WO1997003682A1 - Procedes de traitement de cancers a l'aide de 6-[3-[1-adamantyl]-4-hydroxyphenyl] - Google Patents

Procedes de traitement de cancers a l'aide de 6-[3-[1-adamantyl]-4-hydroxyphenyl] Download PDF

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Publication number
WO1997003682A1
WO1997003682A1 PCT/US1996/011736 US9611736W WO9703682A1 WO 1997003682 A1 WO1997003682 A1 WO 1997003682A1 US 9611736 W US9611736 W US 9611736W WO 9703682 A1 WO9703682 A1 WO 9703682A1
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ahpn
cells
cell
mda
breast cancer
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PCT/US1996/011736
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English (en)
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Joseph A. Fontana
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Centre International De Recherches Dermatologiques C.I.R.D. Galderma
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Priority to US09/011,323 priority Critical patent/US6211239B1/en
Priority to JP9506790A priority patent/JP2000506489A/ja
Priority to EP96924519A priority patent/EP0850067A4/fr
Priority to AU64949/96A priority patent/AU701790B2/en
Publication of WO1997003682A1 publication Critical patent/WO1997003682A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/30—Oestrogens

Definitions

  • the present invention relates to the use of a reti ⁇ noid having unique properties for the treatment or pre ⁇ vention of breast cancer or leukemia. More specifical ⁇ ly, the present invention relates to the use of 6-[3-[l- adamantyl] -4-hydroxyphenyl] -2-naphthalene carboxylic acid (AHPN) to treat or prevent breast cancer or leukemi .
  • AHPN 6-[3-[l- adamantyl] -4-hydroxyphenyl] -2-naphthalene carboxylic acid
  • Retinoids are defined as substances that can elicit specific biological responses by binding to and activat ⁇ ing a specific receptor or set of receptors. Retinoids are known to play a fundamental role in normal cell growth and differentiation. (Roberts, A.B. et al, in "The Retinoids,” ed. by M.B. Sporn, A.B. Roberts and D. S. Goodman, Vol. 2, pp. 209-256, Academic Press, Orlan ⁇ do, Fla., (1984) ; Sporn, M.B. et al, J. Amer. Acad. Dermatol . , 15:756-764 (1986)) .
  • RAR ⁇ , ⁇ and ⁇ retinoic acid nuclear receptors
  • RXR ⁇ , ⁇ and ⁇ retinoid X recep ⁇ tors
  • Retinoic acid receptors mediate gene transcription through a variety of mechanisms. These nuclear recep ⁇ tors can bind to specific DNA consensus sequences termed retinoid receptor response elements (RAREs or RXREs) which are located in the regulatory regions of the reti ⁇ noid target genes (Gudas, L.J., Cell Growth Differ., 3:655-662 (1992) ; Lohnes et al, Cell Sci., 16 (Suppl. ) :69-76 (1992)) . Nuclear receptor binding to these response elements preferably occurs through heterodimer formation between the RAR and RXR, although homodimer binding and subsequent gene activation has also been found (Hermann et al, Mol.
  • the RXRs can mediate gene transcription via heterodimer formation with the RARs, with the vitamin D, thyroid hormone (Yu et al, Cell, 67:1251-1266 (1991) ; Hermann et al, Mol.
  • RARs and thyroid nucle ⁇ ar receptors can, in turn, inhibit the activity of RARs and thyroid nucle ⁇ ar receptors (TRs) (Kliewer et al, Proc. Natl. Acad. Sci., USA, 89:1448-1452 (1992); Tran et al, Mol. Cell Biol., 12:4666-4676 (1992) ; Apfel et al, Mol. Cell Biol., 14:7025-7035 (1994), Casanova et al, Mol. Cell Biol., 14:5756-5765 (1991) ; Song et al, Proc. Natl. Acad. Sci., USA, 91:10809-10813 (1994)) .
  • TRs thyroid nucle ⁇ ar receptors
  • the retinoid receptor response elements usually consist of direct repeats (DRs) in which the half-sites are separated by a number of base pair spacers. Selec ⁇ tivity for binding appears to be determined by the num ⁇ ber of base pairs utilized as spacers, as well as by the sequence of the response element itself (Kim et al, Mol. Endocrinol., 6:1489-1501 (1992), Mader et al, J. Biol. Chem., 268:591-600 (1993)) .
  • DRs direct repeats
  • RAR- mediated as well as TR-mediated, gene transcription occurs by the competitive binding of the orphan receptor coup and v-ErbA to RARE and TREs (Tran et al, Mol . Cell . Biol . , 12:4666-4676 (1992), Hermann et al, Oncogene, 8:55-65 (1993) ) .
  • Most cell types express more than one RAR and RXR receptor.
  • RAR homologous recombination studies have suggested that RAR functional redundancy exists among the different RARs (Li et al, Proc . Natl . Acad. Sci .
  • the RARs bind both RA and its isomer 9-cis-RA, while the RXRs only bind 9-cis-RA (Allenby et al, J. Biol . Chem. , 269:16689-16695 (1995) , and references cited therein) .
  • conformationally restricted retinoids have been synthesized that selectively bind to and enhance transcriptional activation by selective RAR and RXR subtypes (Graupner et al, Biochem. Biophys . Res . Commun . , 179:1554-1561 (1991) ; Lehmann et al, Cancer Res .
  • retinoids Because of the ability of retinoids to affect cell growth and differentiation, these compounds have been disclosed to be useful for the treatment or prevention of diseases and conditions involving abnormal cell proliferation and differentiation. For example, the usage of retinoids as efficient therapeutics for the treatment of various skin diseases and neoplasms has been reported (Roberts, A. B. and Sporn, M.B., in "The Retinoids", Sporn et al, pp 209-286, Academic Press, Orlando, Fla; Bollag et al, Ann . Oncol . , 3:513-526 (1992) ; Smith et al, J. Clin . Oncol . , 10:839-864 (1992) ) .
  • retinoid therapy typically been achieved with a regimen which combines retinoid administration with the administration of other differentiation or cytotoxic agents.
  • retinol and retinoic acid isotretoin (13-cis-retinoic acid) and etretinate have been used, as well as 9-cis retinoic acid and N- (9-hydroxyphenyl) retinoid.
  • retinoids have been reported to be useful for the treatment of a variety of dermatoses including psoriasis, cystic acne, cutaneous disorders of keratina- zation, among others.
  • retinoids have important potential as anti-cancer agents.
  • retinoid compounds have been disclosed to have potential for the prevention of skin cancer, for the treatment of acute myeloid leukemia (AML) , acute promyelocytic leuke ⁇ mia (APL) for the treatment of other hematopoietic malignancies such as myelodysplastic syndrome, juvenile chronic myelogenous leukemia, Sezary syndrome, squamous cell carcinomas of the upper aerodigestive tract, non- small lung cancer, and human head and neck carcinomas.
  • AML acute myeloid leukemia
  • APL acute promyelocytic leuke ⁇ mia
