WO2001007028A2 - Utilisation d'antagonistes de recepteurs de retinoides dans le traitement du cancer de la prostate - Google Patents

Utilisation d'antagonistes de recepteurs de retinoides dans le traitement du cancer de la prostate Download PDF

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WO2001007028A2
WO2001007028A2 PCT/US2000/019849 US0019849W WO0107028A2 WO 2001007028 A2 WO2001007028 A2 WO 2001007028A2 US 0019849 W US0019849 W US 0019849W WO 0107028 A2 WO0107028 A2 WO 0107028A2
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carbons
alkyl
group
phenyl
antagonist
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PCT/US2000/019849
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WO2001007028A3 (fr
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Roshantha A. Chandraratna
Geoffrey Brown
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Allergan Sales, Inc.
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Priority to AU62280/00A priority Critical patent/AU6228000A/en
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Publication of WO2001007028A3 publication Critical patent/WO2001007028A3/fr

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    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/382—Heterocyclic compounds having sulfur as a ring hetero atom having six-membered rings, e.g. thioxanthenes
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Prostate cancer is a serious condition that affects increasing numbers of men worldwide. About one-third of all men have at least some cancerous prostatic cells at age 50, with the incidence increasing to as many as 90 percent of men at age 90. In the United States alone, about 40,000 men die each year from prostate cancer.
  • Prostate cancer is a sex hormone dependent cancer; that is, the growth of the cancer is promoted by male hormones (e.g., androgens such as testosterone and dihydrotestosterone). Removal of the testes (castration) was for many years the standard method of preventing the secretion of male hormones by the gonads, as a means for reducing growth of the cancer. More recently, secretion of male hormones has been perturbed by chemical means by interfering with production of luteinizing hormone (LH), which regulates the synthesis of male hormones.
  • LH luteinizing hormone
  • Luteinizing hormone releasing hormone is a natural hormone produced by the hypothalamus that interacts with luteinizing hormone releasing hormone receptor (LHRH-R) in the pituitary to stimulate production of LH.
  • LHRH-R luteinizing hormone releasing hormone receptor
  • LHRH-R superagonists of the luteinizing hormone releasing hormone receptor
  • LHRH-R superagonists initially act to stimulate LH release and only after prolonged treatment act to desensitize LHRH-R such that LH is no longer produced.
  • the initial stimulation of LH production by the superagonist leads to an initial surge in the production of male hormones such that the initial response to superagonist therapy is aggravation, rather than amelioration, of the patient's condition (e.g., tumor growth increases).
  • This phenomenon known as the "flare reaction”
  • each successive administration of the superagonist can cause a small LH surge (known as the "acute-on chronic” phenomenon) that again can worsen the condition.
  • the "flare reaction” prohibits the use of LHRH-R superagonists in the treatment of late stage prostatic cancer patients where the cancer has metastasized to the spinal cord, since the initial stimulation of cancer growth would cause nerve trunk compression and damage.
  • additional diagnostic tests must be conducted, such as magnetic resonance imaging or a spinal CAT scan, which adds to the cost of superagonist therapy.
  • Retinoids synthetic and natural analogs of retinoic acid exhibit potent growth inhibitory and cell differentiation activities which account for their beneficial effects in cancer in ex vivo and in vivo models. These simple molecules with pleiotropic effects have shown potential as therapeutic agents for the treatment of cancer whether alone or in combination with other agents.
  • Retinoids regulate the growth of various cell types by directly modulating the expression of responsive genes through nuclear retinoid receptors (RARs and RXRs), which are ligand dependent transcription factors.
  • RARs and RXRs nuclear retinoid receptors
  • RAR ⁇ The translocation of RAR ⁇ in acute pro-myelocytic leukemia, decreased expression of RAR ⁇ and reduced activity of the RAR ⁇ promoter in various tumors and cancer cell lines, and restoration of retinoid sensitivity to cancer cells by RAR expression vector transfection, are all indicative of the direct involvement of RAR malfunction in the process of tumorigenesis and also suggest a role of RARs as ligand dependant tumor suppressors.
  • the current use of retinoids in cancer is limited because of their associated toxicities and lack of efficacy at tolerated doses.
  • the present invention provides a method for treating prostate cancer in a patient in need of such treatment, the method comprising administering a therapeutically effective amount of a retinoid receptor antagonist.
