Antisense Oligonucleotides

Antisense oligonucleotides are chemically modified single-strand DNA molecules with a nucleotide sequence that is complementary to the target mRNA and, therefore, are capable of inhibiting expression of the target gene. Bcl-2 upregulation is thought to be responsible for maintaining the viability of tumor cells, as well as inducing a form of multidrug resistance. The bcl-2 gene is a rational target in follicular NHL because it is overexpressed in most tumors.

Oblimersen sodium (Genasense, Genta Incorporated, Berkeley Heights, NJ) is a phosphorothioate oligonucleotide consisting of 18 modified DNA bases (i.e., 18-mer) that targets the first six codons of Bcl-2 mRNA to form a DNA/RNA duplex. This agent is the first antisense molecule to be widely tested in the clinic for the treatment of human tumors.

In the single phase I study of oblimersen in 21 patients with NHL,94 one patient attained a complete response, which lasted unmaintained for longer than 3 years. Combinations of oblimersen with fludarabine, bortezomib, rituximab, and other agents are in development.

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