Suppression of c-myc oncogene expression by a polyamine-complexed triplex forming oligonucleotide in MCF-7 breast cancer cells.
Polyamines are excellent stabilizers of triplex DNA. Recent studies in our laboratory revealed a remarkable structural specificity of polyamines in the induction and stabilization of triplex DNA. 1,3-Diaminopropane (DAP) showed optimum efficacy amongst a series of synthetic diamines in stabilizing triplex DNA. To utilize the potential of this finding in developing an anti-gene strategy for breast cancer, we treated MCF-7 cells with a 37mer oligonucleotide to form triplex DNA in the up-stream regulatory region of the c-myc oncogene in the presence of DAP. As individual agents, the oligonucleotide and DAP did not downregulate c-myc mRNA in the presence of estradiol. Complexation of the oligonucleotide with 2 mM DAP reduced c-myc mRNA signal by 65% at 10 microM oligonucleotide concentration. In contrast, a control oligonucleotide had no significant effect on c-myc mRNA. The expression of c-fos oncogene was not significantly altered by the triplex forming oligonucleotide (TFO). DAP was internalized within 1 h of treatment; however, it had no significant effect on the level of natural polyamines. These data indicate that selective utilization of synthetic polyamines and TFOs might be an important strategy to develop anti-gene-based therapeutic modalities for breast cancer.
Thomas
T J
TJ
Program in Clinical Pharmacology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick 08903, USA.
Faaland
C A
CA
Gallo
M A
MA
Thomas
T
T
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D016259:Genes, myc; D006801:Humans; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D009693:Nucleic Acid Hybridization; D009838:Oligodeoxyribonucleotides / Q000737:chemistry* / Q000494:pharmacology; D011073:Polyamines / Q000737:chemistry*; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D009838:Oligodeoxyribonucleotides; D011073:Polyamines; D012333:RNA, Messenger; D012334:RNA, Neoplasm