  • other hematopoietic malignancies such as myelodysplastic syndrome, juvenile chronic myelogenous leukemia, Sezary syndrome, squamous cell carcinomas of the upper aerodigestive tract, non- small lung cancer, and human head and neck carcinomas.
  • N- (4-hydroxyphenyl) retinamide (4-HPR) induces apoptosis and the differentiation of breast cancer cell lines, assertedly independent of the status of estrogen receptor (ER) and RAR expression (Pellegrini et al, Cell Growth Differ . , 6 (1 ) -. 863 - 869 (1995)) .
  • ER estrogen receptor
  • RAR RAR expression
  • a recent patent issued to Curley et al U.S. Patent No. 5,516,792, assigned to Ohio State Research Foundation, teaches the use of retinoyl beta- glucuronide N-glycoside analogs for the treatment, pre ⁇ vention and study of cancers, including breast cancer.
  • N- (4-hydroxyphenyl) retinamide (4-HPR) a derivative of trans-retinoic acid, is currently in clin ⁇ ical trials as a chemopreventive agent for breast cancer.
  • retinoic acid in combination with RAR-jS receptors has been reported to promote apoptosis of estrogen receptor-positive (ER+) human breast cancer cell lines (Liu et al, Mol. Cell Biol. 16 (3) :1138-1149 (1996) ) .
  • retinoic acid in combination with interferon, specifically alpha interferon or gamma interferon, has been reported to inhibit the prolifera- tion of some breast cancer cell lines (Widschwendter et al, Anticancer Res . , 16 (1) :369-374 (1996); Widschwendter et al, Cancer Res . , 55 (10) :2135-2139 (1995)) .
  • 9-cis retinoic acid has been reported to inhibit the growth of breast cancer cells and to down- regulate estrogen receptor RNA and protein (Rubin et al, Cancer Res . , 54 (24) :6549-6556 (1994)) .
  • retinoids have been reported to have potential as anticancer agents, and specifically for the treatment or prevention of breast cancer and leukemia, the identification of retinoids having improved therapeutic properties which are suitable for the treatment or prevention of such cancers would be highly beneficial. In particular, the identification of retinoids which are cytotoxic to either estrogen receptor positive or estrogen receptor negative breast cancers would be highly beneficial .
  • the subject invention essentially relates to the usage of a specific retinoid, 6- [3-adamantyl-4- hydroxyphenyl] -2-naphthalene carboxylic acid which induces G Q /G- L arrest and apoptosis for the treatment or prevention of breast cancer or leukemia, as well as pharmaceutical compositions adopted for the treatment or prevention of breast cancer or leukemia which contain an effective amount of 6- [3-adamantyl-4-hydroxyphenyl] -2- naphthalene carboxylic acid.
  • Figure 1 shows the inhibition of breast carcinoma cell proliferation by AHPN.
  • Figure 2 shows the effects of varying the concentration of AHPN on MCF-7 and MDA-MB-231 proliferation. MCF-7 cells and MDA-MB-231 cells were seeded in DMEM:F-12 supplemented with 5% FBS in 24-well plates at a cell concentration of 3 x 10 4 and 1 x 10 4 cells, respectively, per well.
  • FIGS 4A and 4B compare AHPN- and RA-mediated RARE and RXRE transactivation and anti-AP-1 activity in MCF-7 and MDA-MB-231 cells.
  • MDA-MB-231 and MCF-7 cells logarithmically growing in 10 cm plates (approximately 3 x 10 6 cells per plate) in regular medium were transiently transfected with the indicated plasmid and treated with either l ⁇ M RA or l ⁇ M AHPN for 48 hours.
  • CAT assays were then effected to measure gene expression.
  • R e ⁇ activity was quantified by laser densitometry. Activation is expressed as the ratio of converted 14 C activity in the diacetate and monoacetate forms to the total 14 C activity.
  • Figure 4A shows the results of a representative CAT assay and Figure 4B is the quantification of two different experiments. The values are expressed relative to respective controls, which were given an arbitrary value of 1. The error bars represent the standard errors.
  • Figure 6 shows DNA fragmentation induced by AHPN in MCF-7 and MDA-MB-231 cells.
  • MCF-7 and MDA-MB-231 cells were seeded in DMEM:F-12 medium supplemented with 5% FBS and incubated overnight.
  • AHPN or RA were added to final concentrations of l ⁇ M and the cells incubated for various times .
  • DNA was extracted and fractionated by gel electrophoresis.
  • Figures 7A-7E show the effect of varying concentrations of AHPN on AHPN-mediated apoptosis in MDA-MB-231 cells.
  • MDA-MB-231 cells were seeded in DMEM:F-12 medium supplemented with 5% FBS, incubated overnight and exposed to vehicle alone (Figure 7A) , or 30nM ( Figure 7B) , lOOnM ( Figure 7C) , or 500nM ( Figure 7D) of AHPN for 72 hours (magnification x 100) . Medium and supplement were changed every 18 hours. Immunoperoxidase staining of cells was effected and the apoptotic index quantified for the different AHPN dosages. These results are contained in Figure 7E.
  • Figures 8A-8E show AHPN-mediated apoptosis in MDA- MB-231 cells.
  • MDA-MB-231 cells were seeded in DMEM:F-12 medium supplemented with 5% FBS, incubated ovemight and exposed to vehicle alone (Figure 8A) , or l ⁇ M AHPN for 24 hours ( Figure 8B) , 48 hours ( Figure 8C) or 72 hours ( Figure 8D) .
  • Immunoperoxidase staining for apoptotic cells was effected (magnification x 100) . The percent of apoptotic cells was then quantified as a function of length of exposure to AHPN. These results are in Figure 8E.
  • Figures 9A-9B show AHPN induction of WAFl/CIPl mRNA expression in MCF-7 and MDA-MB-231 cells.
  • MCF-7 and MDA-MB-231 cells were incubated in DMEM:F-12 (1:1) supplemented with 5% FBS and AHPN (l ⁇ M) was added at various times during a total incubation period of 72 hours. All cultures were harvested at the end of the 72 hour incubation period. The zero-time culture that was incubated over the 72 hour period in the absence of AHPN served as the control for those cells incubated for various times with AHPN. Total RNA was extracted and Northern blots performed.
  • Figure 9A shows a representative Northern blot assay.
  • Figure 9B quantifies the results of two independent experiments .
  • FIG. 10 shows AHPN-enhanced WAFl/CIPl transcription in MDA-MB-231 and MCF-7 cells.
  • MCF-7 and MDA-MB-231 cells logarithmically growing in 10 cm plates (3 x 10 s cells/plate) in DMEM:F-12 (1:1) supplemented with 5% FBS were transiently transfected with a WAFl/CIPl luciferase reporter construct, and luciferase activity then determined.
  • Figures IIA and IIB show AHPN modulation of Jbcl-2 and bax mRNA levels.
  • MCF-7 cells seeded in DMEM:F-12 supplemented with 5% FBS were grown in the presence and absence of l ⁇ M AHPN for varying amounts of time.
  • Total RNA was extracted and Northern blots performed.
  • Figure IIA shows a representative Northern blot assay.
