Anti-neovascular therapy using novel peptides homing to angiogenic vessels

Oku, Naoto; Asai, Tomohiro; Watanabe, Koh; Kuromi, Koichi; Nagatsuka, Mayumi; Kurohane, Kohta; Kikkawa, Hironori; Ogino, Kōichi; Tanaka, Motoyasu; Ishikawa, Dai; Tsukada, Hideo; Momose, Masanobu; Nakayama, Jun; Taki, Takao

doi:10.1038/sj.onc.1205347

Cited by 117 publications

(80 citation statements)

References 29 publications

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“…After determination of the epitope sequences of the obtained phages and modi¢cation of liposomes with these peptides, the APRPG-modi¢ed liposome was revealed to be favorable for the active targeting of the angiogenic endothelium. Furthermore, anti-neovascular therapy using this type of liposome as a carrier of adriamycin markedly suppressed tumor growth possibly through a cytotoxic e¡ect of the drug against angiogenic endothelial cells [10], although an increase in the local concentration of adriamycin released from the liposomes may have partly contributed to this enhanced e⁄cacy.…”

Section: Introductionmentioning

confidence: 99%

“…For this purpose, we recently isolated peptides speci¢c for tumor angiogenic vasculature by using a phage-displayed peptide library [10,11]. In vivo biopanning of phage-displayed peptide library in angiogenic model mice prepared by the dorsal air sac method [12] enabled us to isolate speci¢c phage clones having the ability to bind only to angiogenic vessels, not to tumor cells.…”

Section: Introductionmentioning

confidence: 99%

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Anti‐neovascular therapy by liposomal DPP‐CNDAC targeted to angiogenic vessels

et al. 2002

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We previously reported that liposomalized 5P P-Odipalmitoylphosphatidyl 2P P-C-cyano-2P P-deoxy-1-L L-D-arabinopentofuranosylcytosine (DPP-CNDAC), a hydrophobized derivative of the novel antitumor nucleoside CNDAC, is quite useful for cancer therapy. On the other hand, for anti-neovascular therapy, we recently isolated peptides homing to angiogenic vessels from a phage-displayed random peptide library, and observed that peptide-modified liposomal adriamycin strongly suppressed tumor growth, perhaps through damaging angiogenic endothelial cells. In the present study, we modified DPP-CNDAC-liposomes with one of the angiogenic homing peptides, APRPG, and examined their antitumor activity. Three doses of APRPG-modified DPP-CNDAC-liposomes (15 mg/kg as CNDAC) strongly inhibited tumor growth compared with the same number of doses of unmodified DPP-CNDAC-liposomes. The life span was increased 31.8%, with one completely cured mouse out of the six mice treated. Since the accumulation of liposomes in the tumor tissue was not so much different between APRPG-liposomes and non-modified liposomes, the enhanced therapeutic efficacy may be explained as the alteration of targets, i.e. APRPG-modified DPP-CNDAC-liposomes caused tumor growth suppression through damage of angiogenic endothelial cells. Anti-neovascular therapy promises no drug resistance, and should be effective against essentially any kind of solid tumor; and thus the present results demonstrate another benefit of the therapy, namely, high efficacy of cancer treatment. ß 2002 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Anti‐neovascular therapy by liposomal DPP‐CNDAC targeted to angiogenic vessels

et al. 2002

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“…6) Tumor Implantation and Therapeutic Experiment The therapeutic experiment was performed according to the procedure described previously. 7) Meth A sarcoma cells were grown in BALB/c male mice (Japan SLC Inc. Shizuoka, Japan) under an appropriate schedule, and were diluted with saline to obtain a 5ϫ10 6 cells/ml suspension. Then 0.2 ml of the suspension was injected subcutaneously into the posterior flank of 5-week-old BALB/c male mice.…”

Section: Methodsmentioning

confidence: 99%

“…10) In the present study, we identified a novel peptide, LFPLH, derived from DRWRPALPVVLFPLH which was originally isolated from among homing peptides to angiogenic sites using a phagedisplayed random peptide library. 6) Phage-displayed random peptide libraries are useful to obtain specific peptides interacting with target molecules such as receptors and adhesion molecules. 11,12) The present data indicate that LFPLH may inhibit angiogenesis in a manner similar to WRP-containing peptides, the antiangiogenic activity of which was clarified in our previous study.…”

Section: Fig 3 Effect Of Lfplh and Its Shuffled Peptide On Huvec MImentioning

confidence: 99%

Isolation of a Novel Peptide Homing to Tumor-Derived Neovasculature That Suppresses Tumor Growth.

