Method of inhibiting the proliferation and causing the...

Details Method of inhibiting the proliferation and causing the... Method of inhibiting the proliferation and causing the...

1999-09-02

2001-12-18

McGarry, Sean (Department: 1635)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S023100, C536S024100, C536S024500, C435S006120

Reexamination Certificate

active

06331526

ABSTRACT:

BACKGROUND OF THE INVENTION
The IGF-1 receptor is expressed in many cell types including fibroblasts, epithelial cells, smooth muscle cells, chondrocytes, osteoblasts and several lineages of hemopoietic cells which have IGF-1 receptors and an absolute requirement for IGF-1 for growth in cultures. A review of human cells expressing the IGF-1 receptor and requiring IGF-1 for growth can be found in Baserga and Rubin,
Critical Reviews in Eukaryote Gene Expression,
1993, 3: 47-61; and Goldring and Goldring,
Eukaryote Gene Expression
1991, 1, 301-326. Macaulay,
Br. J. Cancer
1992, 65, 311-320, has reviewed the expression of insulin-like growth factors (both IGF-1 and IGF-2) and their receptors in human cancer. Recently, it was shown that IGF-1 peptide analogs may be useful for inhibiting the growth of IGF-1 dependent cells (Pietrzkowski et al.,
Cancer Res.
1993, 53, 1102-1106). Antisense oligonucleotides to mRNA coding for IGF-1 was used to transform rat glioblastoma cells. The cells reversed the transformed phenotype, and acted immunogenic against the parent glioblastoma cell line, completely inhibiting its growth. Tojan et al.
Science,
1993, 259, 94-97 and Trojan et al.,
Proc. Natl. Acad. Sci. U.S.A.,
1992, 89, 4874-4878. However, effective methods of inhibiting growth and causing differentiation of cells are still greatly desired.
SUMMARY OF THE INVENTION
Methods of inhibiting the growth and causing differentiation of undifferentiated cells with antisense oligonucleotides complementary to a region of the IGF-1 receptor are provided. The antisense oligonucleotides of the present invention comprise sequences complementary to regions of IGF-1 receptor RNA. The oligonucleotides comprise a sequence complementary to a region selected from the sequence of IGF-1 receptor. The antisense oligonucleotides include DNA sequences; and antisense RNA oligonucleotides produced from an expression vector. Each of the antisense oligonucleotides of the present invention are complementary to regions of the IGF-1 receptor sequence. The antisense oligodeoxynucleotide of the present invention comprises a sequence complementary to codons −29 to −24 of the signal sequence, for example, SEQ ID NO: 4. The signal sequence of IGF-1 receptor is a 30 amino acid sequence. Contemplated by this definition are fragments of oligos within the 30 amino acid signal sequence. Alternatively, fragments of oligos within SEQ ID NO: 4 are also contemplated. The antisense oligoribonucleotide, SEQ ID NO: 8 produced from an expression vector comprise a sequence complementary to codons 1 to 309 of the IGF-1 receptor, FIG.
7
. See Ullrich et al.,
EMBO J.,
1986, 5:2503. Contemplated by this definition are fragments of oligos within the coding sequence for the IGF-1 receptor.


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