  • Figure IIB quantifies two independent experiments. The values are expressed relative to respective controls, which were again given an arbitrary value of 1. The error bars represent the standard errors.
  • Figures 12A and 12B show AHPN modulation of cyclin A, Bl, Dl and E on RNA levels.
  • MCF-7 cells seeded in DMEM:F-12 supplemented with 5% FBS were grown in the presence and absence of l ⁇ M AHPN for varying amounts of time.
  • Total RNA was extracted and Northern blots performed.
  • Figure 12A shows a representative Northern blot assay.
  • Figure 12B is a quantification of two independent experiments. The values are expressed relative to respective controls, which were again given an arbitrary value of 1. The error bars represent the standard errors.
  • the present invention is based on the identification of a synthetic retinoid 6- [3-adamantyl-4- hydroxyphenyl] -2-naphthalene carboxylic acid (APHN) which has been discovered to possess novel properties which render it well suited as an anti-cancer agent, in particular for the treatment or prevention of breast cancer or leukemia. Specifically, it has been discovered that this retinoid mediates G 0 /G x arrest and apoptosis of breast cancer and leukemia cell lines.
  • 6- [3-adamanty1-4-hydroxyphenyl] -2-naphthalene carboxylic acid (AHPN) provides for the programmed death of cancer cells.
  • AHPN induces G Q /G X arrest and apoptosis in both retinoic acid-sensitive (RA-sensitive) and retinoic acid- resistant (RA-resistant) cancer cell lines. Further surprising is the fact that AHPN induces G-/G- L arrest and apoptosis of both estrogen receptor positive (ER+) and estrogen receptor negative (ER-) cell lines. By contrast, other compounds such as retinoic acid and tamoxifen have been reported only to be active against ER+ breast cancers. This is therapeutically significant, because this allows AHPN to be used for the treatment or prevention of both ER+ and ER- breast cancers.
  • AHPN AHPN-like protein
  • G Q /G- L the therapeutic activity of AHPN occurs by G Q /G- L , arrest and apoptosis. It is known that apoptosis of cancer cells can be triggered through a number of different pathways. (Isaacs et al, Curr. Opin . Oncol . , 6:82-89 (1994)) .
  • a number of different cellular proteins have been reported to enhance or inhibit G ⁇ arrest or programmed cell death.
  • the cellular proteins bcl -2 Vaux, R.L. Proc . Natl . Acad . Sci .
  • AHPN induces G 0 /G x arrest and apoptosis via a unique pathway which apparently involves the activation of downstream effectors of p53 , but which operates in a p53-independent manner. This is supported by the fact that AHPN has been discovered to markedly enhance WAFl/CIPl mRNA levels in several breast cancer cell lines (MCF-7 and MDA-MB-231) , while significantly decreasing Jbcl-2 mRNA levels in another breast cancer cell line (MCF-7) . Also, AHPN was found to significantly enhance bax mRNA levels by a breast cancer cell line (MCF-7) . By contrast, it was found that AHPN apparently does not modulate either TGF-B1 mRNA or protein levels.
  • That AHPN induces apoptosis is also substantiated by morphological changes which were found to occur to cancer cell lines which were exposed to AHPN in culture. These changes include marked nuclear fragmentation and chromosome condensation. Moreover, that AHPN induced these morphological changes is substantiated by the fact that such morphological changes were observed to progressively increase as AHPN concentration was increased.
  • the effects of AHPN on cancer cells, and in particular on breast cancer cells and leukemia cells indicate that this compound may be used for the treatment or prevention of breast cancer or leukemia in subjects in need of such treatment.
  • AHPN can be used to treat persons who have been diagnosed to have breast cancer or leukemia, or to prevent cancer in persons who are at elevated risk of developing breast cancer or leukemia.
  • the latter group includes persons with a family history of breast cancer or leukemia, or who have been shown to express markers, e.g., proteins, the expression of which is correlated with an increased incidence of breast cancer or leukemia.
  • Treatment or prevention of breast cancer or leukemia is effected by administering a therapeutically or prophylactically effective amount of AHPN to a subject in need of such treatment or prevention.
  • a therapeutically or prophylactically effective dosage of AHPN will range from about .001 mg/kg to 10 mg/kg by body weight, more preferably from .01 to 5 mg/kg by body weight and most preferably the dosage will approximate that which is typical for the administration of retinoic acid, which typically ranges from about 2 ⁇ g/kg/day to 2 mg/kg/day.
  • Such administration may be effected in a single or multiple dosages, which typically will be administered daily.
  • the dosage regimen may be varied dependent upon the condition of the subject treated, and other factors, such as whether AHPN is administered in conjunction with any other anti-cancer agents or treatments such as radiation therapy. Treatment will typically be effected over a prolonged time period.
  • AHPN AHPN for the treatment or prevention of breast cancer or leukemia
  • any pharmaceutically acceptable route e.g., orally, intraocularly, parenterally, topically, or via inhalation.
  • Parenteral administration according to the present invention includes intravenous, intramuscular, subcutaneous, rectal, surgical and intraperitoneal routes of administration as well as the administration of slow or sustained release compositions. Of these, intravenous, intramuscular and subcutaneous routes of administration are generally preferred.
  • AHPN will be provided in the form of a pharmaceutically acceptable formulation by the addition of one or more acceptable carrier(s) or excipients and optionally by the addition of other active agents, e.g., other anti-cancer agents.
  • the carrier(s) or excipient (s) are acceptable in the sense of being compatible with the other ingredients in the formulation and being safe for pharmaceutical usage. (See, e.g., Remingtons Pharmaceutical Sciences, by E. W. Martin (Mack Publ. Co., Eastern PA) , for a listing of typical pharmaceutically acceptable carriers and excipient and conventional methods of preparing pharmaceutically acceptable formulations. )
  • the pharmaceutical compositions may be in the form of solid, semi-solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, suspensions, lotions, creams, gels, or the like, preferably in unit dosage form suitable for single administration of a precise dosage.
