Lack of mutagenicity and clastogenicity of PNAEmu-NLS targeted to a regulatory sequence of the translocated c-myc oncogene in Burkitt's lymphoma.
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 Emu enhancer of the Ig gene locus and upregulated. PNAs complementary to the second exon of c-myc or to the Emu enhancer sequence (PNAEmu-NLS), selectively and specifically block the expression of the c-myc oncogene and inhibit cell growth in vitro and in vivo. PNAEmu-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 PNAEmu-NLS potential therapeutic value, PNAEmu-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 PNAEmu-NLS neither induces mutations nor has clastogenic effects as detectable by treatment under the standard test conditions.
Boffa
L C
LC
Medical Oncology C, National Cancer Research Institute, IST, [corrected] L. go R. Benzi 10, 16132 Genova, Italy. lidia.boffa@istge.it
Menichini
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P
Bolognesi
C
C
Cutrona
G
G
Roncella
S
S
Damonte
G L
GL
Millo
E
E
Mariani
M R
MR
Matis
S
S
Russo
D
D
Ciliutti
P
P
Ferrarini
M
M
D000818:Animals; D002051:Burkitt Lymphoma / Q000235:genetics*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004742:Enhancer Elements, Genetic; D004926:Escherichia coli; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D007148:Immunoglobulin mu-Chains / Q000633:toxicity*; D008214:Lymphocytes / Q000187:drug effects; D015162:Micronucleus Tests; D009153:Mutagens / Q000633:toxicity*; D019913:Nuclear Localization Signals / Q000633:toxicity*; D020135:Peptide Nucleic Acids / Q000633:toxicity*; D021381:Protein Transport; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012486:Salmonella typhimurium
D007148:Immunoglobulin mu-Chains; C489427:MYC protein, human; D009153:Mutagens; D019913:Nuclear Localization Signals; C519481:PNAEmu-NLS; D020135:Peptide Nucleic Acids; D016271:Proto-Oncogene Proteins c-myc; D007041:Hypoxanthine Phosphoribosyltransferase