The objective is to investigate the mechanism of the inhibitory effect of GRGDS (GlyArgGly-AspSer) pentapeptide on pulmonary colonization by murine melanoma (B16F10) cell and to assess the possible therapeutic potential of this molecule in the mouse model system. Since this peptide sequence corresponds to the cellbinding domain of the adhesive glycoprotein fibronectin, our working hypothesis for the peptidemediated inhibition of experimental metastasis is that it results from interference with cellular adhesive function. We will identify which adhesive molecule is inhibited by the pentapeptide by examining the relationship between the effects of GRGDS and related peptides on lung colonization and adhesion of B16F10 melanoma cells to substrata composed of fibronectin, laminin, collagen, vitronectin, and fibrinogen using classical in vitro assays. Identification of the site of pentapeptide interference will be further evaluated in similar in vivo and in vitro studies by utilizing the MCF7 human breast carcinoma cell line that attaches specifically to laminin. We will also examine the possibility that GRGDS decreases lung colonization potential of B16 melanoma cells by inhibition of platelet aggregation or emboli formation using thrombocytopenic animals to see if the peptide inhibitory effect is still manifested. To determine whether GRGDS is effective against tumor cells that metastasize other organs, the M5076 reticulum sarcoma cells that metastasize preferentially to the viscera and liver will be tested in experiments similar to those employed for the B16F10 melanoma. To investigate the possible relevance of interruption of cellular adhesive interactions in cancer therapy, we will examine the clearance rate of intravenously injected radiolabeled active peptides (GRGDS and others). If, as expected, these peptides are rapidly cleared from the blood vascular system, we will explore the effectiveness of their gradual release from subcutaneous implants of biodegradable methyl cellulose pellets against a tumor cell line (B16BL6) that spontaneously metastasizes the lung from a subcutaneous primary tumor. As alternative approaches to maintaining a constant plasma level of peptide sufficient to abrogate metastasis, we will (i) explore the use of implantable miniosmotic pumps, and/or (ii) modify the physical structure of GRGDS to reduce its excretion rate. This study is important for understanding the biology and biochemistry of tumor cell metastasis and may have clinical utility in a prophylacticalic or adjuvant settings.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA045290-03
Application #
3188388
Study Section
Pathobiochemistry Study Section (PBC)
Project Start
1987-07-01
Project End
1990-06-30
Budget Start
1989-07-01
Budget End
1990-06-30
Support Year
3
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Howard University
Department
Type
Schools of Medicine
DUNS #
056282296
City
Washington
State
DC
Country
United States
Zip Code
20059
Kuzmichev, Andrei; Margueron, Raphael; Vaquero, Alejandro et al. (2005) Composition and histone substrates of polycomb repressive group complexes change during cellular differentiation. Proc Natl Acad Sci U S A 102:1859-64
Olden, K; Breton, P; Grzegorzewski, K et al. (1991) The potential importance of swainsonine in therapy for cancers and immunology. Pharmacol Ther 50:285-90
Nagai, T; Yamakawa, N; Aota, S et al. (1991) Monoclonal antibody characterization of two distant sites required for function of the central cell-binding domain of fibronectin in cell adhesion, cell migration, and matrix assembly. J Cell Biol 114:1295-305
Humphries, M J; Matsumoto, K; White, S L et al. (1990) An assessment of the effects of swainsonine on survival of mice injected with B16-F10 melanoma cells. Clin Exp Metastasis 8:89-102
Breton, P; Asseffa, A; Grzegorzewski, K et al. (1990) Swainsonine modulation of protein kinase C activity in murine peritoneal macrophages. Cancer Commun 2:333-8
Humphries, M J; Obara, M; Olden, K et al. (1989) Role of fibronectin in adhesion, migration, and metastasis. Cancer Invest 7:373-93
Humphries, M J; Olden, K (1989) Asparagine-linked oligosaccharides and tumor metastasis. Pharmacol Ther 44:85-105
Humphries, M J; Matsumoto, K; White, S L et al. (1988) Augmentation of murine natural killer cell activity by swainsonine, a new antimetastatic immunomodulator. Cancer Res 48:1410-5
Humphries, M J; Akiyama, S K; Komoriya, A et al. (1988) Neurite extension of chicken peripheral nervous system neurons on fibronectin: relative importance of specific adhesion sites in the central cell-binding domain and the alternatively spliced type III connecting segment. J Cell Biol 106:1289-97
Humphries, M J; Yamada, K M; Olden, K (1988) Investigation of the biological effects of anti-cell adhesive synthetic peptides that inhibit experimental metastasis of B16-F10 murine melanoma cells. J Clin Invest 81:782-90

Showing the most recent 10 out of 11 publications