Tumor genotype-specific growth inhibition in vivo by antisense oligonucleotides against a polymorphic site of the large subunit of human RNA polymerase II.

Abstract:

:Loss of heterozygosity (LOH) reduces genes to hemizygosity in cancer cells and presents an absolute difference between normal and cancer cells. The regions of LOH are usually much larger than the tumor suppressor gene, which is lost, and are expected to contain genes that are essential for cell survival. Single nucleotide polymorphisms (SNPs) are the most common type of genetic variation in man, often giving rise to two or more allelic forms of most genes. SNPs of essential genes that are frequently affected by LOH can be used as a target for a novel therapy against cancer cells with LOH. The SNPs can be targeted by antisense oligonucleotides (ODNs) that will discriminate between two alleles. We have designed allele-specific phosphorothioate ODNs against the gene of the large subunit of RNA polymerase II (POLR2A), a gene located in close proximity to the tumor suppressor gene p53, which frequently shows LOH in cancer cells. This report shows that phosphorothioate antisense ODNs directed against POLR2A can inhibit tumor growth in vivo as efficiently as a well-described antitumor antisense ODN directed against Ha-ras. In addition, we show that a single bp mismatch can be sufficient to obtain allele-specific inhibition of tumor growth, demonstrating that the effects observed are true antisense effects.

journal_name

Cancer Res

journal_title

Cancer research

authors

Fluiter K,ten Asbroek AL,van Groenigen M,Nooij M,Aalders MC,Baas F

subject

Has Abstract

pub_date

2002-04-01 00:00:00

pages

2024-8

issue

7

eissn

0008-5472

issn

1538-7445

journal_volume

62

pub_type

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