title: Low-dose metronomic combined with intermittent bolus-dose cyclophosphamide is an effective long-term chemotherapy treatment strategy.
abstract: Metronomic chemotherapy refers to the close, regular administration of comparatively low doses of cytotoxic drugs, with minimal or no drug-free breaks, over prolonged periods. It is thought to have an antiangiogenic basis. However, whereas surprisingly durable and potent tumor responses have been observed in a number of preclinical tumor models, relapses usually eventually occur using this type of treatment strategy. We therefore decided to test modified metronomic chemotherapy regimens that might significantly delay such relapses, but still maintain modest and acceptable toxicity profiles. Here, we show that repeated administration of bolus doses (BDs) of cyclophosphamide every 3 or 6 weeks, combined with a daily oral low-dose metronomic (LDM) regimen (20 mg/kg/d cyclophosphamide), improves efficacy and significantly delays progression of transplanted PC-3 human prostate cancer xenografts, syngeneic transplanted EMT-6 breast tumors, and "spontaneous" murine erythroleukemia. Efficacy was superior whereas toxicity was mild and comparable to the LDM regimen, the latter assessed by body weight, neutrophil, lymphocyte, and total white blood counts. Antiangiogenic activity, measured by reduction in circulating endothelial precursor cells, revealed that the greatest degree of suppression occurred using the combination treatment. Overall, our results indicate that the administration of intermittent BD combined with chronic oral LDM cyclophosphamide is a potent treatment regimen for controlling tumor growth, which has a low toxicity profile, over prolonged periods of time.
authors.affiliation: Department of Molecular and Cellular Biology, Sunnybrook and Women's College Health Sciences Centre and the Department of Medical Biophysics, University of Toronto, Ontario, Canada.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Shaked
authors.forename: Urban
authors.initials: U
authors.lastname: Emmenegger
authors.forename: Giulio
authors.initials: G
authors.lastname: Francia
authors.forename: Limor
authors.initials: L
authors.lastname: Chen
authors.forename: Christina R
authors.initials: CR
authors.lastname: Lee
authors.forename: Shan
authors.initials: S
authors.lastname: Man
authors.forename: Armen
authors.initials: A
authors.lastname: Paraghamian
authors.forename: Yaacov
authors.initials: Y
authors.lastname: Ben-David
authors.forename: Robert S
authors.initials: RS
authors.lastname: Kerbel
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000009:adverse effects; D003520:Cyclophosphamide / Q000008:administration & dosage* / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D004915:Leukemia, Erythroblastic, Acute / Q000188:drug therapy*; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003520:Cyclophosphamide