Inhibition of tumor invasion and metastasis by peptidic mimetics of Arg-Gly Asp (RGD) derived from the cell recognition site of fibronectin.
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 DR(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 i.v. coinjection with B16-BL6 melanoma more potently than did other pseudo-peptides or the original RGDS peptide. Rrev-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.
Fujii
H
H
Research Institute for Wakan-Yaku (Traditional Sino-Japanese Medicines), Toyama Medical and Pharmaceutical University, Japan.
Nishikawa
N
N
Komazawa
H
H
Orikasa
A
A
Ono
M
M
Itoh
I
I
Murata
J
J
Azuma
I
I
Saiki
I
I
D000818:Animals; D003094:Collagen; D004338:Drug Combinations; D004354:Drug Screening Assays, Antitumor; D005353:Fibronectins / Q000737:chemistry*; D007797:Laminin; D008175:Lung Neoplasms / Q000556:secondary; D008546:Melanoma, Experimental / Q000556:secondary; D051379:Mice; D009361:Neoplasm Invasiveness / Q000517:prevention & control*; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D011509:Proteoglycans; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000473:pathology
D004338:Drug Combinations; D005353:Fibronectins; D007797:Laminin; D010446:Peptide Fragments; D011509:Proteoglycans; C059485:matrigel; D003094:Collagen