Synthetic laminin-like peptides and pseudopeptides as potential antimetastatic agents.
This paper describes our efforts to study structure-activity relationships, improve the antimetastatic potency, and limit the in vivo enzymatic degradation of YIGSR-NH2, a synthetic peptide from the B1 chain of laminin, which reportedly has potential as an antimetastatic agent. To this end we have synthesized a series of psi (CH2NH) peptide analogs (5-9) of YIGSR-NH2 and a number of peptides in which the Tyr residue was replaced with D-Tyr (1), Phe (2), Phe (p-F) (3), and Phe(p-NH2) (4). All new peptides were assayed in vitro for their ability to promote cell attachment in both B16F10 mouse melanoma cells and HT-1080 human fibrosarcoma cells. On the basis of the in vitro assay results, peptides 3-5, 8, and 9 were tested in vivo for their ability to inhibit tumor metastasis to the lungs in mice that were coinjected in the tail vein with B16F10 melanoma cells and 1 mg of peptide. In summary, of the nine new peptides only the Phe(p-NH2) peptide 4 showed consistent in vitro cell attachment activity, but only low in vivo antimetastatic activity.
Zhao
M
M
Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pennsylvania 15261.
Kleinman
H K
HK
Mokotoff
M
M
D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000627:therapeutic use; D002448:Cell Adhesion / Q000187:drug effects; D004563:Electrochemistry; D005354:Fibrosarcoma / Q000473:pathology; D006801:Humans; D007797:Laminin / Q000031:analogs & derivatives* / Q000737:chemistry; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D008546:Melanoma, Experimental / Q000473:pathology; D051379:Mice; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D007797:Laminin; D009842:Oligopeptides