Antitumor effects in mice of low-dose (metronomic) cyclophosphamide administered continuously through the drinking water.
A number of recent preclinical studies have sparked interest in the concept of exploiting conventional chemotherapeutic drugs as antiangiogenics. Such antiangiogenic activity is achieved or optimized by metronomic-dosing protocols in which the drug is given at comparatively low doses using a frequent schedule of administration (e.g., once to three times per week) with no breaks, particularly when combined with an endothelial cell-specific antiangiogenic drug. The use of p.o. chemotherapeutic drugs is particularly suitable for this type of treatment strategy. We tested one such drug, cyclophosphamide (CTX), in a protocol wherein the drug was administered to mice at low doses, of approximately 10-40 mg/kg on a daily basis through the drinking water. CTX is typically given p.o. to patients, but it has almost always been injected when treating preclinical mouse tumor models. We found p.o. CTX to be a safe and convenient treatment with significant antitumor efficacy. Growth delays were observed for human orthotopic breast or ectopic colon cancer xenografts in nude or SCID mice. Established PC3 human prostate tumor xenografts could be induced to almost fully regress, remaining virtually nonpalpable for > or =2 months of continuous therapy, after which tumors began to grow progressively. These re-emergent tumors were not found to be drug resistant when tested in new hosts, using the same treatment protocol. Regression of spontaneously arising, late-stage pancreatic islet cell carcinomas in Rip Tag transgenic mice was also observed. The effects of continuous p.o. CTX treatment were enhanced significantly in an orthotopic, metastatic breast cancer xenograft model when used in combination with an antivascular endothelial growth factor receptor-2 blocking antibody. Maximum tolerated dose levels established for other mouse strains proved highly toxic to SCID mice, whereas daily p.o. low-dose regimens of CTX were well tolerated. Taken together, the results demonstrate the feasibility of delivering CTX in a p.o. metronomic chemotherapy regimen, which proved safe, reasonably efficacious, and potentially applicable to chronic treatment. Such a regimen may be particularly well suited for integration with antiangiogenic drugs.
Man
Shan
S
Departments of Medical Biophysics, Sunnybrook and Women's College Health Sciences Centre, University of Toronto, 2075 Bayview Avenue, Toronto, Ontario, M4N 3M5 Canada.
Bocci
Guido
G
Francia
Giulio
G
Green
Shane K
SK
Jothy
Serge
S
Hanahan
Douglas
D
Bohlen
Peter
P
Hicklin
Daniel J
DJ
Bergers
Gabriele
G
Kerbel
Robert S
RS
D000284:Administration, Oral; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D003520:Cyclophosphamide / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004326:Drinking; D005260:Female; D019073:HT29 Cells / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D020794:Receptor Protein-Tyrosine Kinases / Q000276:immunology; D017978:Receptors, Growth Factor / Q000276:immunology; D040262:Receptors, Vascular Endothelial Growth Factor; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D000906:Antibodies; D018906:Antineoplastic Agents, Alkylating; D017978:Receptors, Growth Factor; D003520:Cyclophosphamide; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor