Research Project
7394762
[unreadable] DESCRIPTION (provided by applicant): Chem-Master International Inc. (CMII) is a small chemical manufacturing company that was established in 1994 to serve the needs of both industrial and academic groups, who did not have easy access to a range of biologically-active substances or their synthetic intermediates. The Company, since its origin, has provided many new and known compounds to larger pharmaceutical companies. In the realm of taxoid chemistry, CMII developed the multi-step convergent commercial process for its production by Indena SpA (Milan, Italy) of SB-T-110131 (discovered by Dr. Ojima and later coded as IDN5109). This also included the development of an entirely new method for the synthesis and introduction of the iso-serine side chain. Based on these accomplishments and experience in multi-step synthesis, we now propose to undertake the synthesis of at least 10g of DHA-SB-T-1214 (discovered and patented by Dr. Ojima) with 97% or better purity. We also propose that this material then be used by Dr. R Bernacki of the Roswell Park Cancer Institute in a series of assays to determine the ability of this PUFA-taxoid substance to arrest or completely terminate the growth of three cancer cell lines, namely DLD-1 (Pgp+; human colon), H460-NSCLC (human lung) and BT-20 (human breast) developed as xenografts in immuno-compromised mice. These tests will be conducted against a panel of related free taxoid drug substances, for comparisons of biologic activity. Although studies with DHA-SB-T-1214 have already shown truly exceptional activity against the DLD-1 xenograft (life extension to 186 days essentially complete cure) some toxicity differences were noted with two different samples of the drug. Thus we believe that these experiments should be repeated with a drug sample that has been highly purified. Tests on the lung and breast cancer cell lines represent an attempt to extend the dominion of DHA-SB-T-1214 to two common but singularly refractory forms of human cancer-- lung and breast. All of the anti-tumor assays will be conducted at three dose levels, the first to determine the maximum tolerated dose (MTD) and the others at one half and one tenth respectively of the MTD. The objective is to define, what dose levels would be appropriate to treat the above types of cancer in a clinical setting. The proposed development of DHA-SB-T- 1214 looks highly justified in view of the past results with the colon cancer cell line DLD-1 where the anti-tumor effects appear to be one order of magnitude better than has been seen with any other drug.7) Project Narrative: [unreadable] [unreadable] The proposed project is of great relevance to human health. Currently there are no really effective drug substances that can abolish or even partially inhibit the growth of human colon cancer because this particular form of cancer over-expresses the MDR phenotype. Remarkably DHA-SB-T-1214, a polyunsaturated fatty acid -taxoid conjugate, seems to be able to penetrate these cancer cells selectively and to by-pass the MDR apparatus, thereafter inducing cell death. The further development of this substance as a possible treatment for both colon and other forms of cancer could scarcely be more relevant in a society where many forms of this multi-variate and largely untreatable disease, seem to be increasing. [unreadable] [unreadable] [unreadable]
