Applicability of anti-neovascular therapy to drug-resistant tumor: suppression of drug-resistant P388 tumor growth with neovessel-targeted liposomal adriamycin.
Anti-neovascular therapy, one of the effective anti-angiogenic chemotherapy, damages new blood vessels by cytotoxic agents delivered to angiogenic endothelial cells and results in indirect eradication of tumor cells. We previously reported that liposomes-modified with a pentapeptide, Ala-Pro-Arg-Pro-Gly (APRPG-Lip) homing to angiogenic site, highly accumulated in tumor tissue, and APRPG-Lip encapsulating adriamycin (APRPG-LipADM) effectively suppressed tumor growth in tumor-bearing mice. In the present study, we examined the topological distribution of fluorescence-labeled APRPG-LipADM as well as TUNEL-stained cells in an actual tumor specimen obtained from Colon 26 NL-17 carcinoma-bearing mice. The fluorescence-labeled APRPG-Lip dominantly localized to vessel-like structure: a part of which was also stained with anti-CD31 antibody. Furthermore, TUNEL-stained cells were co-localized to the same structure. These data indicated that APRPG-LipADM bound to angiogenic endothelial cells and induced apoptosis of them. We also investigated the applicability of anti-neovascular therapy using APRPG-LipADM to ADM-resistant P388 solid tumor. As a result, APRPG-LipADM significantly suppressed tumor growth in mice bearing the ADM-resistant tumor. These data suggest that APRPG-LipADM is applicable to various kinds of tumor including drug-resistant tumor since it targets angiogenic endothelial cells instead of tumor cells, and eradicates tumor cells through damaging the neovessels.
Shimizu
K
K
Department of Medical Biochemistry and COE Program in the 21st Century, University of Shizuoka School of Pharmaceutical Sciences, 52-1 Yada, Shizuoka 422-8526, Japan.
Asai
T
T
Fuse
C
C
Sadzuka
Y
Y
Sonobe
T
T
Ogino
K
K
Taki
T
T
Tanaka
T
T
Oku
N
N
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016503:Drug Delivery Systems / Q000379:methods*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000502:physiology; D007941:Leukemia P388 / Q000188:drug therapy* / Q000473:pathology; D008081:Liposomes; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
D020533:Angiogenesis Inhibitors; D008081:Liposomes; D004317:Doxorubicin