WO2012128653A1 - Utilisation d'anastrozole et d'analogue de vitamine d dans polythérapie contre le cancer du sein - Google Patents

Utilisation d'anastrozole et d'analogue de vitamine d dans polythérapie contre le cancer du sein Download PDF

Info

Publication number
WO2012128653A1
WO2012128653A1 PCT/PL2012/000012 PL2012000012W WO2012128653A1 WO 2012128653 A1 WO2012128653 A1 WO 2012128653A1 PL 2012000012 W PL2012000012 W PL 2012000012W WO 2012128653 A1 WO2012128653 A1 WO 2012128653A1
Authority
WO
WIPO (PCT)
Prior art keywords
vitamin
anastrozole
analogues
analogue
pri
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/PL2012/000012
Other languages
English (en)
Inventor
Joanna Wietrzyk
Beata FILIP-PSURSKA
Andrzej Kutner
Michał CHODYŃSKI
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Instytut Farmaceutiyczny
Original Assignee
Instytut Farmaceutiyczny
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Instytut Farmaceutiyczny filed Critical Instytut Farmaceutiyczny
Publication of WO2012128653A1 publication Critical patent/WO2012128653A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention belongs to the field of breast cancer treatment. Specifically, the invention relates to the use of anastozole and vitamin D analogues in the combined therapy of breast cancer.
  • Anastrozole is the selective, competitive, non-steroidal aromatase inhibitor of the new generation. This drug is used only in advanced breast cancer therapy of postmenopausal women. However, anastrozole based therapy becomes effective, if the cancer cells are characterized by the presence of estrogen and/or progestagen receptors on the membrane sites. Anastrozole is the only aromatase inhibitor approved for adjuvant cancer therapy of estrogen and/or progestagen receptor positive postmenopausal patients.
  • vitamin D cholecalciferol
  • active metabolites and cholecalciferol (vitamin D) analogues influence the calcium-phosphate balance and are used in treatment of meta- bolic diseases and skeleton system disease, especially osteoporosis.
  • vitamin D la,25-dihydroxycholecalciferol
  • its synthetic analogues show antiproliferative action and beneficially influence differentiation of cancer cells and epidermal keratinocytes.
  • cholecalciferol analogues are used in treatment of hyperproliferative diseases, especially skin diseases such as some forms of plaque psoriasis, ichtiosis and keratosis (Beckman M.J., DeLuca H.F., Modern view of vitamin D 3 and its medicinal uses, w: Ellis GP, Luscombe DK, Oxford AW, ed., Progress in Medicinal Chemistry, t.35, Amsterdam, Elsevier Science Publishers, 1998, p.1-56; Vitamin D, 1. 1, ed. II, edited by D. Feldman, Amsterdam, Elsevier Science Publishers, 2005).
  • tacalcitol a natural calcitriol metabolite known under generic name tacalcitol (Peters D.C., Balfour J.A., Tacalcitol., Drugs 1997; 54:265-271). Contrary to other members of vitamin D ana- logues group, tacalcitol does not show calcium side effects, therefore it may be administered in other diseases in higher doses than in dermatology and moreover, it qualifies to general administration.
  • tacalcitol showed also a beneficial effect in vitro and in vivo on differentiation and inhibition of proliferation of some lines of human cancer cells.
  • activity of tacalcitol is statistically significantly higher than activity of its C-24 diastereomer (la,24(S)-dihydroxy cholecalciferol) and natural calcitriol.
  • Calcipotriol (lS,3R,5Z,7E,22E,24S)-24-cyclopropyl-9,10-secochola- 5,7,10(19),22-tetraeno-l,3,24-triol (M.J. Calverley, Tetrahedron 43, 4609 (1987)), also exerts a beneficial effect on inhibition of excessive proliferation of epidermal keratinocites (F.A.C.M. Castelijins i wsp. Acta Derm. Venereol. 79, 111 (1999)). Studies carried out in rats showed that it exerts 100-200-fold lesser influence on calcium metabolism than calcitriol (L. Binderup, E. Bramm, Biochem. Pharmacol. 37, 889 (1988)).
  • vitamin D analogues specifically tacalcitol and 5,6-trans isomer of calcipotriol
  • aromatase inhibitor anastrozole might result in unexpected, synergistic antiproliferative effect. Therefore, the combination of vitamin D analogues with anastrozole may be very effective, when applied in combined therapy of breast cancer.
