Inhibition of tumor metastasis by Arg-Gly-Asp-Ser (RGDS) peptide conjugated with sulfated chitin derivative, SCM-chitin-RGDS.
We have synthesized a new compound in which Arg-Gly-Asp-Ser (RGDS) was conjugated with 6-O-sulfated and 6-O-carboxymethyl-chitin (SCM-chitin), i.e. SCM-chitin-RGDS, and tested the inhibitory effect on lung and liver metastases of three different types of tumors in mice. SCM-chitin-RGDS was more effective for the inhibition of liver metastasis of L5178Y-ML25 lymphoma and lung metastases of colon 26 M3.1 cells than SCM-chitin, RGDS or their mixture. GRGDS peptide, however, required a higher dose (3000 micrograms) to obtain a sufficiently antimetastatic effect. Intermittent i.v. administration of SCM-chitin-RGDS before or after the i.v. inoculation of L5178Y-ML25 cells caused significant inhibition of liver metastasis as compared with the multiple administration of RGDS, SCM-chitin or untreated control. Co-injection of lymphoma cells with SCM-chitin-RGDS or multiple treatment of SCM-chitin-RGDS after tumor inoculation showed significantly enhanced survival rate. SCM-chitin-RGDS also showed the spontaneous lung metastasis produced by intrafootpad injection of B16-BL6 melanoma cells by the multiple i.v. administrations. These results demonstrate that the conjugation of RGDS peptide with SCM-chitin led to augmentation of therapeutic potential to cancer metastasis, thus implying an importance of the conjugation of cell-adhesive RGDS peptide with structurally heparin-like SCM-chitin, which possess binding ability to the heparin-binding domain of fibronectin or laminin and extremely low anticoagulant properties.
Komazawa
H
H
Institute of Immunological Science, Hokkaido University, Sapporo, Japan.
Saiki
I
I
Nishikawa
N
N
Yoneda
J
J
Yoo
Y C
YC
Kojima
M
M
Ono
M
M
Itoh
I
I
Nishi
N
N
Tokura
S
S
D000595:Amino Acid Sequence; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002686:Chitin / Q000031:analogs & derivatives* / Q000737:chemistry; D008113:Liver Neoplasms / Q000556:secondary; D008175:Lung Neoplasms / Q000556:secondary; D008223:Lymphoma / Q000473:pathology; D008546:Melanoma, Experimental / Q000473:pathology; D051379:Mice; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis; D009374:Neoplasms, Experimental / Q000473:pathology; D009842:Oligopeptides / Q000494:pharmacology*
D009842:Oligopeptides; D002686:Chitin; C046617:arginyl-glycyl-aspartyl-serine