The major objective of this study is the evaluation of agents which inhibit the attachment to or degradation of basement membrane components by human metastatic carcinoma cells. Emphasis will be given on studying those agents which affect the metabolism or structure of tumor cell plasma membrane glycoconjugates and/or cytoskeleton as inhibitors of cellular attachment to extracellular matrix (ECM). This includes testing a series of synthetic sugar analogs, oligosaccharides, nucleotide-sugar derivatives, calcium channel blockers and calmodulin inhibitors for their effects on tumor cell attachment and growth. In addition, a number of potential glycosidase inhibitors will be evaluated for their inhibitory effects on tumor cell induced degradation of ECM components. Previous studies with a number of freshly isolated human gynecological and urological tumors have demonstrated that ECM, produced by bocvine corneal endothelial cells, can serve as a good model substrate for studying these phenomena in vitro. a human ovarian tumor cell line established on ECM from a lymph node metastases has been observed to avidly degrade ECM in vitro. Agents with biological activity, selected with this or other human carcinoma cells in vitro, will then be evaluated for therapeutic activity using human tumor xenographs in mice. Alterations in tumor growth rate, metastases and mouse lifespan will be monitored. It is anticipated that the proposed studies will increase our knowledge concerning mechanisms of tumor cell attachment and invasion and perhaps lead to the discovery and development of new and unique drugs having antitumor and antimetastatic activity.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA042898-05
Application #
3184586
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Project Start
1986-09-01
Project End
1993-02-28
Budget Start
1991-03-01
Budget End
1992-02-29
Support Year
5
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Roswell Park Cancer Institute Corp
Department
Type
DUNS #
City
Buffalo
State
NY
Country
United States
Zip Code
14263
Angelino, N J; Bernacki, R J; Sharma, M et al. (1995) Versatile intermediates in the selective modification of the amino function of 2-amino-2-deoxy-D-mannopyranose and the 3-position of 2-acetamido-2-deoxy-D-mannose: potential membrane modifiers in neoplastic control. Carbohydr Res 276:99-115
Woynarowska, B; Skrincosky, D M; Haag, A et al. (1994) Inhibition of lectin-mediated ovarian tumor cell adhesion by sugar analogs. J Biol Chem 269:22797-803
Sharma, M; Bernacki, R J; Hillman, M J et al. (1993) Fluorinated carbohydrates as potential plasma membrane modifiers. Synthesis of 3-deoxy-3-fluoro derivatives of 2-acetamido-2-deoxy-D-hexopyranoses. Carbohydr Res 240:85-93
Tumminello, F M; Bernacki, R J; Gebbia, N et al. (1993) Pepstatins: aspartic proteinase inhibitors having potential therapeutic applications. Med Res Rev 13:199-208
Skrincosky, D M; Allen, H J; Bernacki, R J (1993) Galaptin-mediated adhesion of human ovarian carcinoma A121 cells and detection of cellular galaptin-binding glycoproteins. Cancer Res 53:2667-75
Woynarowska, B; Wikiel, H; Sharma, M et al. (1992) Inhibition of human ovarian carcinoma cell- and hexosaminidase- mediated degradation of extracellular matrix by sugar analogs. Anticancer Res 12:161-6
Hong, C I; Bernacki, R J; Hui, S W et al. (1990) Formulation, stability, and antitumor activity of 1-beta-D-arabinofuranosylcytosine conjugate of thioether phospholipid. Cancer Res 50:4401-6
Allen, H J; Sucato, D; Woynarowska, B et al. (1990) Role of galaptin in ovarian carcinoma adhesion to extracellular matrix in vitro. J Cell Biochem 43:43-57
Sharma, M; Bernacki, R J; Paul, B et al. (1990) Fluorinated carbohydrates as potential plasma membrane modifiers. Synthesis of 4- and 6-fluoro derivatives of 2-acetamido-2-deoxy-D-hexopyranoses. Carbohydr Res 198:205-21
Leto, G; Tumminello, F M; Gebbia, N et al. (1990) Antimetastatic activity of adriamycin in combinations with proteinase inhibitors in mice. Anticancer Res 10:265-9

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