Antisense inhibition of angiogenin expression

Details Antisense inhibition of angiogenin expression Antisense inhibition of angiogenin expression

1998-03-20

2001-07-24

LeGuyader, John L. (Department: 1635)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C435S006120, C435S325000, C435S366000, C435S369000, C435S371000, C435S375000, C536S023100, C536S024300, C536S024310, C536S024330, C536S024500

Reexamination Certificate

active

06265388

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
Embodiments of the present invention relate in general to compositions and methods for inhibiting the expression of the angiogenin gene thereby reducing the effects of angiogenin. Embodiments of the present invention also relate to inhibition of angiogenin gene expression by antisense technologies including, but not limited to, the use of antisense oligodeoxynucleotides and their derivatives. Embodiments of the present invention are further directed to compositions and methods for detecting the angiogenin gene, as well as the detection and diagnosis of abnormal expression of the angiogenin gene in cells and tissues. Embodiments of the present invention are also directed to methods for inhibiting metastasis of cells, such as human tumor cells. Furthermore, this invention is directed to treatment of conditions associated with abnormal angiogenesis, including cancer.
2. Description of Related Art
Angiogenin is a potent inducer of angiogenesis [Fett, J. W., Strydom, D. J., Lobb, R. R., Alderman, E. M., Bethune, J. L., Riordan, J F., and Vallee, B. L. (1985)
Biochemistry
24, 5480-5486], a complex process of blood vessel formation that consists of several separate but interconnected steps at the cellular and biochemical level: (i) activation of endothelial cells by the action of an angiogenic stimulus, (ii) adhesion and invasion of activated endothelial cells into the surrounding tissues and migration toward the source of the angiogenic stimulus, and (iii) proliferation and differentiation of endothelial cells to form a new microvasculature [Folkman, J., and Shing, Y. (1992)
J. Biol. Chem
. 267, 10931-10934; Moscatelli, D., and Rifikin, D. B. (1988)
Biochim. Biophys. Acta
948,67-85]. Angiogenin has been demonstrated to induce most of the individual events in the process of angiogenesis including binding to endothelial cells [Badet, J., Soncin, F. Guitton, J. D., Lamare, O., Cartwright, T., and Barritault, D. (1989)
Proc. NatL. Acad. Sci. U.S.A.
86, 8427-8431], stimulating second messengers [Bicknell, R., and Vallee, B. L. (1988)
Proc. Natl. Acad. Sci. U.S.A
. 85, 5961-5965], mediating cell adhesion [Soncin, F. (1992)
Proc. Natl. Acad. Sci. U.S.A
. 89, 2232-2236], activating cell-associated proteases [Hu, G-F., and Riordan, J. F. (1993)
Biochem. Biophys. Res. Commun
. 197, 682-687], inducing cell invasion [Hu, G-F., Riordan, J. F., and Vallee, B. L. (1994)
Proc. Natl. Acad. Sci. U.S.A
. 91, 12096-12100], inducing proliferation of endothelial cells [Hu, G-F., Riordan, J. F., and Vallee, B. L. (1997)
Proc. Natl. Acad. Sci. U.S.A
. 94, 2204-2209] and organizing the formation of tubular structures from the cultured endothelial cells [Jimi, S-I., Ito, K-I, Kohno, K., Ono, M., Kuwano, M., Itagaki, Y., and Isikawa, H. (1995)
Biochem. Biophys. Res. Commun
. 211, 476-483]. Angiogenin has also been shown to undergo nuclear translocation in endothelial cells via receptor-mediated endocytosis [Moroianu, J., and Riordan, J. F. (1994)
Proc. Natl. Acad. Sci. U.S.A
. 91, 1677-1681] and nuclear localization sequence-assisted nuclear import [Moroianu, J., and Riordan, J. F. (1994)
Biochem. Biophys. Res. Commun
. 203, 1765-1772].
Although originally isolated from medium conditioned by human colon cancer cells (Fett et al., 1985, supra) and subsequently shown to be produced by several other histologic types of human tumors [Rybak, S. M., Fett, J. W., Yao, Q-Z., and Vallee, B. L. (1987)
Biochem. Biophys. Res. Commun
. 146, 1240-1248; Olson, K. A., Fett, J. W., French, T. C., Key, M. E., and Vallee, B. L. (1995)
Proc. Natl. Acad. Sci. U.S.A
