ANTISENSE OLIGONUCLEOTIDES AGAINST THYMIDYLATE SYNTHASE

摘要

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.