  • the present invention also provides a method of inhibiting the growth of a prostate carcinoma cell or tumor, the method comprising contacting the cell or tumor with an effective amount of a retinoid receptor antagonist.
  • the present invention further provides a method for treating prostate cancer comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a retinoid receptor antagonist and a pharmaceutically acceptable carrier or excipient.
  • the present invention provides a method of inhibiting the growth of a prostate carcinoma cell or tumor, the method comprising contacting the cell or tumor with an effective amount of a pharmaceutical composition comprising a retinoid receptor antagonist and a pharmaceutically acceptable carrier or excipient.
  • the antagonist is an RAR antagonist, preferably an RAR ⁇ antagonist. According to another preferred embodiment, the antagonist is an RAR ⁇ selective antagonist.
  • Figure 1 shows the relative activities of retinoid receptor selective compounds on clonogenicity of serum free-grown LNCaP prostate carcinoma cells.
  • Figure 2 shows that RAR antagonism inhibits the clonogenicity of serum free-grown prostate carcinoma cells.
  • Figure 3 shows the relative potency of RAR antagonists against carcinoma cell lines.
  • Figure 4 shows the influence of RAR antagonism on the growth of bulk cultures of LNCaP prostate carcinoma cells.
  • Figure 5 shows that AGN 310 is not effective in inhibiting growth of
  • Figure 6 shows the effect of serum on the growth inhibitory effects of RAR antagonists against LNCaP prostate carcinoma cells.
  • Figure 7 shows the effect of serum on the growth inhibitory effects of RAR antagonists against PC-3 prostate carcinoma cells.
  • Figure 8 shows the effect of RAR ⁇ agonists on LNCaP prostate carcinoma cells.
  • Figure 9 shows the effect of RAR ⁇ agonists on PC-3 prostate carcinoma cells.
  • Figure 10 shows that an RAR ⁇ agonist does not interfere with the growth inhibitory effects of an RAR ⁇ antagonist against LNCaP prostate carcinoma cells.
  • Figure 11 shows that an RAR ⁇ agonist does not interfere with the growth inhibitory effects of RAR antagonists against PC-3 prostate carcinoma cells.
  • the present invention provides a method of treating prostate carcinomas comprising the use of retinoid receptor antagonists.
  • retinoids exert their biological effects through two families of nuclear receptors, retinoic acid receptors (RARs) and retinoid X receptors (RXRs), which belong to the superfamily of steroid/thyroid/vitamin D3 nuclear receptors.
  • RARs and RXRs are ligand-dependent transcription factors which regulate gene expression in two different ways: (a) they upregulate the expression of genes by binding to the RA-responsive elements (RAREs) present in their promoters or (b) they down-regulate the expression of genes by antagonizing the enhancer action of certain other transcription factors, such as API.
  • RARs The distinct isotypes of RARs ( ⁇ , ⁇ and ⁇ ) and RXRs ( ⁇ , ⁇ and ⁇ ) are encoded by three separate genes. Each RAR isotype is further expressed as several isoforms differing in their N- terminal A region, which are generated by alternative splicing and/or by differential usage of two promotors.
  • RAR ⁇ is expressed as two main isoforms ( ⁇ l and ⁇ 2). RAR ⁇ as four isoforms ( ⁇ l, ⁇ 2, ⁇ 3 and ⁇ 4) and RAR ⁇ as two main isoforms ( ⁇ l and ⁇ 2).
  • RARs are believed to function exclusively in vivo as RAR-RXR heterodimers.
  • the present invention relates to the use of any retinoid receptor antagonist presently known in the art, or subsequently developed, in practicing the claimed methods.
  • the synthesis of exemplary receptor antagonists is described, by way of example only, in U.S. patent nos. 5,877,207; 5,514,825; 5,648,514; 5,728,846; 5,739,338; 5,760,276; 5,776,699; 5,773,594; 5,763,635; and 5,808.124 and U.S.S.N. 08/840,040 and 08/845,019, incorporated herein by reference in their entireties.
  • the antagonist is an RAR antagonist, and more preferably an RAR ⁇ antagonist.
  • antagonists with activity specific for a particular isotype and/or isoform or a combination thereof may also be used in the present methods.
  • antagonists specific for RAR ⁇ , ⁇ , ⁇ or combinations thereof may be used.