  • compositions will include, as noted above, a therapeutically or prophylactically effective amount of AHPN in combination with a pharmaceutically acceptable carrier and, in addition, may include other active agents, e.g., other anti-cancer agents, pharmaceutical agents, carriers, adjuvants, diluents, etc.
  • active agents e.g., other anti-cancer agents, pharmaceutical agents, carriers, adjuvants, diluents, etc.
  • conventional nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like.
  • Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc., AHPN and optionally pharmaceutical adjuvants in an excipient, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, or the like, to form a solution or suspension.
  • the pharmaceutical composition may also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, etc. Suitable methods for preparing such dosage forms are well known in the art. ⁇ See, e . g . , Remington ' s Pharmaceutical Sciences, referenced above. )
  • fine powders or granules may contain diluting, dispersing and/or surface active agents, and may be presented in water or in a syrup, in capsules or sachets in the dry state, or in a nonaqueous solution or suspension wherein suspending agents may be included, in tablets wherein binders and lubricants may be included, or in a suspension in water or a syrup. Where desirable or necessary, flavoring, preserving, suspending, thickening, or emulsifying agents may be included. Tablets and granules are preferred oral administration forms, and these may be coated.
  • Parenteral administration if used, is preferably effected by injection.
  • Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions.
  • parenteral administration includes use of a slow release or sustained release system, such that a constant level of dosage is maintained. See e.g., U.S. Patent No. 3,710,795, which is incorporated by reference herein.
  • the subject AHPN formulations may contain other active agents.
  • active agents include any compound suitable for the prevention or treatment of cancer, or more specifically the treatment or prevention of breast cancer or leukemia.
  • the subject AHPN containing formulations may include other retinoids reported to possess anti-cancer activity, e.g., retinoic acid, N- (4- hydroxyphenyl) retinamide (4-HPR) , 9-cis-retinoic acid, retinoyl-glucuronide N-glycoside analogs (see, U. S. Patent No. 5,516,792) , or other anti-cancer agents, e.g. methotrexate, anti-estrogens, such as tamoxifen and toremifene, doxorubicin, daunorubicin, adriamyicin, etc.
  • retinoids reported to possess anti-cancer activity e.g., retinoic acid, N- (4- hydroxyphenyl) retinamide (4-HPR) , 9-cis-retinoic acid, retinoyl-glucuronide N-glycoside analogs (see, U. S. Patent
  • cytokines e.g., interferons such as gamma, beta or alpha interferon, alpha or beta tumor necrosis factors, interleukins, colony stimulating factors, among others.
  • interferons such as gamma, beta or alpha interferon, alpha or beta tumor necrosis factors, interleukins, colony stimulating factors, among others.
  • tamoxifen exhibits synergistic breast cancer chemopreventive effects when combined with the retinoid fenretinimide (4-HPR) (Costa, A. Eur. J. Cancer, 29A(4) :589-592 (1993)) .
  • Dulbecco's modified Eagle's medium Ham's F-12 medium and fetal bovine serum (FBS) were obtained from Gibco-BRL (Grand Island, NY) .
  • Dulbecco's modified Eagle's medium (Phenol red-free) was purchased from Biofluids (Rockville, MD) .
  • HEPES, tamoxifen, and charcoal limpet sulfatase were obtained from Sigma
  • the MCF-7, T47D and MDA-MB-231 cell lines were a kind gift of Dr. Marc Lippman (Lombardi Cancer Center, Washington, D.C) .
  • the MDA-MB-468 cells were provided by Dr. Anne Hamburger (University of Maryland Cancer Center, Baltimore, MD) .
  • Cells were maintained in Dulbecco's modified Eagle's (DMEM) : Ham's F-12 medium, supplemented with 5% FBS as previously reported (Fontana, J.A. , Exp . Cell Res . , 55:136-144 (1987)) .
  • DMEM Dulbecco's modified Eagle's
  • DMEM:F-12 (1:1) medium supplemented with FBS for 24 h.
  • MCF-7 cells were plated at an initial cell concentration of 3 x 10 4 cells per well, while T47D, MDA-MB-231 and MDA-MB-468 were plated at a cell concentration of 1 x IO 4 cells per well.
  • the treatment with RA or AHPN was for 3, 6, or 9 days in the same medium.
  • the medium and retinoids were changed every 2 days.
  • the retinoids were dissolved in dimethyl sulfoxide (DMSO) .
  • the final concentration of DMSO in all the cultures was 0.1%; control cells were incubated with DMSO at the same final concentration.
  • DMSO dimethyl sulfoxide
  • Plasmid constructs, transient transfection and CAT assay The ⁇ 2 -RARE-tic-CAT and the CRBP Il-tk CAT and APO-1- tk CAT reporter plasmids, which were kindly provided by Dr. X-k Zhang of the La Jolla Cancer Center (La Jolla, CA) , carry the RARE and RXRE, respectively, upstream of the thymidine kinase (tk) promoter containing the CAT gene. Variations in transfection efficiencies were adjusted by using the plasmid pRSV2 (MacGregor et al, Somat . Cell Mol . Genet .
  • the full-length human WAF1 cDNA probe was kindly provided by Drs. Kinzler and Vogelstein (Johns Hopkins University, Baltimore, MD) .
  • the human cyclin Dl and E cDNA probes (Xiong et al, Cell , 65:691-699 (1991), and Xiong et al, Genomics, 13:575-584 (1992)) were obtained from Dr. David Beach (Howard Hughes, Cold Spring Harbor Laboratory, NY) .
  • the human cyclin A and Bl cDNA probes (Pines et al, Cell , 58:833-846 (1989) ; and Pines et al, Nature, 346:760-763 (1990)) , were a gift of Dr. Tony Hunter (The Salk Institute, San Diego, CA) . Probes were labelled according to the random primer method of Feinberg et al, (Anal. Biochem. , 132:6-13 (1983)) .
  • Transient transfections were performed as previously described (Sheikh et al, J. Cell . Biochem. , 53:393-404 (1993)) .
  • Cells were plated in a 10 cm plate at a density of 3 x 10 s cells per plate. The medium was changed 2 h before transfection.
  • the cells were co ⁇ transfected with various plasmids and the total amount of DNA was corrected to 20 ⁇ g per plate by adding plasmid pUC19.
  • MDA-MB-231 and MCF-7 cells were shocked with 20% glycerol for 7 min and 2 min, respectively, 6 h following the addition of DNA. Fresh medium was added following washing the cells with 1 x PBS.
  • the cells were harvested 48 h after the transfection.
  • the cells were trypsinized and resuspended in 100 ⁇ l 0.25 M Tris-HCl, pH 8.0. After three cycles of freezing and thawing, cell lysates were collected and CAT assays performed as previously described (Sheikh et al, J. Cell . Biochem . , 53:393-404 (1993)) .
