Recombinant fusion polypeptide with cell- and heparin-binding domains of fibronectin inhibits liver metastasis of L5178Y-ML25 lymphoma cells.
We have investigated the effect of recombinant polypeptides with cell-binding domain (C-274) or with heparin-binding domain (H-271) and their fusion polypeptide (CH-271) on liver metastasis of murine lymphoid tumor. The polypeptides containing heparin-binding domain, H-271 and CH-271, were able to inhibit liver metastasis when co-injected i.v. with L5178Y-ML25 T-lymphoma cells, while C-274 with cell-binding domain showed much weaker antimetastatic activity. Treatment with H-271 or CH-271 substantially prolonged the survival time of mice injected i.v. with L5178Y-ML25 cells. CH-271, containing cell- and heparin-binding domains, was more antimetastatic than H-271. The reason why CH-271 was more effective in inhibiting liver metastasis than H-271 can not be explained in terms of a difference in the stability in the circulation or in the molecular size of the polypeptide. The polypeptides used in this study did not affect the tumor cell growth or viability in vitro. CH-271 was found to be still active in inhibiting liver metastasis even when natural killer cells or macrophages were removed from this system. Furthermore, multiple administrations of CH-271 after tumor implantation effectively inhibited liver metastasis and enhanced the survival rate as compared with H-271, C-274 and untreated control. Thus, the fusion of H-271 with C-274 (i.e. CH-271) augments the antimetastatic property of H-271, possibly through the interaction between tumor cells and the heparin-binding domain of fibronectin.
Saiki
I
I
Section of Chemistry, Hokkaido University, Sapporo.
Matsumoto
Y
Y
Murata
J
J
Makabe
T
T
Yoneda
J
J
Okuyama
H
H
Kimizuka
F
F
Ishizaki
Y
Y
Kato
I
I
Azuma
I
I
D015762:2-Chloroadenosine / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D002448:Cell Adhesion; D005353:Fibronectins / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D005677:G(M1) Ganglioside; D006028:Glycosphingolipids / Q000502:physiology; D006493:Heparin / Q000378:metabolism; D007940:Leukemia L5178 / Q000473:pathology*; D008113:Liver Neoplasms / Q000473:pathology / Q000517:prevention & control / Q000556:secondary; D051379:Mice; D009362:Neoplasm Metastasis / Q000517:prevention & control; D011993:Recombinant Fusion Proteins / Q000378:metabolism / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D016019:Survival Analysis
D005353:Fibronectins; D006028:Glycosphingolipids; D011993:Recombinant Fusion Proteins; D015762:2-Chloroadenosine; D005677:G(M1) Ganglioside; C018835:asialo GM1 ganglioside; D006493:Heparin