  • the present invention relates to the use of anastozole and vitamin D analogues in the combined therapy of breast cancer.
  • the present invention is based on in vitro findings, that vitamin D analogues potentiate antiproliferative activity of aromatase inhibitors towards selected breast cancer cell lines. This is the prove of synergistic activity of selected vitamin D analogues and anastrozole against cancer cells.
  • MCF-7 and SKBR-3 cell lines were used to study in vitro the influence of compositions of therapeutic mixture on cell cycle phases and apoptosis. According to obtained results, cancer cells exposed to individual vitamin D analogue increased their number in G0/G1 phase, whereas combination of vitamin D analogue and anastrozole resulted in decrease of the cell number in G0/G1 phase. For MCF-7 and T47D apoptotic cell lines, the increase in cell number was noticed in comparison with anastrozole itself. When SKBR-3 cells were treated either with anastrozole alone or in combination with vitamin D analogue, increased number of cells in G2/M phase was observed.
  • vitamin D analogues such as, tacalcitol and 5,6-trans isomer of calcipotriol show similar efficacy towards inhibition of tumor growth, when used in a combined therapy.
  • 5,6-trans isomer longer survival time of mice was also noticed.
  • the toxicity of the combined therapy is not the limiting factor of the potential possibility to administer this anticancer combined therapy to humans, according to the present invention.
  • Body mass of mice treated with anastrozole in combination with vitamin D analogues does not differ significantly in comparison with weight of mice treated with anastrozole alone. In some cases the decrease of body mass was noticed, when mice were administered anastrozole in combination with tacalcitol. This fact is related to much higher activity of tacalcitol on calcium metabolism in comparison with that of calcipotriol 5,6-trans isomer.
  • vitamin D analogue is mentioned hereinafter it is to be understood as comprising two major forms thereof, ie. vitamin D 2 or ergocalciferol, and vitamin D 3 or cholecalciferol, known collectively as calciferol.
  • the structural difference between vitamin D 2 and vitamin D 3 is in their side chains.
  • the side chain of D 2 contains a double bond between carbons 22 and 23, and a methyl group on carbon 24, while vitamin D 3 has several forms, namely cholecalciferol which is an inactive, unhydroxylated form of vitamin D 3 , calcifediol (25 -hydroxy vitamin D 3 , 25(OH)D, and calcitriol (1,25-dihydroxy vitamin D 3 ), as well their semisynthetic analogues mentione above.
  • vitamin D analogues are selected from a group comprising tacalcitol, calcipotriol and 5,6-trans-isomer of calcipotriol, ie. 1 S,3R,5E,7E,22E,24S)-24- cyclopropyl-9, 10-secochola-5 ,7,10(19),22-tetraen- 1 ,3 ,24-triol.
  • Use in particular includes administration of combination of vitamin D analogue and anastrozole to inhibit growth of tumor, which is characterized by the expression of estrogen receptor, analogously to MCF 7 line cells
  • compositions may be administered to the patient as a pharmaceutical formulation in a fixed dosage form comprising the therapeutically effective amounts of the active substances in combination with pharmaceutically acceptable carriers and/or excipients.
  • compositions beside the active substance, may contain known pharmaceutically acceptable carriers and/or excipients appropriate for a given pharmaceutical form, not having their own pharmacological action and adverse reactions with the active substance.
  • Therapeutically effective dose of the active substance in treatment of and/or f prevention from cancer may be established by a clinician, based on clinical trials and adjusted to the medical condition, age, body weight of the patient and the risk of methastasis as well as the route of administration and individual response to therapy.
  • the daily dose may be administered to the patient as a single unit dose once daily or divided into several daily doses in determined time intervals.
  • the effective daily dose of vitamin D analogue for adult human may very from 0,1 to 200 ⁇ g, preferably from 0,5 to 50 ⁇ g.
  • Effective daily dose of anastrozole is 1 mg, administered once daily.
  • the pharmaceutical combination according to the present invention may be formulated in the pharmaceutical form acceptable for systemic administration, for example orally, such as tablets, capsules, film-coated tablets, enteric coated tablets; in the form acceptable for parenteral use, such as solutions, suspensions or lyophilisate for reconstitution ex tempore; or in the form for local administration.
  • the selection and amount of carriers and excipients depends on the form and route of administration of the agent.
