Inhibition of tumor invasion and metastasis by peptidic mimetics of Arg- Gly Asp (RGD) derived from the cell recognition site of fibronectin

Hideki Fujii, Naoyuki Nishikawa, Hiroyuki Komazawa, Atsushi Orikasa, Mitsunori Ono, Isamu Itoh, Jun Murata, Ichiro Azuma, Ikuo Saiki

Research output: Contribution to journalArticlepeer-review

25 Citations (Scopus)

Abstract

The partially modified retro- and retro-inverso peptides of the Arg-Gly Asp (RGD) sequence of fibronectin, in which the direction of the Arg residue is reversed and/or the chirality of the amino acid residue is inverted, i.e., mainly R(rev)-COCH2CO-D and (D)R(rev)-COCH2CO-D, have been synthesized to examine their antimetastatic effects in murine lung or liver metastasis models, as well as their inhibitory effect on tumor cell invasion in vitro. R(rev)-COCH2CO-D inhibited lung metastasis produced by IV coinjection with B16-BL6 melanoma more potently than did other pseudo-peptides or the original RGDS peptide. R(rev)-COCH2CO-D also showed antimetastatic effects against several different types of tumor cells such as B16-BL6 melanoma, Colon26 M3.1 carcinoma, and L5178Y-ML25 lymphoma cells, in a dose-dependent manner, and multiple administrations had a therapeutic effect on spontaneous lung metastasis. The invasion of melanoma cells into reconstituted basement membrane Matrigel in vitro was suppressed by R(rev)-COCH2CO-D more effectively than by RGDS. These results indicate that the antimetastatic effect by R(rev)-COCH2CO-D was in part due to the inhibition of tumor invasion. The RGDS peptide decomposed when incubated with fresh plasma in vitro, whereas R(rev)-COCH2CO-D was not affected by this treatment. Thus, the reversion of the Arg-Gly linkage in the RGD sequence resulted in protease resistance leading to the retardation of the clearance of the peptide in vivo, and consequently augmented its antimetastatic and antiinvasive properties. Designed peptide analogues may provide various advantages and be useful for preventing cancer metastasis.

Original languageEnglish
Pages (from-to)333-342
Number of pages10
JournalOncology research
Volume8
Issue number9
Publication statusPublished - 1996
Externally publishedYes

Keywords

  • Arg-Gly Asp-Ser
  • fibronectin
  • invasion
  • metastasis
  • retro-inverso peptide
  • retro-peptide

ASJC Scopus subject areas

  • General Medicine

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