Chronic alcohol intake causes a stress response in the aged rat brain. It is thought that the increased level of Hsc70 is brought about by an increase of denatured proteins.
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...
Chronic alcohol intake causes a stress response in the aged rat brain. It is thought that the increased level of Hsc70 is brought about by an increase of denatured proteins.
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