TY - JOUR
T1 - Lack of mutagenicity and clastogenicity of PNAEμ-NLS targeted to a regulatory sequence of the translocated c-myc oncogene in Burkitt's lymphoma
AU - Boffa, L. C.
AU - Menichini, P.
AU - Bolognesi, C.
AU - Cutrona, G.
AU - Roncella, S.
AU - Damonte, G. L.
AU - Millo, E.
AU - Mariani, M. R.
AU - Matis, S.
AU - Russo, D.
AU - Ciliutti, P.
AU - Ferrarini, M.
PY - 2007/4/2
Y1 - 2007/4/2
N2 - Peptide nucleic acids (PNAs) are synthetic homolog of nucleic acids in which the phosphate-sugar polynucleotide backbone is replaced by a flexible polyamide. They bind complementary polynucleotide sequences with higher affinity and specificity than their natural counterparts. PNAs linked to the appropriate nuclear localization signal (NLS) peptide have been used to selectively down-regulate the expression of several genes in viable cells. For example in Burkitt's lymphoma (BL) cells the c-myc oncogene is translocated in proximity to the Eμ enhancer of the Ig gene locus and upregulated. PNAs complementary to the second exon of c-myc or to the Eμ enhancer sequence (PNAEμ-NLS), selectively and specifically block the expression of the c-myc oncogene and inhibit cell growth in vitro and in vivo. PNAEμ-NLS administration to mice did not exhibit toxic effects even at the highest concentration allowed by the experimental conditions. Because of the accumulating data confirming PNAEμ-NLS potential therapeutic value, PNAEμ-NLS was evaluated for the inability to induce mutations in tester strains of Salmonella typhimurium, Escherichia coli, and at the hprt locus in Chinese hamster ovary cells (CHO). Moreover, the induction of chromosomal aberrations in CHO cells and of micronuclei in human lymphocytes were investigated. We may conclude that PNAEμ-NLS neither induces mutations nor has clastogenic effects as detectable by treatment under the standard test conditions.
AB - Peptide nucleic acids (PNAs) are synthetic homolog of nucleic acids in which the phosphate-sugar polynucleotide backbone is replaced by a flexible polyamide. They bind complementary polynucleotide sequences with higher affinity and specificity than their natural counterparts. PNAs linked to the appropriate nuclear localization signal (NLS) peptide have been used to selectively down-regulate the expression of several genes in viable cells. For example in Burkitt's lymphoma (BL) cells the c-myc oncogene is translocated in proximity to the Eμ enhancer of the Ig gene locus and upregulated. PNAs complementary to the second exon of c-myc or to the Eμ enhancer sequence (PNAEμ-NLS), selectively and specifically block the expression of the c-myc oncogene and inhibit cell growth in vitro and in vivo. PNAEμ-NLS administration to mice did not exhibit toxic effects even at the highest concentration allowed by the experimental conditions. Because of the accumulating data confirming PNAEμ-NLS potential therapeutic value, PNAEμ-NLS was evaluated for the inability to induce mutations in tester strains of Salmonella typhimurium, Escherichia coli, and at the hprt locus in Chinese hamster ovary cells (CHO). Moreover, the induction of chromosomal aberrations in CHO cells and of micronuclei in human lymphocytes were investigated. We may conclude that PNAEμ-NLS neither induces mutations nor has clastogenic effects as detectable by treatment under the standard test conditions.
KW - Anti-gene therapy
KW - Chromosomal aberrations
KW - Eμ enhancer
KW - Micronuclei
KW - Mutagenicity
KW - Peptide nucleic acids (PNA)
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U2 - 10.1016/j.mrgentox.2006.11.009
DO - 10.1016/j.mrgentox.2006.11.009
M3 - Article
C2 - 17267263
AN - SCOPUS:33847262432
VL - 628
SP - 129
EP - 137
JO - Mutation Research - Genetic Toxicology and Environmental Mutagenesis
JF - Mutation Research - Genetic Toxicology and Environmental Mutagenesis
SN - 1383-5718
IS - 2
ER -