title: Synergistic antitumor activity of metronomic dosing of cyclophosphamide in combination with doxorubicin-containing PEGylated liposomes in a murine solid tumor model.
abstract: Cyclophosphamide (CPA) and doxorubicin (DXR)-containing sterically stabilized liposomes (DXR-SL) have a proven clinical activity. We propose that a metronomic CPA dosing schedule enhances accumulation of DXR-SL in solid tumors, because it causes apoptosis in the endothelial cells of the growing tumor vasculature and thereby may increase the permeability of the tumor microvessels. To establish the validity of this hypothesis we investigated the therapeutic benefits of metronomic CPA dosing (p.o.) combined with DXR-SL (i.v.) in a Lewis lung carcinoma, subcutaneously growing in C57BL/6 mouse. The metronomic CPA dosing clearly promoted accumulation and subsequent deep diffusion of SL in the solid tumor as a result of rather a transient increase in the density of CD31(+)-microvessels, which shows high permeability to SL. It appears that the enhancing effect of metronomic CPA dosing is strongly dependent on the dose of CPA as well as on the time at which the treatment was initiated. Our study indicates that the use of metronomic chemotherapy combined with nanocarriers may be of significant clinical and practical importance in treating intractable solid tumors.
authors.affiliation: Department of Pharmacokinetics and Biopharmaceutics, Subdivision of Biopharmaceutical Science, Institute of Health Biosciences, The University of Tokushima, 1-78-1, Sho-machi, Tokushima 770-8505, Japan. ishida@ph.tokushima-u.ac.jp
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Ishida
authors.forename: Emi
authors.initials: E
authors.lastname: Shiraga
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kiwada
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D018827:Carcinoma, Lewis Lung / Q000098:blood supply / Q000188:drug therapy*; D045744:Cell Line, Tumor; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use; D004334:Drug Administration Schedule; D004357:Drug Synergism; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin; D003520:Cyclophosphamide