  • Such receptor isotype specific antagonists may be preferred in order to reduce any side effects associated with the use of non-specific antagonists.
  • agonist means a compound that will stimulate the ligand-mediated transactivational activity of the specified retinoid receptor.
  • antagonist means a compound that will inhibit or block the ligand-mediated transactivational activity of the specified retinoid receptor.
  • inverse agonist means a compound that will decrease a basal level of transactivational activity of the specified retinoid receptor, wherein the basal level is that amount of transactivational activity observed in the absence of added agonist.
  • selective means that a given ligand demonstrates at least about a 10 fold greater binding affinity, as indicated by, for example, K value, (dissociation constant) for one receptor subtype than for another receptor subtype.
  • specific means that a given ligand demonstrates at least about a 500 fold greater binding affinity, and more preferably at least about a 1000 fold greater binding affinity, for a one receptor subtype than for another receptor subtype.
  • the antagonist is a compound of formula (I):
  • X is S, SO, SO 2 , O, NR,, [C(R,) 2 ] capital where each Ri is independently or together H or alkyl of 1 to 6 carbons, and n is 1 or 2; or X is absent;
  • Xi is absent and X 2 is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3 , fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons; provided that at least X is present, or Xi and X are each C; are optionally present bonds; each R 2 is independently or together hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3 , fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons, NH , NRiH, N(R 2 , N(R,)COR,, NR ⁇ CON(R,) 2 or OCOR,; each R 3 is independently or together hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br or I; m is an integer having the
  • A is (CH 2 ) q where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;
  • B is hydrogen, COOH, COOR 8 , CONR 9 R ⁇ 0 , -CH 2 OH, CH 2 ORn, CH 2 OCOR ⁇ , CHO, CH(OR [2 ) 2 , CHOR 13 O, -COR 7 , CR 7 (OR !2 ) 2 , CR 7 OR 13 O, or tri-lower alkylsilyl, where R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R 8 is an alkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or Rg is phenyl or lower alkylphenyl, R 9 and Rio independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, Rn is lower
  • R ⁇ 4 is (R ⁇ 5 ) r -phenyl, (R ⁇ 5 ) r -naphthyl, or (R ⁇ 5 ) r -heteroaryl where the heteroaryl group has 1 to 3 heteroatoms selected from the group consisting of O, S and N, r is an integer having the values of 0-6, and
  • Ris is independently H, F, Cl, Br, I, NO 2 , N(R 8 ) 2 , N(R 8 )COR 8 , NR 8 CON(R 8 ) 2 , OH, OCORs, OR 8 , CN, an alkyl group having 1 to 10 carbons, fluoro substituted alkyl group having 1 to 10 carbons, an alkenyl group having 1 to 10 carbons and 1 to 3 double bonds, alkynyl group having 1 to 10 carbons and 1 to 3 triple bonds, or a trialkylsilyl or (trialkylsilyl)oxy group where the alkyl groups independently have 1 to 6 carbons; or a pharmaceutically acceptable salt or ester thereof.
  • X is present and Xi is absent, providing compounds of formula (la):
  • X is absent and Xj and X 2 are C, providing compounds of formula (lb):
  • X is present and Xi and X are C, providing compounds of formula (Ic):
  • Y is phenyl and Rj 4 is (Ri 5 ) r -phenyl, where preferably the bond between R ⁇ 4 and the heterocyclic moiety comprising X allows for free rotation of the R ⁇ 4 group.
  • r is 1 and R i 5 is COOH.
  • the antagonist is AGN 310, whose structure is set forth below.
  • the antagonist is AGN 301, whose structure is also set forth below. Further specific antagonists within the scope of formula (I), method of synthesis as well as definitions of terminology used to define compounds of formula (I), are more fully described in U.S. 5,776,699. Structures of specific compounds, antagonists as well as agonists, referenced in this disclosure are set forth below:
  • AGN 310 is an RAR antagonist
  • AGN 301 is an RAR ⁇ selective antagonist
  • AGN 204 is an RXR agonist
  • AGN 365 is an RAR ⁇ selective agonist
  • AGN 574 is an RAR ⁇ specific antagonist
  • AGN 431 is an RAR ⁇ selective antagonist
  • AGN 078 is an RAR ⁇ specific agonist
  • AGN 153 is an RAR ⁇ selective agonist
  • AGN 168 is an RAR ⁇ selective agonist
  • AGN 109 is an RAR antagonist
  • AGN 175 is an RAR antagonist
  • AGN 299 is an RAR ⁇ selective agonist
  • AGN 183 (TTNPB) is an RAR agonist; and AGN 393 is an RXR antagonist.
