Tumor genotype-specific growth inhibition in vivo by antisense oligonucleotides against a polymorphic site of the large subunit of human RNA polymerase II.
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.
Fluiter
Kees
K
Neurozintuigen Laboratory, Academical Medical Center, 1105 AZ,Amsterdam, the Netherlands.
ten Asbroek
Anneloor L M A
AL
van Groenigen
Marjon
M
Nooij
Marleen
M
Aalders
Maurice C G
MC
Baas
Frank
F
D000483:Alleles; D000818:Animals; D020137:Base Pair Mismatch; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D051379:Mice; D016376:Oligonucleotides, Antisense / Q000235:genetics* / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D012319:RNA Polymerase II / Q000235:genetics*; D013873:Thionucleotides / Q000235:genetics / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D016376:Oligonucleotides, Antisense; D013873:Thionucleotides; D012319:RNA Polymerase II