Prevention of cancer metastasis in mice with fibronectin-related substances.
Since the adhesive interaction between tumor cells and host cells, or extracellular matrix (ECM), presumably plays a crucial role in metastatic formation during a series of complex events, we used synthetic or recombinant polypeptide analogues, poly(RGD) or CH-271-based on Arg-Gly-Asp(RGD) sequence or functional domains in fibronectin. Use of these analogues regulated the mechanisms involved in cell adhesion during the metastatic process. Poly(RGD) effectively inhibited the experimental lung and liver metastasis when coinjected i.v. with different types of tumors. In a spontaneous lung metastasis model using B-16-BL6 melanoma, multiple administrations of this polypeptide, before or after surgical excision of the primary tumor, resulted in significant inhibition of tumor metastasis without affecting the growth of the primary tumor. Further, it substantially prolonged the survival time of mice. The mechanism responsible for the inhibition of tumor metastasis by the polypeptides is partly associated with the ability to interfere with cell functions such as adhesiveness, motility, and invasiveness in the cellular adhesive process of metastasis. The combination of CH-271 fusion polypeptide and anticancer drugs, i.e., anti-adhesion therapy and chemotherapy, caused a dramatic inhibition of lung and liver metastasis of tumors when compared with either treatment alone, or in the control. Since the polypeptides derived from cell adhesion molecules showed no short-term toxicity to the host, they may provide a promising approach for the control of cancer metastasis.
Azuma
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Institute of Immunological Science, Hokkaido University, Sapporo, Japan.
Saiki
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D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D002352:Carrier Proteins / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D002686:Chitin / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D015195:Drug Design; D005353:Fibronectins / Q000037:antagonists & inhibitors*; D006801:Humans; D008113:Liver Neoplasms / Q000517:prevention & control / Q000556:secondary; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000517:prevention & control / Q000556:secondary; D009842:Oligopeptides; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use
C105814:6-O-sulfated carboxymethyl chitin; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D005353:Fibronectins; D009363:Neoplasm Proteins; D009842:Oligopeptides; D010446:Peptide Fragments; D010455:Peptides; D011993:Recombinant Fusion Proteins; C065723:poly (arginyl-glycyl-aspartic acid); D002686:Chitin; C047981:arginyl-glycyl-aspartic acid