  • X' is O, S, SO, S0 2 , N, NR 3 or C(R 3 ) 2 ; or -X'-R 14 is -C(R ⁇ 4 )H 2 or - C(R ⁇ 4 )-(CH 2 ) n H where n is 1-6;
  • Yi is phenyl, naphthyl or heteroaryl selected from the group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl, naphthyl and heteroaryl groups being optionally substituted with one R' 3 and one or two R 2 groups;
  • R' 3 is H, (Ci-Cio) alkyl, 1-adamantyl, 2-tetrahydropyranoxy, trialkylsilanyl and trialkylsilanyloxy where alkyl comprises 1 to 6 carbons, alkoxy and alkylthio where alkyl comprises 1 to 10 carbons, or OCH O(C[. 6 )alkyl; and Z, Y, A, B, R 2 , R 3 and R ]4 are as defined above; where preferred embodiments include compounds of formula (Ila): R 14 B
  • R' 3 is alkyl
  • X is S, SO, SO 2 , O, NR,, [C(R ⁇ ) 2 ] resort, -C(R ⁇ ) 2 -NR,-, -C(R ⁇ ) 2 -S-, -
  • any compound or agent having retinoid receptor antagonist activity may be used.
  • Means for determining antagonist activity of a given agent or compound are known in the art. For example, a holoreceptor transactivation assay and a ligand binding assay which measure the antagonist agonist like activity of the compounds of the invention, or their ability to bind to the several retinoid receptor subtypes, respectively, are described in published PCT Application No. WO 93/11755 (particularly on pages 30-33 and 37-41) published on Jun. 24, 1993, the specification of which is also incorporated herein by reference.
  • a pharmaceutically acceptable salt may be prepared for any compound in this invention having a functionality capable of forming a salt, for example an acid functionality.
  • a pharmaceutically acceptable salt is any salt which retains the activity of the parent compound and does not impart any deleterious or untoward effect on the subject to which it is administered and in the context in which it is administered.
  • Pharmaceutically acceptable salts may be derived from organic or inorganic bases.
  • the salt may be a mono or polyvalent ion.
  • the inorganic ions sodium, potassium, calcium, and magnesium.
  • Organic salts may be made with amines, particularly ammonium salts such as mono-, di- and trialkyl amines or ethanol amines. Salts may also be formed with caffeine, tromethamine and similar molecules. Where there is a nitrogen sufficiently basic as to be capable of forming acid addition salts, such may be formed with any inorganic or organic acids or alkylating agent such as methyl iodide. In such cases, preferred salts are those formed with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid. Any of a number of simple organic acids such as mono-, di- or tri-acid may also be used.
  • the compounds of the present invention may have trans and cis (E and Z) isomers.
  • the compounds of the present invention may contain one or more chiral centers and therefore may exist in enantiomeric and diastereomeric forms.
  • Still further oxime and related compounds of the present invention may exist in syn and anti isomeric forms.
  • the scope of the present invention is intended to cover all such isomers per se, as well as mixtures of cis and trans isomers, mixtures of syn and anti isomers, mixtures of diastereomers and racemic mixtures of enantiomers (optical isomers) as well.
  • compositions comprising one or more compounds of the invention together with a pharmaceutically acceptable diluent or excipient.
  • compositions are in unit dosage forms such as tablets, pills, capsules (including sustained- release or delayed-release formulations), powders, granules, elixirs, tinctures, syrups and emulsions, sterile parenteral solutions or suspensions, aerosol or liquid sprays, drops, ampoules, auto-injector devices or suppositories; for oral, parenteral (e.g., intravenous, intramuscular or subcutaneous), intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation, and may be formulated in an appropriate manner and in accordance with accepted practices such as those disclosed in Remington 's Pharmaceutical Sciences, Gennaro, Ed., Mack Publishing Co., Easton PA, 1990.
  • compositions may be in sustained-release form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection.
  • suitable topical formulations for administration to, e.g. eye or skin or mucosa.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, pharmaceutically acceptable oils, glycerol, water and the like.
