Received for publication September 20, 2007.
Revised February 24, 2008.
Accepted for publication February 25, 2008.

Targeting MDR1 Gene: Synthesis and Cellular Study of Modified Daunomycin-TFO Conjugates Able to Inhibit Gene Expression in Resistant Cell Lines

Abstract

Reversal of the multidrug resistant (MDR) phenotype is very important for chemotherapy success. In fact, the expression of the MDR1 gene-encoded P-gp actively expels antitumor agents such as daunomycin (DNM) out of the cells, resulting in drug resistance. We show that upon conjugation to triplex-forming oligonucleotides it is possible to address DNM in resistant cells (MCF7-R and NIH-MDR-G185). The oligonucleotide moiety of the conjugate changes the cellular penetration properties of the antitumor agent that is no more the target of P-gp in resistant cells. We observe an accumulation of conjugated DNM in cells up to 72h. For more efficient delivery in the cells nuclei, tranfectant agents must be used. In addition, the conjugate recognizes a sequence located in exon 3 of MDR1 and inhibits its gene expression as measured both by Western blot and RT PCR.

Key words: MDR/p-Glycoprotein, Regulation of gene expression, Nucleoside/Nucleotide derivatives, Resistance, DNA intercalation, Topoisomerases

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