Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1997-02-27
1999-02-16
LeGuyader, John L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
435 6, 435 911, 4351723, 435366, 435375, 536 231, 536 2431, 536 245, 514 44, C12Q 168, C12N 1585, C07H 2104, A61K 4800
Patent
active
058721061
DESCRIPTION:
BRIEF SUMMARY
This is a 371 of PCT/EP95/02793, filed Jul. 17, 1995.
BACKGROUND OF THE INVENTION
The present invention relates to antisense oligonucleotides complementary to mRNA of urokinase human receptor and to pharmaceutical compositions containing them as the active ingredients.
Plasminogen activation is considered a central process in the regulation of pericellular proteolysis which occurs under both normal and pathological conditions, including cancer invasion, when tissue destruction and cell migration are required. Even though the roles of tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA) in in vivo neoplasias and in vitro transformed cells have not yet been elucidated, however, it is now well established that u-PA plays a paramount role in neoplastic cell transformation (Physiol. rev. 73(1): 161-195, 1993).
After secretion as a zymogen (pro-u-PA), the active form is obtained by cleavage at lysine 158 into two chains connected by a disulfide bridge. As a result of their interaction with a specific receptor (u-PAR) (Advances in Cancer Res. 57:273-328, 1991) which belongs to the glycosyl-phosphatidyl inositol-anchored proteins family (Exp. Cell. Res. 203:427-434, 1992), pro-u-PA and the active enzyme equilibrate between solution and the cell surface. (Pro)-u-PA binds to the receptor by a sequence framed within the amino-terminal fragment of the A chain thus exposing the B chain, which contains the catalytic site, to the extracellular milieu. On some cell lines, growing as monolayers in vitro, urokinase receptors are located at specific sites on the ventral side of the cell: the so-called focal contacts. Other components of the plasminogen activation system have been identified on the extra-cellular side of cell contacts and have been suggested to play a regulatory role in the modulation of cell-substratum adhesion and extra-cellular matrix destruction. In particular, the presence of u-PA at the main contact sites of the cell has been considered critical in determining the detachment of the cell from the substratum and progression within tissues. Using cell monolayers, it has been observed that the adhesion sites specifically concentrate u-Pa binding sites (Advances in Cancer Res. 57:273-328, 1991).
A number of evidences exist that the expression of urokinase receptor is a basical factor of the invasive characteristics of tumour cells. It has particularly been suggested that the contribution of u-PAR to the invasive phenotype may involve the increased plasmin production by receptor-bound u-PA (J. Biol. Chem. 266: 752-758, 1991). Some authors (Cancer Res. 53:3139-3117, 1993) reported that the overexpression of an exogenous cDNA coding for the u-PA binding site in a human osteosarcoma cell line induced the increase of cell migration in the matrigel test, in addition to increased laminin degradation. In another study (Proc. Natle. Acad, Sci. USA 90:5021-5025, 1993), it was shown that displacement of receptor bound u-PA by a mutant u-PA lacking enzymatic activity, caused the reduction of brain, lung and regional lymph nodes metastasis of prostate cancer cells PC-3. Still other authors (Br. J. Cancer 67:537-544, 1993) have shown that the matrigel invasion by the ovarian cancer cell lines HOC-1 was inhibited by peptides corresponding to the u-PA receptor binding fragment.
It is therefore evident that the u-PA/u-PAR system may be a target for drugs which, decreasing or blocking the invasive action of the cells, may be useful as anti-tumor and anti-metastatic agents.
It has been already shown, for instance, that antibodies against human u-PA prevent the metastasis formation in chicken embryonal lung of human carcinoma cells (Cell 35:611-619, 1983). The anti-messenger strategy has also been used against the u-PA gene in NIH 3T3 cells: in such a case, the selective block of the u-PA gene induced in the cells an alternative invasive mechanism based on the gene expression of another protease, cathepsin L (Cancer Res. 52:6682-6689, 1992).
SUMMARY OF THE INVENTION
It has now been foun
REFERENCES:
Cancer Research, vol. 50, pp. 7623-7633, 1 Dec. 1990, "Relationship between Secreted Urokinase Plasminogen Activator Activity and Metastatic Potential in Murine B16 Cells etc.", H. Yu et al.
The EMBO Journal, vol. 9, No. 2, Feb. 1990, Oxford, UK, pp. 467-474, "Cloning and expression of the receptor for human urokinase plasminogen activator, a central molecule etc.", A.L. Roldan et al.
Anti-cancer Drug Design, vol. 10, No. 1, Jan. 1995, Oxford, UK, pp. 97-102, "Antimessenger oligonucleotide for urokinase receptor gene inhibits invasivity of transformed etc.", A. Quattrone et al.
Rojanasakul, Antisense Oligonucleotide Therapeutics: Drug Delivery and Targeting, Advanced Drug Delivery Reviews 18, 115-131 (Jan. 15, 1996), (Dispatched Jan. 30, 1996).
Capaccioli Sergio
Del Rosso Mario
Fibbi Gabriella
Quattroni Alessandro
Consiglio Nazionale Delle Ricerche
LeGuyader John L.
Shibuya Mark L.
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