Inhibition of metastasis of lewis lung carcinoma by a synthetic peptide within growth factor‐like domain of urokinase in the experimental and spontaneous metastasis model

Abstract

Four synthetic peptides (residues 20-30 and 17-34) within the growth factor-like domain (GFD) of murine and human urokinase-type plasminogen activator (uPA) were examined to determine whether they inhibit production of experimental and spontaneous lung metastasis by murine Lewis lung carcinoma (3LL) cells. In an in vivo experimental metastasis assay, which determines mainly the later steps of the metastatic migration process (extravasation from the bloodstream and then growth into pulmonary tumor), none of the peptides introduced by i.v. single co-injection into syngeneic C57B1/6 mice inhibited pulmonary metastasis, when 3LL cells were pre-incubated with the peptides followed by i.v. co-injection of the peptide and cells. In addition, none of the peptides, when injected i.p. daily for 7 days after i.v. tumor cell inoculation, reduced the number of lung tumor colonies. In a second in vivo assay that measures metastasis from a primary tumor (spontaneous metastasis model), multiple i.p. injections of the mouse peptide 17-34 for 7 days after s.c. tumor cell inoculation significantly inhibited metastatic lung tumor colonization in a dose-dependent manner, whereas human peptide 17-34 had no effect. Mouse and human peptide 20-30 had no effect either. The inhibition of lung metastasis was not due to direct antitumor effects of mouse peptide 17-34. Our results indicate that occupation of uPA receptors on 3LL cells by the enzymatically inactive mouse peptide 17-34 or prevention of rebinding of uPA synthesized by tumor cells to their receptor specifically reduced tumor cell invasion and formation of metastasis and that uPA may regulate more efficiently the mechanism involved in the entry of tumor cells into vascular circulation than extravasation during the metastatic process.

Role of plasminogen activator-plasmin system in tumor angiogenesis

“…Most approaches have focused on using linear or cyclic peptides based on the sequence of the growth factor domain of uPA [110,111]. Despite the promise of such peptides, their usefulness in vivo remains to be established.…”

Adenovirus-mediated delivery of a uPA/uPAR antagonist suppresses angiogenesis-dependent tumor growth and dissemination in mice

“…9 In another study, intraperitoneal injections of peptides from murine ATF inhibited both primary tumor growth and dissemination. 10 Disruption of cell surface uPA/uPAR also inhibited bFGF-or VEGFinduced angiogenesis in an artificial bFGF-enriched extracellular matrix model. 6 In this study, we have used xenograft and syngeneic murine models to assess the antitumoral effects that follow local or systemic administration of a defective adenovirus expressing a secretable uPAR antagonist of murine origin (AdmATF).…”

“…Among them, the amino-terminal fragment of urokinase (ATF) is of particular interest because it can also exert a direct effect on the tumor cells and inhibit metastasis in experimental models. [9][10][11] Urokinase and its high affinity receptor, a GPI-anchored membrane protein (CD87), are believed to be critical elements in tumor biology because they control cell motility, tissue remodeling and the bioavailability of angiogenic factors. For example, uPA/uPAR complex formation at the cell surface is required for efficient activation of plasmin, a wide range protease that can degrade components of the basement membrane and the extracellular matrix (eg vitronectin, laminin, fibronectin), a prerequisite for tumor cell invasion.…”

Inhibition of urokinase plasminogen activator with a novel enzyme inhibitor, wxc-340, ameliorates endotoxin and surgery-accelerated growth of murine metastases

“…In our study, there was no evidence of any haemorrhagic complications or derangement of coagulation parameters. Furthermore, there was no skin irritation at the injection site unlike reports involving other u-PA inhibitors (Kobayashi et al, 1996). Mice that received WXC-340 before LPS administration and subsequently daily subcutaneous WXC-340 (0.3 mg kg À1 ) had significantly lower numbers of tumour nodules (A), lung weight (B) and lung-to-body weight ratio (C) than control animals receiving daily PBS ( @ ; Po0.05).…”

“…Mimetics of the growth factor-like domain of u-PA inhibit experimental and spontaneous metastases in a murine model of lung cancer (Kobayashi et al, 1996) and u-PAR antagonists inhibit primary tumour growth and angiogenesis in syngenic mouse models (Min et al, 1996). A recently developed selective u-PA inhibitor, WX-UK1 impaired development of lung metastases in a rat model of spontaneous metastatic orthotopic breast adenocarcinoma, whereas Ertongur et al (2004) demonstrated that this compound inhibited in vitro tumour cell Matrigel invasion by a variety of human cancer cell lines (Setyono-Han et al, 2005).…”