  • luciferase assays the cells were washed with PBS, and 300-400 ⁇ l of lysis buffer (25mM glycylglycine pH 7.8, 1.5 mM MgS04 a, 4 mM EGTA, 100 mM DTT and 1% Triton X-100) added to the cells and the cell harvested. The lysates were centrifuged for 5 min in a microcentrifuge. The supematants were supplemented with 12 mM K 2 HP0 4 and 1.6 mM ATP and assayed for luciferase activity by measuring light units in a standard luminometer for 10 s. Relative light units were corrected with respect to ⁇ -galactosidase activity.
  • lysis buffer 25mM glycylglycine pH 7.8, 1.5 mM MgS04 a, 4 mM EGTA, 100 mM DTT and 1% Triton X-100
  • Apoptosis was detected by labelling the 3'OH ends of DNA utilizing digoxigenin incorporation by terminal deoxynucleootidyltransferase.
  • Antidigoxigenin antibodies and immunoperoxidase staining were utilized to demonstrate digoxigenin-nucleotide incorporation by utilizing the Apotag detection system (Oncor, Gaithersburg, MD) .
  • Apotag detection system Oncor, Gaithersburg, MD
  • cells were spun onto microscope slides, rinsed with PBS and finally incubated in a reaction mixture containing terminal transferase and digoxigenin dUTP at 37°C for 1 h. The specimens were then washed, antidigoxigenin antibody coupled to horseradish peroxidase was then added, and the cells were incubated for 30 min at room temperature.
  • dia inobenzidine tetrachloride (DAKO, Carpenteria, CA) was added and the cells incubated for 10 min. The percent peroxidase positive cells were determined by counting 200 cells in random fields in two separate experiments.
  • estrogen receptor (ER) -positive breast carcinoma cells are sensitive to the antiproliferative effects of RA while ER-negative cells are refractory (Roman et al, Cancer Res . , 53:5940-5945 (1993) ; Sheikh et al, J. Cell . Biochem. , 53:393-404 (1993) ; and van der Burg et al, Mol . Cell . Endo . , 91:149-157 (1993)) . Therefore, in order to determine whether /AHPN displays the same spectrum of antiproliferative activity against breast carcinoma cells as RA, the ability of AHPN to inhibit the proliferation of both ER-positive and ER-negative breast carcinoma cells was investigated.
  • the concentration of AHPN required for 50% inhibition of growth was 300 nM and 150nM for MCF-7 and MDA-MB- 231 cells, respectively (see Figure 2) .
  • RA did not inhibit the growth of MDA-MB-231 or MDA-MB-468 cells and displayed an IC 50 of 100 nM when tested against MCF-7 and T47D cells (Sheikh et al, J. Biol . Chem. , 269:21440-21447 (1994)) .
  • AHPN arrested MCF-7 and MDA-MB-231 cells in the Go/Gi phase Figure 3A and 3B
  • AHPN has been reported as RAR ⁇ -selective in both retinoid receptor binding and transcriptional activation assays (Bernard et al, Biochem. Biophys . Res . Commun . , 186:977-983 (1992)).
  • Tritiated 6- (5,6,7,8-tetrahydro- 5,5,8,8-tetramethyl-2-anthracenyl)benzoic acid gave K d values for RAR ⁇ and RAR ⁇ that were higher by 32-fold and 84-fold, respectively, than for the RAR ⁇ .
  • Transcriptional activation assays in HeLa cells using expression vectors for the receptors and the (TRE) 3 -tk- CAT reporter plasmid required AHPN concentrations for 50% maximal activation that were 19-fold and 3.9-fold higher for RARot and RAR ⁇ , respectively than for RAR ⁇ (Bernard et al, Biochem. Biophys . Res . Commun . , 186:977- 983 (1992) ) .
  • the present inventors theorized that if AHPN- mediated inhibition of breast carcinoma proliferation occurred through activation of RAR ⁇ , similar or greater transactivation of a transfected RARE-mediated reporter gene with AHPN than that found with RA, in MDA-MB-231 cells, which only possesses RAR ⁇ and are refractory to the antiproliferative effects of RA (Roman et al, Cancer Res . , 53:5940-5945 (1993) ; Sheikh et al, J " . Cell . Biochem. , 53:393-404 (1993); and van der Burg et al, Mol . Cell . Endo . , 91:149-157 (1993)) would be expected to be seen.
  • AHPN AHPN-controlled CAT reporter gene.
  • the ⁇ 2 -RARE is predominantly activated by RAR/RXR heterodimers and to a lesser extent by RXR homodimers and has a direct repeat 5 (DR5) -type response element located in the promoter region of the RAR ⁇ 2 gene (Zhang, Nature, 355:441-446 (1992) ; and Zhang et al, Mol . Cell . Biol . , 14:4311-4323 (1994)) .
  • DR5 direct repeat 5
  • AHPN displayed significantly decreased potency than RA in its ability to transactivate the endogenous retinoid receptors in both MCF-7 and MDA-MB-231 cells.
  • AHPN apparently does not mediate its antiproliferative effects through the RAR pathway since AHPN is a much more potent inhibitor of MCF-7 and MDA-MB-231 growth than RA but displays markedly less transactivation of the ⁇ 2 RARE response element than RA in both cell types .
  • HL-60R cells do not possess a functional RAR and their growth is not inhibited by RA (Robertson et al, Blood, 80:1885-1889 (1982)) .
  • the effect of AHPN on HL-60R growth was also studied to further assess the role of the RAR pathway on AHPN-mediated inhibition of growth.
  • AHPN was found to markedly inhibit the proliferation of HL-60R leukemia cells while RA had no effect ( Figure 5) . These results further substantiate that the RAR pathway is not involved in AHPN-mediated growth inhibition.
  • RXR homodimer selective pathway the ability of AHPN to transactivate two naturally occurring RXREs, i.e. APO-AI and CRBPII which were transfected into MCF-7 and MDA-MB-231 was compared.
  • the APO-AI which is activated by RXR/RXR homodimers and to a lesser extent by RAR/RXR heterodimers, is a DR-2 type response element located in the promoter region of the APO-AI gene (Zhang et al, Nature, 358:587-597 (1992) ; and Zhang et al, Mol . Cell . Biol . , 14:4311-4323 (1994)) .
  • the CRBPII RXRE is activated by RXR/RXR homodimers and is a DR-1-type retinoid response element.
  • SR11246 which induces RXR homodimer formation, was a good activator of the RXRE pathway, while minimal activation of the RXRE was noted in the presence of AHP ⁇ ( Figure 4) .
  • RA through its RAR and RXR nuclear receptors can antagonize c-Fos/c-Jun- mediated activation of the AP-1 consensus sequence
  • AHPN-mediated apoptosis was also evaluated in MDA- MB-231 cells utilizing the Apotag assay in which 3 'OH ends of the DNA breaks associated with apoptosis are labeled with digoxigenin-coupled dUTP using terminal deoxynucleotidyl transferase and digoxigenin detected using immunoperoxidase staining.
  • increasing AHPN concentrations resulted in a progressive increase in the percent of apoptotic cells as indicated by fragmentation of the DNA and nuclear immunoperoxidase staining.
  • exposure to 1 ⁇ M AHPN for varying periods of time (0, 24, 48 of 72 h) resulted in a progressive increase in the percent of apoptotic cells
  • Apoptosis can be triggered in cells through a variety of pathways (Isaacs, J.T., Curr. Opinion in Oncol . , 6:82-89 (1994)) .
