Therapeutically promising PNA complementary to a regulatory sequence for c-myc: pharmacokinetics in an animal model of human Burkitt's lymphoma.
In Burkitt's lymphoma (BL) cells c-myc is often translocated in proximity to the Emu enhancer of the Ig gene locus. This translocation causes c-myc hyperexpression and an increase in the cells' proliferative capacity. A peptide nucleic acid (PNA) complementary to enhancer Emu intronic sequence (PNAEmu), linked to a nuclear localization signal (NLS), selectively and specifically blocks the expression of the c-myc oncogene under Emu control in vitro, suggesting potential therapeutic use. To explore this issue further, we have determined the pharmacokinetics of (14)C-labeled PNAEmu in SCID mice where a human tumor is established by inoculation of cells from a BL cell line. The data demonstrate that the compound has a relatively long life in vivo in tissues and, in particular, in BL tumor mass. Furthermore, in this animal model, PNAEmu shows low or no toxicity. All these results are in favor of a successful preclinical application in a BL human tumor animal model of a PNA targeting a regulatory, nontranscribed DNA sequence that can selectively inhibit the hyperexpression of a translocated gene linked to neoplastic cell expansion.
Boffa
Lidia C
LC
SS. Epigenetics, Istituto Nazionale per la Ricerca sul Cancro, IST, Genova, Italy.
Cutrona
Giovanna
G
Cilli
Michele
M
Mariani
Maria Rita
MR
Matis
Serena
S
Pastorino
Martina
M
Damonte
Gianluca
G
Millo
Enrico
E
Roncella
Silvio
S
Ferrarini
Manlio
M
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002051:Burkitt Lymphoma / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D020135:Peptide Nucleic Acids / Q000235:genetics / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics*
D000970:Antineoplastic Agents; C489427:MYC protein, human; D020135:Peptide Nucleic Acids; D016271:Proto-Oncogene Proteins c-myc