Breast cancer attacks one out of every nine women. Among the many indicators and prognostic factors in breast cancer, the c- MYC proto-oncogene is amplified and overexpressed in many early and advanced stage mammary tumors. Antisense DNA therapy is proving effective in human clinical trials against viruses and oncogenes. Nuclease resistant reactive oligonucleotides offer powerful tools for intervention against malignant cells with activated oncogenes. The hypothesis of this proposal is that oligonucleotide therapy will achieve antiproliferative potency by specifically ablating c-MYC overexpression in breast cancer cells at subtoxic doses. For this purpose, the Novosibirsk laboratory will synthesize alkylating [4-(N-2-chloroethyl, N-methylamino) benyzylmethylamino] and cleaving (bleomycin A5) derivatives of nuclease resistant phosphorothioate DNAs, 2'-O-methyl RNAs, and their chimeras, potentiated with phenazinium and/or steroid modifications, targeted against c-MYC mRNA targets. The unique heterobifunctional oligonucleotide derivatives with 3'- cholesterol and 5'-reactive groups efficiently penetrate into cells, resist intracellular nucleases, and modify nucleic acids site-specifically. The Novosibirsk laboratory will also synthesize bleomycin A5 derivatives of nuclease resistant triplex-forming DNAs, potentiated with phenazinium and/or steroid modifications, targeted against c-myc DNA oligopurine promoter sequences. The Philadelphia laboratory will test the antigen reduction and antiproliferative efficacy of the reactive oligonucleotides in a tumorigenic human breast cancer cell line, BT474, which overexpresses c-MYC, compared with MCF7 cells, which do not overexpress c-MYC without estrogen stimulation. This new joint effort has been initiated by the visit of Dr. Smith to the Novosibirsk laboratory to measure anti-c-MYC bleomycin A5 oligomer reactivity with c-MYC RNA. In future years, the most potent nuclease resistant reactive oligonucleotides determined in cell culture will then be tested for preclinical potency by measuring inhibition of tumor growth in nude mice due to subcutaneous implantation of the BT474 and MCF7 cell lines.
| Wickstrom, Eric (2015) DNA and RNA derivatives to optimize distribution and delivery. Adv Drug Deliv Rev 87:25-34 |
