We have investigated the anti-angiogenic effect of a polymeric
peptide based on the
Arg-Gly-Asp (RGD) core sequence of
fibronectin as a monomer unit, i.e.,
poly(RGD), in syngeneic mice and in vitro. Single intratumoral administration of
poly(RGD) on day 0, 1 or 7 after
tumor implantation achieved a significant reduction of B16-BL6
melanoma colonization in the lungs, but did not affect the size of the primary
tumor at the time of
amputation. The number of capillary blood vessels oriented toward the
tumor mass increased during the early growth phase after the intradermal inoculation of the
tumor.
Poly(RGD) significantly inhibited the formation of
tumor neovascularization when co-injected with the
tumor cells or separately injected intratumorally or intravenously on day 1 or 3 after
tumor inoculation. This inhibitory effect of
poly(RGD) was dose-dependent.
Poly(RGD) was able to inhibit the haptotactic migration of endothelial cells along a gradient of substratum-immobilized
fibronectin but not
laminin.
Tumor-
conditioned medium (CM) by itself did not act as a
chemoattractant when it was added in the lower compartment of a Transwell chamber, but promoted the endothelial cell migration to immobilized
fibronectin or
laminin.
Poly(RGD) inhibited the enhanced cell migration to
fibronectin but not to
laminin in response to CM. Thus,
poly(RGD)-mediated inhibition of
tumor metastasis may be partly due to the inhibition of
tumor-induced angiogenesis at primary and secondary sites.