Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – 9,10-seco- cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2000-04-21
2003-09-23
Mertz, Prema (Department: 1646)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
9,10-seco- cyclopentanohydrophenanthrene ring system doai
C424S085100, C424S194100, C424S010400, C424S078310
Reexamination Certificate
active
06624154
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to compositions comprising a retinoid X receptor agonist and an agent capable of activating protein kinase A. The invention also relates to methods of treating hyperproliferative diseases by administering a retinoid X receptor agonist and an agent capable of activating protein kinase A.
2. Related Art
Retinoids and Receptors
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)).
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 retinoic acid (RA) (Petkovich et al.,
Nature
330:444-450 (1987); Giguère et al.,
Nature
330:624-629 (1987)) has greatly advanced the understanding of how the retinoids may exert their pleiotropic effects (Leid, M., et al.,
TIBS
17:427-433 (1992); Linney, E.,
Current Topics in Dev. Biol
. 27:309-350 (1992)). It is thought that the effects of the RA signal are mediated through two families of receptors—the RAR family and 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, M., 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)).
Receptors belonging to the retinoic acid receptor family (RAR&agr;, &bgr; and &ggr; and their isoforms) are activated by both all-trans- and 9-cis-RA (Leid, M., et al.,
TIBS
17:427-433 (1992); Chambon, P.,
Semin. Cell Biol
. 5:115-125 (1994); Dolle, P., et al.,
Mech. Dev
. 45:91-104 (1994)). Unlike the RARs, members of the retinoid X receptor family (RXR&agr;, &bgr; and &ggr;) are activated exclusively by 9-cis-RA (Chambon, P.,
Semin. Cell Biol
. 5:115-125 (1994); Dollé, P., et al.,
Mech. Dev
. 45:91-104 (1994); Linney, E.,
Current Topics in Dev. Biol
. 27:309-350 (1992); Leid, M., et al.,
TIBS
17:427-433 (1992); Kastner et al., In:
Vitamin A in Health and Disease
, R. Blomhoff, ed., Marcel Dekker, New York (1993)).
Nuclear receptors (NRs) are members of a superfamily of ligand-inducible regulatory factors that include receptors for steroid hormones, thyroid hormones, vitamin D3 and retinoids (Leid, M., et al.,
Trends Biochem. Sci
. 17:427-433 (1992); Leid, M., et al.,
Cell
68:377-395 (1992); and Linney, E.
Curr. Top. Dev. Biol
., 27:309-350 (1992)). NRs exhibit a modular structure which reflects the existence of several autonomous functional domains. Based on amino acid sequence similarity between the chicken estrogen receptor, the human estrogen and glucocorticoid receptors, and the v-erb-A oncogene, Krust, A., et al. (
EMBO J
. 5:891-897 (1986)) defined six regions—A, B, C, D, E and F—which display different degrees of evolutionary conservation among various members of the nuclear receptor superfamily. The highly conserved region C contains two zinc fingers and corresponds to the core of the DNA-binding domain (DBD), which is responsible for specific recognition of the cognate response elements. Region E is functionally complex, since in addition to the ligand-binding domain (LBD), it contains a ligand-dependent activation function (AF-2) and a dimerization interface. An autonomous transcriptional activation function (AF-1) is present in the non-conserved N-terminal A/B regions of the steroid receptors. Interestingly, both AF-1 and AF-2 of steroid receptors exhibit differential transcriptional activation properties which appear to be both cell type and promoter context specific (Gronemeyer, H.,
Annu. Rev. Genet
. 25:89-123 (1991)).