  • a number of cellular proteins either enhance or inhibit G arrest or programmed cell death.
  • the cellular proteins J cl-2 (Vaux, Proc. Natl . Acad. Sci .
  • AHPN markedly enhanced WAFl/CIPl mRNA levels in both MCF-7 cells and MDA-MB-231 cells .
  • AHPN elevated WAFl/CIPl mRNA levels as early as 1 h after addition to MDA-MB-231 cells, and within 6 h after addition to MCF-7 cells ( Figure 9) .
  • MDA-MB-231 cells expressed significantly lower WAFl/CIPl mRNA levels than MCF-7 cells due to the presence of a mutated (nonfunctional) p53, as previously demonstrated (Sheikh et al, Oncogene, 9:3407-3415 (1994)) .
  • RA did not modulate WAFl/CIPl mRNA levels (data not shown) in either cell type. That AHPN enhanced WAFl/CIPl gene transcription may be seen from the results contained in Figure 10.
  • Bcl -2 expression enhances cell survival and blocks TGF ⁇ l induced cell death while bax promotes cell death and may enhance p53-mediated apoptosis (Selvakumaran et al, Oncogene, 9:1791-1798 (1994)) . Accordingly, the effect of AHPN on bcl -2 and bax mRNA expression was examined. These results indicated that while AHPN significantly enhanced WAFl/CIPl mRNA levels in MCF-7 cells within 6 h, it significantly decreased Jbcl-2 mRNA levels ( Figure 11) .
  • Bcl -2 mRNA expression could not be detected in MDA-MB- 231 cells in the absence or presence of AHPN.
  • AHPN (1 ⁇ M) significantly elevated bax mRNA levels within 6 h in MCF-7 cells, while Jbax mRNA expression could not be detected in MDA-MB-231 cells.
  • AHPN (1 ⁇ M) did not modulate TGF ⁇ l mRNA or protein levels in either MCF-7 or MDA-MB- 231 cells (data not shown) .
  • Cyclins are important mediators of cell cycle progression (van der Hewel et al, Science, 262:2050- 2054 (1994)) .
  • numerous investigators have suggested that cyclin Dl and cyclin E are rate-limiting for progression through G (Jiang et al, Oncogene, 8:3447-3457 (1993) ; Jo et al, Genes Dev. , 7:1559- 1571 (1993) ; and Baldin et al, Genes Dev. , 7:812-821 (1994) ) . Since exposure to 7AHPN resulted in G-/G- L arrest, the effect of AHPN treatment on cyclin E, Dl, A and Bl expression in MCF-7 cells was examined.
  • cyclin Dl mRNA levels were significantly decreased within 6 h of exposure to AHPN. Decreases in cyclin A and cyclin Bl mRNA were also noted within 6 h following the addition of AHPN, while there was no modulation of cyclin E mRNA levels ( Figure 12) .
  • AHPN displays enhanced binding to and transactivation of the RAR ⁇ receptor
  • AHPN apparently also functions through a RAR and RXR-independent mechanism.
  • AHPN was found to significantly inhibit the proliferation of both ER-positive MCF-7 and T47D cells, as well as ER- negative MDA-MB-231 and MDA-MB-468 cells, whereas RA inhibited only ER-positive breast carcinoma cell proliferation.
  • MDA-MB-231 cells AHPN was found to display significantly less transactivation than RA of the RAR receptor on the RAR ⁇ 2 RARE as well as the APO-1 RXRE, which can also be activated by RAR-RXR heterodimers.
  • results indicate there to be no correlation between AHPN transactivation of the RAR ⁇ receptor and its ability to inhibit breast carcinoma cell proliferation, even in MDA-MB-231 cells which only possess a functional RAR ⁇ receptor. Also, the results indicate that AHPN does not activate the RXRE pathway (as demonstrated by the lack of CAT activity on transfection of MCF-7 and MDA-MB-231 cells with the CRBPII and APO-1 RXRE-tk-CAT reporter constructs in the presence of AHPN) . Further, AHPN was found to inhibit the proliferation of the RA-resistant HL-60R cells which possess a defective RAR ⁇ due to a point mutation in the RAR ⁇ gene resulting in its truncation and inability to bind RA.
  • HL-60R cells do not possess a RAR ⁇ or RAR ⁇ receptor (Nervi et al, Proc . Na tl . Acad. Sci . USA, 86:5854-5858 (1989) ) . Accordingly, these results indicate that growth inhibition by AHPN is not mediated via the RAR pathway in these cells.
  • WAFl/CIPl inhibits the function of a number of cyclin/cyclin-dependent protein kinase (CDK) complexes including cyclin A-CDK2, cyclin E-CDK2 and cyclin D-CDK- resulting in the arrest of the cells in G x (Hunter et al, Cell , 79:573-582 (1994)) .
  • p53-mediated G arrest in response to DNA damage appears to require the elevation of WAFl/CIPl levels (Hunter et al, Cell , 79:573-582 (1994) ) .
  • the WAFl/CIPl promoter has a p53 consensus sequence and thus the post-transcriptional elevation of p53 levels following DNA damage results in enhanced WAFl/CIPl gene transcription and subsequent G 1 arrest. It has previously been shown that MCF-7 cells possess a wild-type (functional) p53 while MDA-MB-231 cells possess a mutant (nonfunctional) p53 (Sheikh et al, Oncogene, 9:3407-3415 (1994)) . Niewolik et al ( Oncogene, 10:881-890 (1995)) have also reported that p53 derived from MDA-MB-231 cells does not bind to the p53 consensus sequence.
  • RA-mediated differentiation of HL-60 cells is associated with a p53 independent elevation of WAFl/CIPl levels (Jiang et al, Oncogene, 9:3397-3406 (1994) ; and Steinman et al, Oncogene, 9:3389-3396 (1994)) .
  • Michiel et al ( Cancer Res . , 54:3391-3395 (1994)) have hypothesized the existence of two separate pathways for the induction of WAFl/CIPl , a mitogen-activated p53-independent mechanism and a DNA damage-activated, p53-dependent mechanism.
  • AHPN significantly decreased cyclin Dl, A and B mRNA levels, perhaps also contributing to G 1 arrest.
  • the bcl -2 oncoprotein is found in the inner mitochondrial membrane, as well as other subcellular compartments, i.e., the endoplasmic reticulum and the nuclear membrane (Oltvai et al, Cell , 74:609-619 (1993)) , where its overexpression results in prolongation of cell survival (Hockenberry et al, Proc . Natl . Acad . Sci . USA, 88:6961-6965 (1991) ) .
  • Bcl -2 is reported to both homodimerize and heterodimerize with a number of other proteins, including bax, bcl X L , bcl X s , and Mcl -1 (Sato et al, Proc . Natl . Acad . Sci . USA, 91:9238-9242 (1994)) .
  • MDA-MB-231 This discrepancy may be attributable to different strains of MDA-MB-231.
  • the results also indicate that MDA-MB-231 cells areakily sensitive to AHPN-mediated Gg/Gi arrest and programmed-cell death. It is possible that the low levels of Jbcl-2 may enhance the sensitivity of MDA-MB-231 to this retinoid.
  • AHPN displays a wide spectrum of action by inhibiting the growth of both ER-positive and ER-negative breast carcinoma cell lines.
  • exposure to AHPN results in programmed death of breast carcinoma and leukemia cells.
  • AHPN is well suited for the treatment or prevention of breast cancer or leukemia.

