B.D. Full patents since 1976 are now available online, so it is fairly easy to check out patent claims. On March 11, 1993, AGN filed a patent (#5,399,580) on drugs that act as RXR agonists (including Panretin, 9-cis retinoic acid) for treating tumors.
Almost a year later (Feb 4, 1993) Roche filed a patent (#5,428,071) on use of Panretin (9-cis retinoic acid) for treating malignant and pre-malignant lesions of epithelial origin.
Here's backround for the AGN patent:
1. Field of the Invention
The present invention is directed to a process for inducing apoptosis in tumor cells by administration of compounds having
agonist-like activity at RXR retinoid receptor sites. More specifically, the present invention is directed to a method of treating
mammals suffering from tumors with RXR agonist compounds.
2. Brief Description of the Prior Art
Compounds which have retinoid like activity are well known in the art, and are described in numerous United States and foreign
patents and in scientific publications. It is generally known and accepted in the art that retinoid like activity is useful for treating
animals of the mammalian species, including humans, for curing or alleviating the symptoms and conditions of numerous diseases
and conditions such as dermatoses, acne, Darier's disease, psoriasis, icthyosis, eczema and atopic dermatitis, and for treating and
preventing malignant hyperproliferative diseases such as epithelial cancer, breast cancer, prostatic cancer, head and neck cancer
and myeloid leukemias, for reversing and preventing atherosclerosis and restenosis resulting from neointimal hyperproliferation, for
treating and preventing other non-malignant hyperproliferative diseases such as endometrial hyperplasia, benign prostatic
hypertrophy, proliferative vitreal retinopathy and dysplasias, for treating autoimmune diseases and immunological disorders (e.g.
lupus erythematosus) for treating chronic inflammatory diseases such as pulmonary fibrosis, for treating and preventing diseases
associated with lipid metabolism and transport such as dyslipidemias, for promoting wound healing, for treating dry eye syndrome
and for reversing and preventing the effects of sun damage to skin.
The compounds developed in the prior art with retinoid like properties, are, however, not without disadvantages. Several such prior
art compounds cause serious irritation when applied to the skin (which is an important mode of application for treatment of skin
conditions) and cause mucotaneous toxicity when administered orally as well. Many of the prior art compounds having retinoid like
activity are teratogenic and have still other side effects.
In addition to numerous prior art patents and publications which describe specific compounds or classes of compounds of retinoid
like activity, several co-pending applications and recently issued patents which are assigned to the assignee of the present
application, are directed to further compounds having retinoid like activity and/or to methods of treatment of mammals including
humans with retinoid-like compounds.
Relatively recently it was recognized in the prior art that there is more than one retinoid cellular response pathway in biological
systems, and that at least two main families of receptors exist in biological systems for naturally occurring retinoid hormones.
These relatively recent developments in the prior art are described in the articles: D. J. Mangelsdorf et al. "Nuclear receptor that
identifies a novel retinoic acid response pathway", Nature Vol 345 May 17, 1990 pp 224-229; and J. N. Rottman et al. A Retinoic
Acid-responsive Element in the Apoliprotein AI Gene Distinguishes between Two Different Retinoic Acid Response Pathways,
Molecular and Cellular Biology, July 1991, pp 3314-3820. The following additional references relate to retinoic acid receptors. M.
Petkovich et al. "A human retinoic acid receptor which belongs to the family of nuclear receptor", Nature, Vol. 330, Dec. 3, 1987,
pp 444-450; V. Giguere et al. "identification of a receptor for the morphogen retinoic acid", Nature, Vol 330, Dec. 17, 1987, pp
624-629; N. Brand et al. "Identification of a second human retinoic acid receptor", Nature, Vol 332, Apr. 28, 1988, pp 850-853; A.
Krast et al., "A third human retinoic acid receptor, hRAR", Proc. Nat'l Acad. Sci. USA, Vol 86, July 1989, pp 5310-5314; D. J.
Mangelsdorf et al., "Characterization of three RXR genes that mediate the action of 9-cis-retinoic acid", Genes & Development,
Vol. 6, 1992, pp. 329-344.
The two main families of retinoid receptors are termed RAR (Retinoic .Acid Receptor) and RXR (Retinoid X Receptor) in the art,
and each of these two families is known to have subtype:s, which are designated by letters of the Greek alphabet, such as
RAR.sub..alpha., RAR.sub..beta. and RAR.sub..gamma.. The above-noted article by D. J. Mangelsdorf et al, states that some
retinoid-like compounds (retinoic acid analogues) activated the RAR receptors much more strongly than the RXR receptors.
SUMMARY OF THE INVENTION
It has been discovered in accordance with the present invention that retinoid-like compounds which act as agonists of the RXR
retinoid receptor sites induce apoptosis of tumor cells in cell cultures, and are therefore suitable for use as drugs to bring about
apoptosis, of tumors in mammals, including humans. Specifically, it has been discovered in accordance with the present invention
that retinoid-like compounds which are RXR specific agonists (hence not active on RAR receptor sites) induce apoptosis in
tumors. Retinoid-like compounds which are both RAR and RXR agonists also induce apoptosis, such compounds are termed "pan
agonist" compounds. Retinoid-like compounds which are specific for RAR receptor sites (not active at the RXR receptors) have
not been demonstrated to cause apoptosis in tumor cell lines, and therefore RAR specific comounds can not be used in the method
of treatment of the present invention.
The RXR agonist compounds are administered in accordance with the present invention to mammals afflicted with tumors, in
pharmaceutical compositions adapted for systemic, or topical administration, or for intra-lesional administration. The range of
concentration of the active ingredient RXR agonist compound in the pharmeceutical compositions is approximately between 0.001
and 5 percent by weight, and such that the composition delivers approximately 0.1 mg to 100 mg of the active ingredient per kg
body weight of the patient, per day of treatment.
The ability of a compound to act as an agonist of the RXR receptors can be determined in a state-of-the-art assay procedure
termed "Cationic Liposome Mediated Transfection Assay" which is desribed in detail below. |
