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 Eμ 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 Eμ intronic sequence (PNAEμ), linked to a nuclear localization signal (NLS), selectively and specifically blocks the expression of the c-myc oncogene under Eμ control in vitro, suggesting potential therapeutic use. To explore this issue further, we have determined the pharmacokinetics of ¹⁴C-labeled PNAEμ 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, PNAEμ 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.