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Abstract

Procédés de traitement ou de prévention du cancer du sein ou de la leucémie chez des sujets nécessitant un traitement, qui consistent à administrer de l'acide carboxylique de 6-[3-[1-adamantyl]-4-hydroxyphényl]-2-naphtalène, un rétinoïde qui induit l'arrêt G0/G1 et l'apoptose. Lesdits procédés sont utiles pour le traitement des cancers du sein qui expriment ou n'expriment pas les récepteurs d'oestrogène.
PCT/US1996/011736 1995-07-17 1996-07-17 Procedes de traitement de cancers a l'aide de 6-[3-[1-adamantyl]-4-hydroxyphenyl] WO1997003682A1 (fr)

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US09/011,323 US6211239B1 (en) 1996-07-17 1996-07-17 Method for treating or preventing breast cancer or leukemia using 6-[3-[1-adamantyl]-4-hydroxyphenyl]-2-naphthalene carboxylic acid (AHPN)
JP9506790A JP2000506489A (ja) 1995-07-17 1996-07-17 Ａｈｐｎを用いる癌の治療方法
EP96924519A EP0850067A4 (fr) 1995-07-17 1996-07-17 Procedes de traitement de cancers a l'aide de 6- 3- 1-adamantyl]-4-hydroxyphenyl]
AU64949/96A AU701790B2 (en) 1995-07-17 1996-07-17 Method for treating cancers using 6-{3-{1-adamantyl}- 4-hydroxyphenyl}

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Cited By (14)

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WO1997013505A2 (fr) * 1995-10-09 1997-04-17 Centre International De Recherches Dermatologiques Galderma (C.I.R.D. Galderma) UTILISATION D'UN LIGAND AGONISTE SPECIFIQUE RAR-η POUR AUGMENTER LE TAUX D'APOPTOSE
EP0920312A1 (fr) * 1996-07-08 1999-06-09 Galderma Research & Development Derives d'adamantyle induisant l'apoptose et leur utilisation comme agents anticancereux
US6462064B1 (en) 1996-07-08 2002-10-08 Galderma Research & Development S.N.C. Apoptosis inducing adamantyl derivatives and their usage as anti-cancer agents, especially for cervical cancers and dysplasias
DE10255861A1 (de) * 2002-11-29 2004-06-17 Axxima Pharmaceuticals Ag Gegen Hepatitis C-Virusinfektionen nützliche Verbindungen und Substanzen
WO2004050101A2 (fr) * 2002-11-29 2004-06-17 Gpc Biotech Ag Formulations utiles pour lutter contre les infections par le virus de l'hepatite c
US6765013B2 (en) 1999-08-31 2004-07-20 Incyte San Diego Thiazolidinedione derivatives for the treatment of diabetes and other diseases
US7071218B2 (en) 2001-11-15 2006-07-04 Incyte San Diego Incorporated N-substituted heterocycles for the treatment of hypercholesteremia, dyslipidemia and other metabolic disorders; cancer, and other diseases
US7102000B2 (en) 2002-03-08 2006-09-05 Incyte San Diego Inc. Heterocyclic amide derivatives for the treatment of diabetes and other diseases
US7153875B2 (en) 2001-03-07 2006-12-26 Incyte San Diego Heterocyclic derivatives for the treatment of cancer and other proliferative diseases
US7196108B2 (en) 2002-03-08 2007-03-27 Incyte San Diego Inc. Bicyclic heterocycles for the treatment of diabetes and other diseases
US7229962B2 (en) 2001-07-26 2007-06-12 Medexgen Co., Ltd. Tetravalent etanercept
US7265139B2 (en) 2001-03-08 2007-09-04 Incyte San Diego Inc. RXR activating molecules
EP3301085A1 (fr) 2016-09-29 2018-04-04 Biogem S.Ca.R.L. Derives de retinoïde a activite antitumorale
WO2022229017A1 (fr) 2021-04-27 2022-11-03 Biogem S.C.A R.L. Dérivé adamantylique de rétinoïde présentant une activité anticancéreuse

