Antimetastatic effects of synthetic polypeptides containing repeated structures of the cell adhesive Arg-Gly-Asp (RGD) and Tyr-Ile-Gly-Ser-Arg (YIGSR) sequences

Abstract

Summary We have investigated the inhibitory effect on experimental or spontaneous lung metastases of polypeptides which contain repetitive structures of the Arg-Gly-Asp (RGD) or Tyr-Ile-Gly-Ser-Arg (YIGSR) sequence derived from adhesion molecules, and studied their biological characterisation after administration. In the spontaneous metastasis model, multiple intravenous (i.v.) administrations of poly (RGD) and poly (YIGSR) resulted in a reduction of lung tumour colonies, although the monomer peptides, RGD or YIGSR, had no effect under these conditions. The treatment with poly(RGD) substantially prolonged the survival time for mice injected i.v. with B16-BL6 cells as compared to the treatment with RGD and random poly(R, G, D). Tumour cell adhesion to the fibronectin-substrates was remarkably inhibited by adding poly(RGD) freely in solution. Poly(RGD) was found to inhibit completely the ability of platelets to enhance tumour cell adhesion to fibronectin-substrate and tumour cell-elicited platelet aggregation in vitro, but poly(R, G, D) had no such effect. We also found that poly(RGD) led to a decrease in the arrest and retention of tumour cells after its co-injection with radiolabelled tumour cells and that the radiolabelled polypeptide can be at least decomposed into small fragments during circulation. Poly(RGD) was found to be still active in inhibiting experimental lung metastasis even when the contributions of NK cells or macrophages were removed from this system after pretreatment with anti-asialo GM1 serum, 2-chloroadenosine or carrageenan. The results indicate that the poly(RGD)-mediated inhibition of tumour metastasis may be due to the interference of the adhesive interaction of tumour cells with a specific site in the target organs. Derivatives of polypeptides which contain RGD and/or YIGSR sequences derived from cell adhesion proteins may thus provide a promising approach for the control and prevention of cancer metastasis.

Anti-metastatic gene therapy utilizing subcutaneous inoculation of EC-SOD gene transduced autologous fibroblast suppressed lung metastasis of Meth-A cells and 3LL cells in mice

“…Anti-adhesion peptides have been reported to suppress metastasis, however, they require frequent administration in vivo. 19 Unfortunately, the SOD protein's short half-life in circulation would necessitate continuous infusion of SOD for months or years, rendering it impractical for long-term effectiveness. Although artificial modified SOD such as lecithinized SOD which gives longer retention in plasma has been developed, it peaks in plasma 1 h after administration and declines rapidly in 24 h. 13 Therefore, a gene therapy strategy which facilitates the constant availability of transgene product would be ideal and practical.…”

Diminution of 37-kDa laminin binding protein expression reduces tumour formation of murine lung cancer cells

“…It has been known that peptides containing the β 1 integrin recognition sequence, RGD, can inhibit experimental or spontaneous metastasis (Saiki et al, 1989;Pasqualini et al, 1997). As well as integrin, 37LBP/p40 plays a role in the attachment and migration of tumour cells in vitro to laminincoated surfaces and in vivo during lung colonization by intravenously injected tumour cells (Wewer et al, 1987).…”

Peptide-Based Polymer Therapeutics

“…After subcutaneous administration, it reduces frequency of relapse and disease progression [115]. In the early 90s, Poly(Arg-Gly-Asp) was demonstrated to inhibit lung metastasis and migration of B16-BL6 melanoma in mice [116,117]. VivaGel ® is another example of a polymeric drug under clinical development and it is based on a multivalent lysine-dendrimer.…”