  • suitable binders, lubricants, disintegrating agents, flavoring agents and coloring agents can also be incorporated into the mixture.
  • Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
  • Lubricants used in these dosage forms include, without limitation, sodium oleate, sodium stearate. magnesium stearate. sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • the active ingredient is mixed with a suitable pharmaceutical excipient. e.g., such as the ones described above, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
  • a suitable pharmaceutical excipient e.g., such as the ones described above
  • other pharmaceutical diluents e.g., water
  • the solid preformulation composition may then be subdivided into unit dosage forms of the type described above containing from 0.1 to about 50 mg of the active ingredient of the present invention.
  • the tablets or pills of the present composition may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner core containing the active compound and an outer layer as a coating surrounding the core.
  • the outer coating may be an enteric layer which serves to resist disintegration in the stomach and permits the inner core to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with conventional materials such as shellac, cetyl alcohol and cellulose acetate.
  • the liquid forms in which the present compositions may be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical carriers.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, gelatin, methylcellulose or polyvinyl-pyrrolidone. Other dispersing agents which may be employed include glycerin and the like.
  • sterile suspensions and solutions are desired. Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.
  • the compositions can also be formulated as an ophthalmic solution or suspension formation, i.e., eye drops, for ocular administration.
  • subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
  • terapéuticaally effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease being treated.
  • compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses two, three or four times daily.
  • compounds for the present invention may be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to persons skilled in the art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • the dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound employed.
  • a physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the disease or disorder which is being treated.
  • the daily dosage of retinoid receptor antagonists or reverse agonists may vary over a wide range from 0.01 to 100 mg per adult human per day.
  • the compositions are preferably provided in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0 or 50.0 mg of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • a unit dose typically contains from about 0.001 mg to about 50 mg of the active ingredient, preferably from about 1 mg to about 10 mg of active ingredient.
  • An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.0001 mg/kg to about 25 mg/kg of body weight per day.
  • the range is from about 0.001 to 10 mg/kg of body weight per day, and especially from about 0.001 mg/kg to 1 mg/kg of body weight per day.
  • the compounds may be administered on a regimen of 1 to 4 times per day.
  • PC-3 and DU145 including both serum-grown cells and cells that had been maintained in serum free conditions for 2 years. Activity was measured using a plate clonogenic assay and confirmed by analysis of the effects on bulk cultures of lines.
  • the compounds tested in the initial screens are as follows:
  • AGN 078 8 AGN 365 9: AGN 153 10: AGN 301 20
  • Data are mean +/- SE of values from the 3 separate experiments.
  • AGN 204 RAR ⁇ agonists (AGN 078, 153, 365); RAR ⁇ agonists (AGN 168,
  • RAR ⁇ AGN 310
  • RAR ⁇ AGN 301
  • the RAR ⁇ antagonist AGN 310 was observed to be growth inhibitory, whereas AGN 109 was inactive.
  • the compounds that were observed to be more active than all-trans retinoic acid against all of the three lines tested were the RAR ⁇ antagonist AGN 310 and the RAR ⁇ specific antagonist AGN 301.
  • Treatment with 100 nM of the RAR ⁇ antagonist resulted in survival of ⁇ 1% of control plates and the same dose of the RAR ⁇ -selective antagonist reduced colony formation to « 40% of control plates.
  • Significant growth inhibitory activity was only observed when these agents were tested against cells grown under serum-free conditions.
  • the RXR agonist AGN 204 showed some inhibitory activity against serum- grown and serum free-grown cells, but this was not substantially greater than that observed with all-trans retinoic acid.
  • Example 2 AGN 310 and AGN 301. together with all-trans retinoic acid, were titrated against serum free-grown LNCaP, PC-3 and DU145 cells. Two-fold (high doses) and ten-fold (low doses) dilutions of ATRA and AGN310 and AGN 301 were used to inhibit clonogenic growth of serum free grown prostate carcinoma cell lines. Data are means of values from 3 separate experiments. As observed in the initial screens, the RAR ⁇ antagonist AGN 310 was observed to be 5 to 1 Ox more active than the RAR ⁇ -specific antagonist AGN 301. Both of these compounds were more active than all-trans retinoic acid (see figure 3). IC 50 values (concentration of compound which inhibits growth by 50%)) for these three compounds against all three lines are given in the following table:
  • RAR antagonists or a component of serum interferes with the growth inhibitory activity of compounds, the activity against serum free-grown cells plated in the presence and absence of 10 and 20%) fetal calf serum was determined.
