Antimetastatic effect of synthetic Glu-Ile-Leu-Asp-Val peptide derivatives containing D-amino acids.
The aim of this study was to increase the antimetastatic potency of the fibronectin-related peptide, Glu-Ile-Leu-Asp-Val (EILDV), and to determine the minimal core sequence of EILDV required to inhibit tumor metastasis in vivo. The EILDV subpeptide analog, ILDV, markedly inhibited the adhesion of B16-BL6 melanoma cells to fibronectin. EILD and ILD were only slightly inhibitory, and the smaller overlapping tripeptide, LDV, was inactive. The inhibitory activities of ILDV and LDV on the migration of B16-BL6 melanoma cells were as potent as those of EILDV, whereas ILD did not inhibit cell migration. These results suggested that the minimal sequences essential for cell adhesion and migration are ILD and LDV, respectively. However, the antimetastatic effects of all subpeptide analogs were lower than that of EILDV. In order to improve the stability in vivo, we synthesized various EILDV-related peptides substituted with a D-amino acid. EILDV containing D-Glu or D-Ile inhibited cell adhesion and migration as potent as EILDV, whereas replacing Leu, Asp or Val with the corresponding D-isomer reduced the antiadhesive activities. The inhibitory effect of EILDV-related peptides containing D-Leu, D-Asp or D-Val on migration was also lower than that of EILDV. All synthetic EILDV-related peptides containing D-amino acids inhibited metastasis by B16-BL6 melanoma cells to the same extent as EILDV, whereas the specific activity of EILDV was decreased by the D-amino acid substitution. These results indicated that the balance of stability in vivo and biological activity in vitro is important in inhibiting tumor metastasis.
Kaneda
Y
Y
Faculty of Pharmaceutical Sciences, Osaka University, Japan.
Yamamoto
Y
Y
Okada
N
N
Tsutsuml
Y
Y
Nakagawa
S
S
Kakiuch
M
M
Maeda
M
M
Kawasaki
K
K
Mayumi
T
T
D000595:Amino Acid Sequence; D000596:Amino Acids; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000627:therapeutic use / Q000633:toxicity; D002352:Carrier Proteins / Q000138:chemical synthesis* / Q000627:therapeutic use / Q000633:toxicity*; D002448:Cell Adhesion / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000596:Amino Acids; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D009842:Oligopeptides; C094697:glutamyl-isoleucyl-leucyl-aspartyl-valine