. 92, 442-446], angiogenin also is a constituent of human plasma and normally circulates at a concentration of 250 to 360 ng/ml [Shimoyama, S., Gansauge, F., Gansauge, S., Negri, G., Oohara, T., and Beger, H. G. (1996)
Cancer Res
. 56, 2703-2706; Blaser, J., Triebl, S., Kopp, C., and Tschesche, H. (1993)
Eur. J. Clin. Chem. Clin. Biochem
. 31, 513-516].
While angiogenesis is a tightly controlled process under usual physiological conditions, abnormal angiogenesis can have devastating consequences as in pathological conditions such as arthritis, diabetic retinopathy and tumor growth. It is now well-established that the growth of virtually all solid tumors is angiogenesis dependent [Folkman, J. (1989)
J. Natl. Cancer Inst
. 82, 4-6]. Angiogenesis is also a prerequisite for the development of metastasis since it provides the means whereby tumor cells disseminate from the original primary tumor and establish at distant sites [Mahadevan, V., and Hart, I. R. (1990) Rev. Oncol. 3, 97-103; Blood C. H., and Zetter B. R. (1990)
Biochim. Biophys. Acta
1032, 89-118]. Therefore, interference with the process of tumor-induced angiogenesis should be an effective therapy for both primary and metastatic cancers.
Several inhibitors of the functions of angiogenin have been developed. These include: (i) monoclonal antibodies (mAbs) [Fett, J. W., Olson, K. A., and Rybak, S. M. (1994)
Biochemistry
33, 5421-5427], (ii) an angiogenin-binding protein [Hu, G-F, Chang, S-I, Riordan J. F., and Vallee, B. L. (1991)
Proc. Natl. Acad. Sci. U.S.A
. 88, 2227-2231; Hu, G-F., Strydom, D. J., Fett, J. W., Riordan, J. F., and Vallee B. L. (1993)
Proc. Natl. Acad. Sci. U.S.A
. 90,1217-1221; Moroianu, J., Fett, J. W., Riordan, J. F., and Vallee B. L. (1993)
Proc. Natl. Acad. Sci. U.S.A
. 90, 3815-3819], (iii) the placental ribonuclease inhibitor (PRI) [Shapiro, R., and Vallee, B. L. (1987)
Proc. Natl. Acad. Sci. U.S.A
. 84, 2238-2241], (iv) peptides synthesized based on the C-terminal sequence of angiogenin [Rybak, S. M., Auld, D. S., St. Clair, D. K., Yao, Q-Z., and Fett, J. W. (1989)
Biochem. Biophys. Res. Commun
. 162, 535-543], and (v) inhibitory site-directed mutants of angiogenin [Shapiro, R., and Vallee, B. L. (1989)
Biochemistry
28, 7401-7408]. All inhibit angiogenin's activities but are not directly cytotoxic to human tumor cells grown in tissue culture.
mAbs or the angiogenin-binding protein when administered locally into xenografts of human tumor cells that were injected subcutaneously (s.c.) into athymic mice are able to delay or, remarkedly, completely prevent the appearance of colon, lung and fibrosarcoma tumors in these animals [Olson et al., 1995, supra, Olson, K. A., French, T. C., Vallee, B. L., and Fett, J. W. (1994)
Cancer Res
. 54, 4576-4579]. Histological examination revealed that the mechanism of tumor growth inhibition was via an anti-angiogenesis mechanism (Olson et al., 1995, supra). Thus, the inactivation of tumor-produced angiogenin or inhibition of expression of the angiogenin gene by tumor cells promise to be a powerful means of managing cancer, either alone or in combination with more conventional therapies (i.e., chemotherapy, radiotherapy, immunotherapy, etc.).
Expression of specific genes may be suppressed by oligonucleotides having a nucleotide sequence complementary to the mRNA transcript of the target gene thereby selectively impeding translation and has been termed an “antisense” methodology. In addition, “antigene” or “triplex” methodologies may also suppress expression of genes by using an oligonucleotide which is complementary to a selected site of double stranded DNA thereby forming a triple-stranded complex to selectively inhibit transcription of the gene. Both “antisense” and “antigene” methodologies find utility as molecular tools for genetic analysis. Antisense oligonucleotides have been extensively used to inhibit gene expression in normal and abnormal cells in studies of the function of various cell proteins. Major advances have been made in the development of antisense or antigene reagents for the treatment of disease states in animals and humans [“Antisense Therapeutics” Agrawal, S. (ed.), Humana Press, 1996; Crooke, S. T., and Bennett, C. F. (1996)
Annu. R

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