Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – C-o-group doai
Reexamination Certificate
1998-04-24
2001-02-06
Schwartzman, Robert A. (Department: 1636)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
C-o-group doai
Reexamination Certificate
active
06184256
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to the fields of mammalian gene expression, retinoid receptor biology and mammalian disease therapeutics. Specifically, the present invention relates to methods for identifying compositions useful in differentially modulating the expression of two or more mammalian genes, particularly matrix metalloproteinase (MMP) genes. In addition, the invention relates to methods of treating a mammal (such as a human) suffering from or predisposed to a physical disorder, using pharmaceutical compositions comprising the compositions identified by the above-described methods. The methods and compositions of the present invention are useful in treating a variety of physical disorders in mammals including cancers (particularly carcinomas), inflammatory disorders, fibrotic disorders, ocular disorders and osteoporosis.
2. Related Art
Matrix Metalloproteinases
The matrix metalloproteinase (MMP) family consists of extracellular proteinase with amino acid sequence homologies and similarities in protein domain organization, which have been implicated in a variety of tissue remodeling processes (Hembry, R. M., et al.,
Am. J. Pathol
. 143(2):628-642(1993); Murphy, G.,
Acta Orthop. Scand
. 66 (Suppl. 266):55-60 (1995)). One member of the MMP family is stromelysin-3, the expression of which has been associated with cutaneous wound healing (Okada, A., et al.,
Gene
185:187-193 (1997)), mammary gland involution (Lefebvre, O., et al.,
J. Cell Biol
. 119:997-1002 (1992)), cycling endometrium (Rodgers, W. H., et al.,
J. Clin. Invest
. 94:946-953 (1994)), embryonic development (Lefebvre, O., et al.,
Development
121:947-955 (1995)) and metamorphosis (Patterson, D., et al,
Dev. Biol
. 167:252-262 (1995)), where its expression was predominantly found in cells of mesodermal origin. In human carcinomas, stromelysin-3 was the first MMP identified as being expressed by stromal cells (Basset, P., et al,
Nature
348:699-704 (1990); Rouyer, N., et al.,
Metastasis
14:269-275 (1994)). Although human stromelysin-3 appears to be unable to degrade any major component of the extracellular matrix (Pei, D., et al.,
J. Biol. Chem
. 269:25849-25855 (1994); Noël, A., et al,
J. Biol. Chem
270:22866-22872 (1995)) and exhibits unusual activation properties (Pei, D., and Weiss, S. J.,
Nature
375:244-247 (1995); Santavicca, M., et al.,
Biochem. J
. 315:953-958 (1996)), its role in cancer progression is supported by high expression levels which are predictive of a poor clinical outcome (Engel, G., et al.,
Int. J. Cancer
58:830-835 (1994); Chenard, M.-P., et al.,
Int. J. Cancer
69(6):448-451 (1996)). Furthermore, stromelysin-3 has been shown to facilitate the tumor “take” of cancer cells in nude mice (Noël, A., et al.,
J. Clin. Invest
. 97:1924-1930 (1996)).
Following the identification of stromelysin-3, a number of other MMPs were found to be expressed by stromal cells of human carcinomas (MacDougall, J. R., and Matrisian, L. M.,
Canc. Metast. Rev
. 14:351-362 (1996)). Together, these results indicate that the production of MMPs by stromal cells represents a significant contribution to the overall proteolytic activities in malignant tumors (MacDougall, J. R., and Matrisian, L. M.,
Cancer Metastasis Rev
. 14:351-362 (1996); Stetler-Stevenson, W. G., et al.,
Semin. Cancer Biol
. 7:147-154 (1996), and references cited therein). Despite the observation that most stromal MMPs are expressed by fibroblastic cells, no regulatory sequence that could account for this cell-specific expression pattern has yet been identified in the promoter of the corresponding genes.
Retinoids
A number of studies have demonstrated that retinoids (vitamin A derivatives) are essential for normal growth, vision, tissue homeostasis, reproduction and overall survival (for reviews and references, See Sporn et al.,
The Retinoids
, Vols. 1 and 2, Sporn et al., eds., Academic Press, Orlando, Fla. (1984)). For example, retinoids have been shown to be vital to the maintenance of skin homeostasis and barrier function in mammals (Fisher, G. J., and Voorhees, J. J.,
FASEB J
. 10:1002-1013 (1996)). Retinoids are also apparently crucial during embryogenesis, since offspring of dams with vitamin A deficiency (VAD) exhibit a number of developmental defects (Wilson, J. G., et al.,
Am. J. Anat
. 92:189-217 (1953); Morriss-Kay, G. M., and Sokolova, N.,
FASEB J
. 10:961-968 (1996)). With the exceptions of those on vision (Wald, G., et al.,
Science
162:230-239 (1968)) and spermatogenesis in mammals (van Pelt, H. M. M., and De Rooij, D. G.,
Endocrinology
128:697-704 (1991)), most of the effects generated by VAD in animals and their fetuses can be prevented and/or reversed by retinoic acid (RA) administration (Wilson, J. G., et al.
