Antisense nucleic acid compound targeted to VEGF

Details Antisense nucleic acid compound targeted to VEGF Antisense nucleic acid compound targeted to VEGF

1996-12-23

2000-11-21

Elliott, George C.

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

Involving nucleic acid

435 911, 435325, 536 231, 536 245, C07H 2104, C12Q 168, C12N 1585

Patent

active

061500925

DESCRIPTION:

BRIEF SUMMARY
FIELDS IN INDUSTRY

The present invention relates to an antisense nucleic acid compound which has a nucleotide sequence complementary to a nucleotide contained in the nucleotide sequence of a gene coding for a vascular endothelial growth factor and which inhibits the expression of the vascular endothelial growth factor (VEGF), as well as to uses thereof.


BACKGROUND OF THE INVENTION

Extensive research has conventionally been made of tumors and tumor cells as a basis of development of an anticancer drug. As a result, it was found that solid tumors need oxygen and nutrients supplied through blood vessels for their homeostasis in vivo, and without such blood vessels, they cannot be grown to 2 mm or more in diameter in vivo [Basic Science of Cancer, authored by I. F. Tannock and R. P. Hill and translated by Naoyuki Taniguchi, Medical Science International (1993); and "Hatsugan to Gan Saibo" (Carcinogenesis and Cancer Cells)], Cancer Bioscience 3, edited by Toshio Kuroki, Tokyo University Press (1991)).
For this arrival of blood vessels to solid tumors, it was proposed that solid tumor cells produce and secrete a certain factor (a tumor angiogenic factor) to induce blood vessels (J. Folkman, Annals of Surgery, Vol. 175, pp. 409-416 (1972)).
Recently, attention has been paid to a vascular endothelial growth factor as one of the substances which functions as a tumor angiogenic factor (N. Ferrara et al., Endocrine Reviews, Vol. 3, No. 1, pp. 18-31 (1992)). The vascular endothelial growth factor is the same substance as so-called "vascular permeability factor", and in some cases it is also called "vascular endothelial growth factor/vascular permeability factor". As such factor, 4 kinds of molecular species, which occur depending on the difference of splicing, are found in humans.
Recently, it has been found that this vascular endothelial growth factor does not exert direct action (e.g. growth promotion) on solid tumor cells in experiments with cells (in vitro). However, it has been found that this factor promotes the growth of solid tumors in experiments on with animals (in vivo). It has been further revealed that the growth of solid tumors is inhibited by administration of an anti-VEGF antibody to animals. These findings indicate that the vascular endothelial growth factor is a tumor angiogenic factor (K. J. Kim et al., Nature, Vol. 362, April 29 issue, pp. 841-844 (1993); S. Kondo et al., Biochemical and Biophysical Research Communications, Vol. 194, No. 3, pp. 1234-1241 (1933)).
From the foregoing, inhibition of the vascular endothelial growth factor leads to inhibition of growth of solid tumor cells, and this should be applicable in the development of anticancer agents. In fact there is a report on a method to use an anti-VEGF antibody. In this prior method, function of the vascular endothelial growth factor (i.e. function of facilitating the growth of solid tumors) biosynthesized via translation of mRNA is inhibited by the anti-VEGF antibody.
However, this prior method is based on the assumption that the vascular endothelial growth factor is present, so it is required for said factor which is not necessary to depress growth of tumor to be produced. Hence, this method cannot be effective until such substance is produced. Further, because the vascular endothelial growth factor itself is biosynthesized without special inhibition, this method is problematic if the specificity and binding ability of the anti-VEGF antibody is poor and the inhibitory action of the antibody is incomplete.
The object of the present invention is to provide a nucleic acid compound (i.e. antisense nucleic acid compound) which completely or almost completely inhibits expression of the vascular endothelial growth factor itself by inhibiting production of the vascular endothelial growth factors at the translation of mRNA, in place of inhibiting the action of the produced vascular endothelial growth factor by use of said anti-VEGF antibody.


SUMMARY OF THE INVENTION

To solve the problem, complementary nucleotides (i.e. antisense nucleic a

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Tseng et al., Antisense oligonucleotide technology in the development of cancer therapeutics, Cancer Gene Therapy, vol. 1(1), pp. 65-71, Mar. 1994.
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In: Antisense Res. Dev.; 5; Spring 95; 87-8; OP-10 Abstract and 1st International Antisense Conference in Japan; Dec. 4-7, 1994; "Selection of Antisense Oligodeoxyribonucleotides that Inhibit VEGF/VPF Expression in a Cell-free System."

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