Antisense oligonucleotides against thymidylate synthase

Details Antisense oligonucleotides against thymidylate synthase Antisense oligonucleotides against thymidylate synthase

C - Chemistry, Metallurgy

12

N

C12N 15/11 (2006.01) A61K 31/505 (2006.01) A61K 31/70 (2006.01) C07H 21/02 (2006.01) A61K 38/00 (2006.01)

Patent

CA 2301957

Antisene oligonucleotides targeted to sequences in thymidylate synthase (TS) mRNA. In particular the invention relates to antisense oligonucleotides targeted to sequences in the 3' end of TS mRNA, which are both cytostatic on their own when administered to human tumour cell lines, and which also enhance the toxicity of anticancer drugs such as Tomudex. The invention also relates to antisense oligonucleotides targeted to sequences at or near the translation start site at the 5' end of TS mRNA which induce TS gene transcription and enhance cell growth. The invention further relates to a combination product comprising an antisense oligonucleotide in combination with an anticancer agent such as Tomudex (N-(5[N-3, 4-dihydro-2-methyl-4- oxoquinazolin-6- ylmethyl) -N-methylamino] -2-thenoyl)-L-glutamic acid) or the Zeneca development compound ZD 9331 ((S)-2-(2-fluoro-4- [N-(4-hydroxy-2,7- dimethylquinazolin-6-ylmethyl) -N-(prop-2-ynyl)amino] benzamido)-4-(1H-1, 2,3,4-tetrazol-5-yl) butyric acid), and to the use of such a combination product in the treatment of cancer.

L'invention concerne des oligonucléotides antisens ciblés sur des séquences d'ARN messager de thymidylate synthase (TS). L'invention concerne plus particulièrement des oligonucléotides antisens ciblés sur des séquences de la terminaison 3' de l'ARN messager TS, qui sont cytostatiques et qui augmentent la toxicité d'anticancéreux tels que le Tomudex. L'invention concerne aussi des oligonucléotides antisens ciblés sur des séquences au niveau de ou à proximité du site de départ de traduction au niveau de la terminaison 5' de l'ARN messager TS qui induisent la transcription du gène TS et augmentent la croissance cellulaire. L'invention concerne en outre un produit combiné comprenant un oligonucléotide antisens combiné à un agent anticancéreux tel que le Tomudex (N-(5-[N-3, 4-dihydro-2-méthyl-4- oxoquinazoline-6-ylméthyl) -N-méthylamino] -2-thénoyl) -L-acide glutamique) ou le composé ZD 9331 de développement du Zeneca ((S)-2(2-fluoro-4- [N-(4-hydroxy-2,7- diméthylquinazoline-6-ylméthyl) -N-(prop-2-ynyl)amino] benzamido)-4-(1H-1, 2,3,4-tétrazol-5-yl)acide butyrique et l'utilisation d'un tel produit combiné dans le traitement du cancer.

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