogenesis.
authors.affiliation: Department of Medical Biophysics, Platform Biological Sciences, Sunnybrook Research Institute, S-217 Research Building, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5.
authors.forename: Giulio
authors.initials: G
authors.lastname: Francia
authors.forename: Yuval
authors.initials: Y
authors.lastname: Shaked
authors.forename: Kae
authors.initials: K
authors.lastname: Hashimoto
authors.forename: John
authors.initials: J
authors.lastname: Sun
authors.forename: Melissa
authors.initials: M
authors.lastname: Yin
authors.forename: Carolyn
authors.initials: C
authors.lastname: Cesta
authors.forename: Ping
authors.initials: P
authors.lastname: Xu
authors.forename: Shan
authors.initials: S
authors.lastname: Man
authors.forename: Christina
authors.initials: C
authors.lastname: Hackl
authors.forename: Julie
authors.initials: J
authors.lastname: Stewart
authors.forename: Mark
authors.initials: M
authors.lastname: Uhlik
authors.forename: Anne H
authors.initials: AH
authors.lastname: Dantzig
authors.forename: F Stuart
authors.initials: FS
authors.lastname: Foster
authors.forename: Robert S
authors.initials: RS
authors.lastname: Kerbel
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology; D001808:Blood Vessels / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D011355:Prodrugs / Q000008:administration & dosage / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D011355:Prodrugs; D003841:Deoxycytidine; D000093542:Gemcitabine