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.
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