Am. J. Anat
. 92:189-217 (1953); Thompson et al.,
Proc. Royal Soc
. 159:510-535 (1964); Morriss-Kay, G. M., and Sokolova, N.,
FASEB J
. 10:961-968 (1996)). The dramatic teratogenic effects of maternal RA administration on mammalian embryos (Shenefelt, R. E.,
Teratology
5, 103-108 (1972), Kessel, M.,
Development
115:487-501 (1992); Creech Kraft, J., In
Retinoids in Normal Development and Teralogeniesis
, G. M. Morriss-Kay, ed., Oxford University Press, Oxford, UK, pp. 267-280 (1992)), and the marked effects of topical administration of retinoids on embryonic development of vertebrates and limb regeneration in amphibians (Mohanty-Hejmadi, et al.,
Nature
355:352-353 (1992); Tabin, C. J.,
Cell
66:199-217 (1991)), have contributed to the notion that RA may have critical roles in morphogenesis and organogenesis.
Retinoid Receptors
Except for those involved in visual perception (Wald, G. et al.,
Science
162:230-239 (1968)), the molecular mechanisms underlying the highly diverse effects of retinoids have until recently remained obscure. The discovery of nuclear receptors for RA (Petkovich et al.,
Nature
330:444-450 (1987); Giguere et al.,
Nature
330:624-629 (1987)) has greatly advanced the understanding of how the retinoids may exert their pleiotropic effects (Leid et al.,
TIBS
17:427-433 (1992); Linney, E.,
Current Topics in Dev. Biol
. 27:309-350 (1992)). Since this discovery it has become apparent that the genetic activities of the RA signal are mediated through two families of receptors—the RAR family and the RXR family—which belong to the superfamily of ligand-inducible transcriptional regulatory factors that include steroid/thyroid hormone and vitamin D3 receptors (for reviews see Leid et al.,
TIBS
17:427-433 (1992); Chambon, P.,
Semin. Cell Biol
. 5:115-125 (1994); Chambon, P.,
FASEB J
. 10:940-954 (1996); Giguere, V.,
Endocrinol. Rev
. 15:61-79 (1994); Mangelsdorf, D. J., and Evans, R. M.,
Cell
83:841-850 (1995); Gronemeyer, H., and Laudet, V.,
Protein Profile
2:1173-1236 (1995)).
RAR Receptors
Receptors belonging to the RAR family (RAR&agr;, &bgr; and &ggr; and their isoforms) ate activated by both all-trans- and 9-cis-RA (Leid et al.,
TIBS
17:427-433 (1992); Chambon, P.,
Semin. Cell Biol
. 5:115-125 (1994); Dollé, P., et al.,
Mech. Dev
. 45:91-104 (1994); Chambon, P.,
FASEB J
. 10:940-954 (1996)). Within a given species, the DNA binding (C) and the ligand binding (E) domains of the three RAR types are highly similar, whereas the C-terminal domain F and the middle domain D exhibit no or little similarity. The amino acid sequences of the three RAR types are also notably different in their B regions, and their main isoforms (&agr;1 and &agr;2, &bgr;1 to &bgr;4, and &ggr;1 and &ggr;2) further differ in their N-terminal A regions (Leid et al.,
TIBS
17:427-433 (1992)). Amino acid sequence comparisons have revealed that the interspecies conservation of a given RAR type is greater than the similarity found between the three RAR types within a given species (Leid et al.,
TIBS
17:427-433 (1992)). This interspecies conservation is particularly striking in the N-terminal A regions of the various RAR&agr;, &bgr; and &ggr; isoforms, whose A region amino acid sequences are quite divergent. Taken together with the distinct s
Anglard Patrick
Basset Paul
Guérin Eric
Institut National de la Santé de la Recherche Médicale
Schwartzman Robert A.
Sterne Kessler Goldstein & Fox P.L.L.C.
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