title: Zoledronic acid enhances antitumor efficacy of liposomal doxorubicin.
abstract: Previously, we found that the injection of zoledronic acid (ZOL) into mice bearing tumor induced changes of the vascular structure in the tumor. In this study, we examined whether ZOL treatment could decrease interstitial fluid pressure (IFP) via change of tumor vasculature, and enhance the antitumor efficacy of liposomal doxorubicin (Doxil®). When ZOL solution was injected at 40 µg/mouse per day for three consecutive days into mice bearing murine Lewis lung carcinoma LLC tumor, depletion of macrophages in tumor tissue and decreased density of tumor vasculature were observed. Furthermore, ZOL treatments induced inflammatory cytokines such as interleukin (IL)-10 and -12, granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor (TNF)-α in serum of LLC tumor-bearing mice, but not in normal mice, indicating that ZOL treatments might induce an inflammatory response in tumor tissue. Furthermore, ZOL treatments increased antitumor activity by Doxil in mice bearing a subcutaneous LLC tumor, although they did not significantly increase the tumor accumulation of doxorubicin (DXR). These results suggest that ZOL treatments might increase the therapeutic efficacy of Doxil via improvement of DXR distribution in a tumor by changing the tumor vasculature. ZOL treatment can be an alternative approach to increase the antitumor effect of liposomal drugs.
authors.affiliation: Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Hattori
authors.affiliation: Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Shibuya
authors.affiliation: Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Kojima
authors.affiliation: Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan.
authors.forename: Andang
authors.initials: A
authors.lastname: Miatmoko
authors.affiliation: Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan.
authors.forename: Kumi
authors.initials: K
authors.lastname: Kawano
authors.affiliation: Laboratory of Cell Regulation, Department of Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8521, Japan.
authors.forename: Kei-Ichi
authors.initials: K
authors.lastname: Ozaki
authors.affiliation: Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan.
authors.forename: Etsuo
authors.initials: E
authors.lastname: Yonemochi
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000627:therapeutic use; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D016207:Cytokines / Q000097:blood / Q000235:genetics; D004164:Diphosphonates / Q000008:administration & dosage* / Q000494:pharmacology; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004357:Drug Synergism; D045604:Extracellular Fluid / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D007093:Imidazoles / Q000008:administration & dosage* / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000627:therapeutic use; D000077211:Zoledronic Acid
chemical_list: D000903:Antibiotics, Antineoplastic; D016207:Cytokines; D004164:Diphosphonates; D007093:Imidazoles; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D000077211:Zoledronic Acid; D004317:Doxorubicin