The role of doxorubicin in non-viral gene transfer in the lung.

Griesenbach U, Meng C, Farley R, Gardner A, Brake MA, Frankel GM, Gruenert DC, Cheng SH, Scheule RK, Alton EW

Biomaterials

Biomaterials. 2009 Apr;30(10):1971-7. doi: 10.1016/j.biomaterials.2008.12.037. Epub 2009 Jan 18.

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Proteasome inhibitors have been shown to increase adeno-associated virus (AAV)-mediated transduction in vitro and in vivo. To assess if proteasome inhibitors also increase lipid-mediated gene transfer with relevance to cystic fibrosis (CF), we first assessed the effects of doxorubicin and N-acetyl-l-leucinyl-l-leucinal-l-norleucinal in non-CF (A549) and CF (CFTE29o-) airway epithelial cell lines. CFTE29o- cells did not show a response to Dox or LLnL; however, gene transfer in A549 cells increased in a dose-related fashion (p < 0.05), up to approximately 20-fold respectively at the optimal dose (no treatment: 9.3 x 10(4) +/- 1.5 x 10(3), Dox: 1.6 x 10(6)+/-2.6 x 10(5), LLnL: 1.9 x 10(6) +/- 3.2 x 10(5)RLU/mg protein). As Dox is used clinically in cancer chemotherapy we next assessed the effect of this drug on non-viral lung gene transfer in vivo. CF knockout mice were injected intraperitoneally (IP) with Dox (25-100 mg/kg) immediately before nebulisation with plasmid DNA carrying a luciferase reporter gene under the control of a CMV promoter/enhancer (pCIKLux) complexed to the cationic lipid GL67A. Dox also significantly (p < 0.05) increased expression of a plasmid regulated by an elongation factor 1alpha promoter (hCEFI) approximately 8-fold. Although administration of Dox before lung gene transfer may not be a clinically viable option, understanding how Dox increases lung gene expression may help to shed light on intracellular bottle-necks to gene transfer, and may help to identify other adjuncts that may be more appropriate for use in man.

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