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ES2395401T3 (es) * 2006-03-23 2013-02-12 Tmrc Co., Ltd. kit para la terapia del cáncer y composición farmacéutica para la terapia del cáncer
JP5054006B2 (ja) * 2006-06-23 2012-10-24 ロート製薬株式会社 ヒアルロン酸産生促進能を有する組成物

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US4717720A (en) * 1985-04-11 1988-01-05 Centre International De Recherches Dermatologiques (C.I.R.D.) Benzonaphthalene derivatives and compositions

Non-Patent Citations (1)

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See also references of EP0850067A4 *

Cited By (26)

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US6506796B1 (en) 1995-10-09 2003-01-14 Centre International De Recherches Dermatologiques Galderma Use of a RAR-γ-specific agonist ligand for increasing the rate of apoptosis
WO1997013505A3 (fr) * 1995-10-09 1997-05-29 Cird UTILISATION D'UN LIGAND AGONISTE SPECIFIQUE RAR-η POUR AUGMENTER LE TAUX D'APOPTOSE
WO1997013505A2 (fr) * 1995-10-09 1997-04-17 Centre International De Recherches Dermatologiques Galderma (C.I.R.D. Galderma) UTILISATION D'UN LIGAND AGONISTE SPECIFIQUE RAR-η POUR AUGMENTER LE TAUX D'APOPTOSE
US6686386B1 (en) 1995-10-09 2004-02-03 Galderma Research & Development S.N.C. Use of a RAR-γ-specific agonist ligand for increasing the rate of apoptosis
US6593359B1 (en) 1995-10-09 2003-07-15 Centre International De Recherches Dermatologioues Galderma (C.I.R.D. Galderma) Use of a RAR-γ-specific agonist ligand for increasing the rate of apoptosis
US6825226B2 (en) 1996-07-08 2004-11-30 Galderma Research & Development, S.N.C. Apoptosis inducing adamantyl derivatives and their usage as anti-cancer agents, especially for cervical cancers and dysplasias
EP0920312A4 (fr) * 1996-07-08 2000-11-02 Galderma Res & Dev Derives d'adamantyle induisant l'apoptose et leur utilisation comme agents anticancereux
US6462064B1 (en) 1996-07-08 2002-10-08 Galderma Research & Development S.N.C. Apoptosis inducing adamantyl derivatives and their usage as anti-cancer agents, especially for cervical cancers and dysplasias
EP0920312A1 (fr) * 1996-07-08 1999-06-09 Galderma Research & Development Derives d'adamantyle induisant l'apoptose et leur utilisation comme agents anticancereux
US6765013B2 (en) 1999-08-31 2004-07-20 Incyte San Diego Thiazolidinedione derivatives for the treatment of diabetes and other diseases
US7226940B2 (en) 1999-08-31 2007-06-05 Incyte San Diego, Inc. Substituted heterocycles for the treatment of diabetes and other diseases
US6974826B2 (en) 1999-08-31 2005-12-13 Incyte San Diego Inc. Imidazolidinedione derivatives for the treatment of diabetes and other diseases
US7153875B2 (en) 2001-03-07 2006-12-26 Incyte San Diego Heterocyclic derivatives for the treatment of cancer and other proliferative diseases
US7265139B2 (en) 2001-03-08 2007-09-04 Incyte San Diego Inc. RXR activating molecules
US7670602B2 (en) 2001-07-26 2010-03-02 Medexgen Co., Ltd Concatameric immunoadhesion molecule
US7229962B2 (en) 2001-07-26 2007-06-12 Medexgen Co., Ltd. Tetravalent etanercept
US8372961B2 (en) 2001-07-26 2013-02-12 Medexgen Co., Ltd. Polynucleotides encoding concatameric immunoadhesion molecules
US7071218B2 (en) 2001-11-15 2006-07-04 Incyte San Diego Incorporated N-substituted heterocycles for the treatment of hypercholesteremia, dyslipidemia and other metabolic disorders; cancer, and other diseases
US7102000B2 (en) 2002-03-08 2006-09-05 Incyte San Diego Inc. Heterocyclic amide derivatives for the treatment of diabetes and other diseases
US7196108B2 (en) 2002-03-08 2007-03-27 Incyte San Diego Inc. Bicyclic heterocycles for the treatment of diabetes and other diseases
WO2004050101A3 (fr) * 2002-11-29 2004-09-10 Axxima Pharmaceuticals Ag Formulations utiles pour lutter contre les infections par le virus de l'hepatite c
WO2004050101A2 (fr) * 2002-11-29 2004-06-17 Gpc Biotech Ag Formulations utiles pour lutter contre les infections par le virus de l'hepatite c
DE10255861A1 (de) * 2002-11-29 2004-06-17 Axxima Pharmaceuticals Ag Gegen Hepatitis C-Virusinfektionen nützliche Verbindungen und Substanzen
EP3301085A1 (fr) 2016-09-29 2018-04-04 Biogem S.Ca.R.L. Derives de retinoïde a activite antitumorale
WO2018060354A1 (fr) 2016-09-29 2018-04-05 Biogem S.Ca.R.L. Dérivés de rétinoïdes à activité antitumorale
WO2022229017A1 (fr) 2021-04-27 2022-11-03 Biogem S.C.A R.L. Dérivé adamantylique de rétinoïde présentant une activité anticancéreuse

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