Synthetic Inducers of Apoptosis in Metastatic Cells

Period of Performance: 09/30/1997 - 03/31/1999

Unknown

Phase 1 SBIR

Recipient Firm

Metastat, Inc.
Eugene, OR 97401
Principal Investigator

Abstract

The long-term objective of the proposed research is the development of a new family of antimetastatic drugs acting on the molecular level as an induce of apoptosis in metastatic cancer cells. The proposed research is based on our recent experimental observations that: 1) aggressive metastatic phenotype is associated with high resistance to apoptosis; and 2) synthetic glycoamine analogs, previously selected as a strong inhibitors of both homotypic cancer cell aggregation and colony formation in dense agarose, act as antimetastatic agents and induce of apoptosis in metastatic cancer cells. The initial stage of the project will be focused on synthesis and selection of the most potent induces of apoptosis in metastatic caner cells from a panel of low molecular weight synthetic compounds structurally related to the synthetic glycoamines. Specifically, we plan: 1) To perform the synthesis, purification, and structural characterization of a family of structurally related glycoamines with expected apoptosis induction activity; 2) To select the limited number (up to 3) of the most effective induces of apoptosis employing a panel of highly metastatic murine and human cancer cell lines, viability assay, cell death detection ELISA and cellular DNA degradation ELISA; 3) To confirm apoptosis induction activity of the selected compounds based on biochemical (DNA fragmentation analysis) and cytological (the TUNEL assay) criteria of apoptosis in target cells; 4) To evaluate the antimetastatic activity in vivo of the selected number (up to 3) of the most potent inducers of apoptosis alone and in combination with chemotherapy (doxorubicin and paclitaxel) employing nude mice model and highly metastatic human breast carcinoma cell line MDA-MB-435. Successful completion of the first phase of research should lead to the ability to conduct initial toxicology studies and a comprehensive in vivo evaluation of the most effective apoptosis inducers in Phase II research employing nude mice model and established highly metastatic human cancer cells. PROPOSED COMMERCIAL APPLICATION: The proposed research would result in development of a new family of antimetastatic drugs acting at the molecular level as apoptosis inducers in cancer cells. We plan to file a patent application following completion of Phase I research. The estimated market for this type of therapy is $600 million a year for treatment of breast cancer.