  • Experiments were undertaken using LNCaP and PC3 cells. Colony growth of LNCaP cells was moderately stimulated by plating the cells in serum conditions (up to 146%) of control serum free plated cells). Massive stimulation of PC3 colony formation was observed when these cells were plated in serum (up to 300%>).
  • Figure 8 - LNCaP cells AGN 310 and AGN 301 were tested at lOOnM for their ability to inhibit colony formation in the presence and absence of the RAR ⁇ agonist AGN 194078 and AGN 195153.
  • the agonists were used at 100 and 500 nM.
  • the data obtained from the individual agonists and at each concentration were similar and therefore pooled. Columns are: 1 (no agent); 2 (RAR ⁇ agonists alone); 3 (RAR ⁇ antagonist alone); 4 (RAR ⁇ antagonist & RAR ⁇ agonists); 5 (RAR ⁇ -s elective antagonist alone); and 6 (RAR ⁇ -selective antagonist & RAR ⁇ agonists).
  • Figure 9 - PC-3 cells AGN 310 and AGN 301 were tested at lOOnM for their ability to inhibit colony formation in the presence and absence of the RAR ⁇ agonists AGN 194078 and AGN 195153.
  • the agonists were used at 100, 200 and 500 nM.
  • Figure 10 - LNCaP cells AGN 310 was tested at lOOnM for their ability to inhibit colony formation in the presence and absence of the RAR ⁇ agonist AGN 190299.
  • Figure 1 1 - PC-3 cells: AGN 310 and AGN 301 were tested at lOOnM for their ability to inhibit colony formation in the presence and absence of the RAR ⁇ agonist AGN 190299.
  • HL60 cells express RAR ⁇ and treatment with 100 nM ATRA gave rise to 80%> neutrophils (displaying stimulated NBT reduction) within 5 days.
  • AGN194310 a pan-antagonist of RARs
  • AGN194301 an antagonist of RAR ⁇
  • Flask cultures of LACaP (serum free) cells were seeded. Then treated with 1 ⁇ M AGN 194310 or left untreated. Cells were harvested daily from the flasks, trypsinized, and polled with cells in suspension. The effect of AGN 194310 was determined as a percentage of the cells present in untreated flasks; treatment of cells with AGN 194310 resulted in an 80 ⁇ 1 1 % reduction in cell number by day 3, as compared with untreated cell cultures.
  • IGF- 1 insulin-like growth factor- 1
  • LNCaP ITS+ cells were grown and exposed to the long R3 form of IGF- I at 2-fold dilutions between 0.1 and 100 ng/ml.
  • IGF-1 did not block the inhibition of colony formation in the plate assay when LNCaP ITS + cells were also treated with 100 nM of AGN194310.
  • IGF-1 activity was verified by transferring FBS-grown cells of the breast carcinoma line MCF-7 to 10%o charcoal stripped serum. Transfer of flask cultures of these cells to charcoal stripped serum and the addition of 100 ng/ml of IGF- 1 caused an increase in viable cell numbers to 164 ⁇ 27 % of the number of cells present in control cultures grown in charcoal stripped serum in the absence of agent.
  • IGF-1 stimulated the growth of LNCaP cells to a smaller extent; viable cell numbers were increased to 123 ⁇ 5 %.
  • the RAR pan-antagonist AGN 194310 was tested against primary prostate carcinoma cells.
  • Bulk cell cultures were taken from core biopsies of two patients suffering from prostate cancer. Cultures were established using a commercially available serum-free medium; cells were verified as being epithelial in nature and contained few contaminating fibroblasts-like cells. These cultures were treated on day 0 with either 10 nM or 100 nM AGN 194310, lOnM or 100 nM ATRA, or vehicle alone. Flask cultures of primary carcinoma cells were tested, at passages 2, for their sensitivities to 10 and 100 nM of the pan-antagonist of RARs AGN 194310 and of ATRA together with appropriate vehicle controls. Cell growth in vehicle treated cultures was similar to that observed in untreated cultures.

