Catalytic Cleavage Approach to Cancer Chemotherapy

Several lanthanide(III) derivatives of texaphyrin are being developed as agents for magnetic resonaphotodynamic therapy and as radio-sensitizers. The investigator has discovered that some lanthanide(unique agents for effecting site specific hydrolysis of RNA. The objectives of the Phase I applicatisynthesis to give large amounts of lanthanide(III)texaphyrin- oligonucleotide analogue conjugates fowill be synthesized and modified with the commercial aminohexyl- amidite at the 5'-end of the silicaMMT group protecting the amine is removed on the support and the amide-forming coupling reaction carcolumn-bound conjugate. The ribozyme analogue is released and deprotected with ammonia to afford 5'-DyTx-DNA conjugate. In case this method fails, a phoshoramidite derivative of DyTX will be preparedlast "monomer" in the automated synthesis. The DyTx OH groups will be protected as esters and deprotwith ammonia. This ribozyme analogue will differ from the earlier preparation in its structure havinlinker. Methods will have to be developed for the large scale purification of the ribozyme analoguesdialysis or ion exchange chromatography. The second part of the application seeks to test the efficihydrolysis is carried out by the agent in the presence of competing secondary and higher order strucproteins. Hybridization and cleavage studies will be taken up on synthetic RNA substrate of about 30Cleavage fragments generated by the ribozyme analogue will be assayed by electrophoresis and quantitdensitometry. The synthesized ribozyme analogues will be directed against c-myc oncogene in cell culvitro efficacy. Biodistribution, pharmacokinetics, activity and safety are planned in the Phase II s