Asai

Fukatsu

Kuromi

et al. 2002

Biological & Pharmaceutical Bulletin

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Tumor angiogenesis is prerequisite for solid tumor growth, since tumor cells require oxygen and nutrients from the blood. Thus angiogenesis inhibitors are a new category of drugs for inducing tumor dormancy. Antiangiogenic agents are thought to be free of severe side effects, effective for any type of solid tumor, 1,2) and to suppress hematogenous metastases.3) We speculate that specific ligands against molecules on angiogenic endothelial cells have the potential to suppress angiogenesis, since angiogenic vasculature has different properties from preexisting systemic vasculature. 4,5) Furthermore, such ligands may provide vascular targeting probes for tumor angiogenic vasculature. We recently isolated peptides specific for tumor angiogenic vasculature by using a phagedisplayed peptide library.6,7) Briefly, we injected a phage-displayed peptide library into dorsal air sac (DAS)-bearing angiogenic model mice, 8) which enabled us to isolate phage clones specific for only angiogenic sites but not for tumor cells. Then the peptide sequences of the isolated phage clones were analyzed. Among them, ASSSYPLIHWRPW-AR, DRWRPALPVVLFPLH, and PRPGAPLAGSWPGTS presented phages highly accumulated in the tumor tissues of two different tumor cell types. 6) One of the isolated peptides, ASSSYPLIHWRPWAR, suppressed the migration of vascular endothelial growth factor (VEGF)-stimulated human umbilical vein endothelial cells (HUVECs) in vitro, and dendoric ASSSYPLIHWRPWAR-peptide [KK 2 K 4 (ASSSYPLI-HWRPWAR) 8 ] suppressed the formation of new blood vessels in DAS model mice.7) Thus we determined the epitope sequence of ASSSYPLIHWRPWAR-peptide using fragment peptides such as ASSYPLIH and IHWRPWAR. IHWRP-WAR showed tumor growth suppression but ASSYPLIH did not. In such way, we determined the epitope sequence for the ASSSYPLIHWRPWAR-peptide to be WRP. 7)In the present study, we similarly determined the epitope sequence for DRWRPALPVVLFPLH. Interestingly, not only DRWRPALP, which has the WRP sequence, but also PV-VLFPLH showed tumor growth suppression in vivo. Thus further study was performed focused on PVVLFPLH to obtain a novel peptide epitope causing tumor dormancy through inhibition of angiogenesis. MATERIALS AND METHODSPeptide Synthesis Peptides were synthesized using Rink amide resin and a peptide synthesizer ACT357 (Advanced ChemTech, Louisville, KY, U.S.A.) as described previously. 6)Tumor Implantation and Therapeutic Experiment The therapeutic experiment was performed according to the procedure described previously. 7) Meth A sarcoma cells were grown in BALB/c male mice (Japan SLC Inc. Shizuoka, Japan) under an appropriate schedule, and were diluted with saline to obtain a 5ϫ10 6 cells/ml suspension. Then 0.2 ml of the suspension was injected subcutaneously into the posterior flank of 5-week-old BALB/c male mice. Synthetic 15-mer peptides and fragment peptides (20 mg/kg/day) were injected subcutaneously into a site adjacent to the tumor of tumorbearing mice every day starting on day 1 until day 10 after tumor implantation. Inject...

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“…13 In addition, some peptides selected with phage display have also been used as antagonists of VEGF to its receptor. [14][15][16] In addition, a cyclic peptide corresponding to amino acids 79-93 of the VEGF sequence was reported to inhibit angiogenesis. 17 Its biological properties make VEGF an important therapeutic target, and it has been shown that the anti-VEGF signal pathway can inhibit tumor growth in vivo.…”

Section: A Fusion Protein With the Receptor-binding Domain Of Vasculamentioning

confidence: 99%

A fusion protein with the receptor-binding domain of vascular endothelial growth factor-A (VEGF-A) is an antagonist of angiogenesis in cancer treatment: Simultaneous blocking of VEGF receptor-1 and 2

Tseng¹,

Chen²,

Lin³

et al. 2010

Cancer Biology & Therapy

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[[abstract]]Vascular endothelial growth factor (VEGF) is an angiogenic factor that signals through VEGFR-1 and VEGFR-2, which are expressed preferentially in proliferating endothelial cells. Thus, simultaneous blockage of both VEGF receptors may provide a more efficient therapeutic response in cancer treatment. We created a recombinant fusion protein (RBDV-IgG1 Fc), which is composed of the receptor binding domain of human VEGF-A (residues 8-109) and the Fc region of human IgG1 immunoglobulin. The recombinant protein can bind to both mouse VEGFR-1 and VEGFR-2 to decrease VEGF-induced proliferation and tube formation of endothelial cells in vitro. In this study, the RBDV-IgG1 Fc fusion protein reduced the effects of proliferation, migration and tube formation induced by VEGF in murine endothelial cells in vitro. In vivo tumor therapy with RBDV-IgG1 Fc resulted in tumor inhibition by reducing angiogenesis. Pathological evidence also shows that RBDV-IgG1 Fc can seriously damage vessels, causing the death of tumor cells. These findings suggest that this chimeric protein has potential as an angiogenesis antagonist in tumor therapy

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Anti-neovascular therapy using novel peptides homing to angiogenic vessels

Cited by 117 publications

References 29 publications

Anti‐neovascular therapy by liposomal DPP‐CNDAC targeted to angiogenic vessels

Anti‐neovascular therapy by liposomal DPP‐CNDAC targeted to angiogenic vessels

Isolation of a Novel Peptide Homing to Tumor-Derived Neovasculature That Suppresses Tumor Growth.

A fusion protein with the receptor-binding domain of vascular endothelial growth factor-A (VEGF-A) is an antagonist of angiogenesis in cancer treatment: Simultaneous blocking of VEGF receptor-1 and 2

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