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  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract

La présente invention concerne des méthodes de traitement du cancer de la prostate consistant à administrer une dose thérapeutiquement efficace d'un antagoniste de récepteurs de rétinoïdes. Par ailleurs, la présente invention concerne des méthodes destinées à inhiber le développement d'une cellule cancéreuse ou tumeur de la prostate, cette méthode consistant à faire réagir ladite cellule ou tumeur au contact d'une dose efficace d'un antagoniste de récepteurs de rétinoïdes.
PCT/US2000/019849 1999-07-23 2000-07-21 Utilisation d'antagonistes de recepteurs de retinoides dans le traitement du cancer de la prostate WO2001007028A2 (fr)

Priority Applications (1)

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AU62280/00A AU6228000A (en) 1999-07-23 2000-07-21 The use of retinoid receptor antagonists in the treatment of prostate carcinoma

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US14528799P 1999-07-23 1999-07-23
US60/145,287 1999-07-23

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US10363272B2 (en) 2017-08-31 2019-07-30 Io Therapeutics, Inc. RAR selective agonists in combination with immune modulators for cancer immunotherapy
US10588881B2 (en) 2015-10-31 2020-03-17 Io Therapeutics, Inc. Treatment of nervous system disorders using combinations of RXR agonists and thyroid hormones
US10647661B2 (en) 2017-07-11 2020-05-12 Vertex Pharmaceuticals Incorporated Carboxamides as modulators of sodium channels
US10835507B2 (en) 2016-03-10 2020-11-17 Io Therapeutics, Inc. Treatment of muscular disorders with combinations of RXR agonists and thyroid hormones
US10940127B2 (en) 2015-11-25 2021-03-09 Io Therapeutics, Inc. Use of CYP26-resistant RAR alpha selective agonists in the treatment of cancer
US10946001B2 (en) 2016-03-10 2021-03-16 Io Therapeutics, Inc. Treatment of autoimmune diseases with combinations of RXR agonists and thyroid hormones
US10945976B2 (en) 2011-12-13 2021-03-16 Io Therapeutics, Inc. Autoimmune disorder treatment using RXR agonists
US10966950B2 (en) 2019-06-11 2021-04-06 Io Therapeutics, Inc. Use of an RXR agonist in treating HER2+ cancers
US11517549B2 (en) 2017-09-20 2022-12-06 Io Therapeutics, Inc. Treatment of disease with esters of selective RXR agonists
US11896558B2 (en) 2021-12-07 2024-02-13 Io Therapeutics, Inc. Use of an RXR agonist and taxanes in treating Her2+ cancers

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US9717702B2 (en) 2005-09-30 2017-08-01 Io Therapeutics, Inc. Treatment of cancer with specific RXR agonists
US10973788B2 (en) 2005-09-30 2021-04-13 Io Therapeutics, Inc. Treatment of cancer with specific RXR agonists
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US8101662B2 (en) * 2005-09-30 2012-01-24 Io Therapeutics, Inc. Treatment of cancer with specific RXR agonists
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US11166927B2 (en) 2011-12-13 2021-11-09 Io Therapeutics, Inc. Autoimmune disorder treatment using RXR agonists
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US11246845B2 (en) 2011-12-13 2022-02-15 Io Therapeutics, Inc. Autoimmune disorder treatment using RXR agonists
US11576881B2 (en) 2011-12-13 2023-02-14 Io Therapeutics, Inc. Autoimmune disorder treatment using RXR agonists
US11547684B2 (en) 2011-12-13 2023-01-10 Io Therapeutics, Inc. Autoimmune disorder treatment using RXR agonists
US10945976B2 (en) 2011-12-13 2021-03-16 Io Therapeutics, Inc. Autoimmune disorder treatment using RXR agonists
US10588881B2 (en) 2015-10-31 2020-03-17 Io Therapeutics, Inc. Treatment of nervous system disorders using combinations of RXR agonists and thyroid hormones
US10980759B2 (en) 2015-10-31 2021-04-20 Io Therapeutics, Inc. Treatment of nervous system disorders using combinations of RXR agonists and thyroid hormones
US10980760B2 (en) 2015-10-31 2021-04-20 Io Therapeutics, Inc. Treatment of nervous system disorders using combinations of RXR agonists and thyroid hormones
US10695312B2 (en) 2015-10-31 2020-06-30 Io Therapeutics, Inc. Treatment of nervous system disorders using combinations of RXR agonists and thyroid hormones
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