It has been shown that activation of RA-responsive promoters likely occurs through RAR/RXR heterodimers rather than through homodimers (Yu, V.C., et al.,
Cell
67:1251-1266 (1991); Leid, M., et al.,
Cell
68:377-395 (1992b); Durand et al.,
Cell
71:73-85 (1992); Nagpal, S., et al.,
Cell
70:1007-1019 (1992); Zhang, X. K., et al.,
Nature
355, 441-446 (1992); Kliewer et al.,
Nature
355:446-449 (1992); Bugge et al.,
EMBO J
. 11:1409-1418 (1992); Marks et al.,
EMBO J
. 11:1419-1435 (1992); Yu, V. C. et al.,
Cur. Op. Biotech
. 3:597-602 (1992); Leid, M., et al.,
TIBS
17:427-433 (1992); Laudet and Stehelin,
Curr. Biol
. 2:293-295 (1992); Green,
S., Nature
361:590-591 (1993)). The RXR portion of these heterodimers has been proposed to be silent in retinoid-induced signaling (Kurokawa, R., et al.,
Nature
371:528-531 (1994); Forman, B. M., et al.,
Cell
81:541-550 (1995); Mangelsdorf, D. J., and Evans, R. M.,
Cell
83:835-850 (1995); Vivat, V. et al.,
EMBO J
. 16:5697-5709 (1997)) but conflicting results have been reported as far as the ligand-binding ability of RXR in heterodimers is concerned (Kurokawa, R., et al.,
Nature
371:528-531 (1994); Chen, J.-Y. et al.,
Nature
382:819-822 (1996); Kersten, S. et al.,
Biochem
. 35:3 816-3824 (1996); Chen, Z. et al.,
J. Mol. Bio
. 275:55-65 (1998); Li, C. et al.,
Proc. Natl. Acad. Sci. USA
94:2278-2283 (1997). The results of these and of genetic studies strongly suggest that RAR/RXR heterodimers are indeed functional units that transduce the RA signal in vivo (Chambon, P.,
Semin. Cell Biol
. 5:115-125 (1994); Kastner, P. et al.,
Cell
83:859-869 (1995); Mascrez, B. el al.,
Development
125:4691-4707 (1998)). Thus, the basis for the highly pleiotropic effect of retinoids may reside, at least in part, in the control of different subsets of retinoid-responsive promoters by cell-specifically expressed heterodimeric combinations of RAR/RXR subtypes (and isoforms), whose activity may be in turn regulated by cell-specific levels of all-trans- and 9-cis-RA (Leid, M., et al.,
TIBS
17:427-433 (1992)).
The RXR receptors may also be involved in RA-independent signaling. For example, the observation of aberrant lipid metabolism in the Sertoli cells of RXR&bgr;
+
mutant animals suggests that functional interactions may also occur between RXR&bgr; and the peroxisomal proliferator-activated receptor signaling pathway (WO 94/26100; Kastner, P., et al.,
Genes & Dev
. 10:80-92 (1996)).
Therapeutic Uses of Retinoids
Overview
As retinoic acid is known to regulate the proliferative and differentiative capacities of several mammalian cell types (Gudas, L. J., et al., In:
THE RETINOIDS
, 2nd ed., Sporn, M. B., et al., eds., New York: Raven Press, pp. 443-520 (1994)), retinoids are used in a variety of chemopreventive and chemotherapeutic settings. The prevention of oral, skin, head and neck cancers in patients at risk for these tumors has been reported (Hong, W. K., et al., N.
Engl. J. Med
. 315:1501-1505 (1986); Hong, W. K., et al., N.
Engl. J. Med
. 323:795-801 (1990); Kraemer, K. H., et al.,
N. Engl. J. Med
. 318:1633-1637 (1988); Bollag, W., et al.,
Ann. Oncol
. 3:513-526 (1992); Chiesa, F., et al., Eur.
J. Cancer B. Oral Oncol
. 28:97-102 (1992); Costa, A., et al.,
Cancer Res
. 54:Supp. 7,2032-2037(1994)). Retinoids have also been used to treat squamous cell carcinoma of the cervix and the skin (Verma, A. K.,
Cancer Res
. 47:5097-5101 (1987); Lippman S. M., et al.,
J. Natl Cancer Inst
. 84:235-241 (1992); Lippman S. M., et al.,
J. Natl Cancer Inst
. 84:241-245 (1992)) and Kaposi's sarcoma (Bonhomme, L., et al.,
Ann. Oncol
. 2:234-235 (1991)), and have found significant use in the therapy of acute promyelocytic leukemia (Huang, M. E., et al.,
Blood
72:567-572 (1988); Castaigne, S., et al.,
Blood
76:1704-1709 (1990); Chomienne, C., et al.,
Blood
76:1710-1717 (1990); Chomienne, C., et al.,
J. Clin. Inve
Benoit Gérard
Gottardis Marco
Gronemeyer Hinrich
Lanotte Michel
Bristol--Myers Squibb Company
Mertz Prema
Sterne Kessler Goldstein & Fox P.L.L.C.
LandOfFree
Compositions and methods for treatment of hyperproliferative... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Compositions and methods for treatment of hyperproliferative..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Compositions and methods for treatment of hyperproliferative... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3024811