  • the appropriate drug form may be formulated with use of techniques well known to those skilled in the art, using any pharmaceutically carriers, solvents, fillers and other excipients.
  • a pharmaceutical preparation for oral administration may specially be in the form of capsules.
  • the active substance is combined with a carrier and gelatin capsules are filled with the obtained composition.
  • Capsule filling is in the form of oil solution, suspension or emulsion.
  • Appropriate carriers include, for example castor, coconut, olive, palm, corn, peanut oil, synthetic and natural triglycerides of fatty acids, unsaturated medium-chain fatty acids, modified long- chain fatty acids, glycol esters, polyethylene glycols and others.
  • Appropriate excipients are tensides, for example lecithine, mono- and diglycerides and esters of polyoxyethylenesorbitan.
  • Capsules may be soft and hard gelatin capsules, differing by composition of gelatin shell for its preparation.
  • Gelatin shell in case of soft capsules include plastisizers, such as glycerol, sorbitol; preservatives, such as benzoic acid and its salts, alkyl hydroxybenzoates; colourants and flavourings.
  • composition for parenteral administration may be in the form of suspension ready to use, lyophilisate form for reconstitution ex tempore or a concentrate for preparation of intravenous infusions.
  • Carriers appropriate for intravenous pharmaceutical formulations include, for example, sterile aqueous solutions, such as saline solution, carbohydrate solution, for example glucose, mannitol, dextrose lactose and aqueous solutions of buffers, for example phosphate buffer.
  • the agent may contain other excipients, conventionally used in order to ensure osmolarity, antioxidants, preservatives and others.
  • the cells of MCF-7 human breast cancer, SKBR-3, and T47D lines were exposed to vitamin D analogues: PRI-2191, PRI-2205 and calcitriol as the reference, for 120 h.
  • the cells suspended in culture medium 10 5 cells/ml were seeded, each 10 4 cells in 100 ⁇ into single wells.
  • To control cells culture medium 100 ⁇ /well was added, tested compounds in medium of appropriate concentration were added to the other wells.
  • the final concentration of vitamin D analogues was 100 nM (or 10 nM for T47D cell line) in 200 ⁇ /well. Each experiment was repeated 3-4 times.
  • SRB assay was performed [Skehan et al., J. Natl. Cancer Inst., 82:1107- 1112, 1990], according to which inhibition of target cells proliferation was determined, after 120 h incubation.
  • vitamin D analogues The influence of vitamin D analogues on anastrozole antiproliferative activity towards human breast cancers cells studies in vitro The influence of vitamin D analogue: PRI-2191 and PRI-2205 on anastrozole antiproliferative activity was studied in vitro.
  • %H 100-[(100 - %cyt) * (100 - %wit)] /100
  • Fig.l. Inhibition of proliferation of human breast cancer cells after 120 h incubation with calcitriol, PRI-2191 or PRI-2205 in combination with anastrozole
  • the following assay was performed to estimate the influence of combination of vitamin D analogue and anastrozole on cell cycle phases and cancer cell apoptosis.
  • the cells were suspended in culture medium 10 x 10 5 cells/ml, the cell monolayer was generated by seeding 1 ml of the suspension into single wells of a 24-well flat bottom plate (Corning, NY, USA). After 24 h incubation, tested compounds in culture medium or 0,01% ethanol as the control were added to each well (1 ml/well). The stocks of tested compounds and ethanol were prepared at four times higher concentrations then the final concentrations reached in the wells.
  • vitamin D analogues and calcitriol were added at 100 nM or 10 nM final concentration (for T4TD cell line, Fig. 4).
  • vitamin D analogues and calcitriol were added at 100 nM or 10 nM final concentration (for T4TD cell line, Fig. 4).
  • anastrozole in culture medium at 100 ⁇ g/ml final concentration was added.
  • the cells were incubated with tested compounds for 120 h. The experiment was repeated 4-5 times.
  • the cells were incubated with tested compounds in a 24-well format (Sarstedt). 1 ml of the cell suspension in culture medium, 2,5x10 4 cell/ml (T47D) and 0,5x10 5 cell/ml (MCF-7, SKBR-3), was transferred into each well. To the wells, 500 ⁇ of vitamin solution at following concentrations: 10 nM (T47D cells) and 100 nM (MCF-7, SKBR-3 cells), as well as 500 ⁇ of anastrozole solution at 0,1 mg/ml concentration were added.
  • PBS phosphate- buffered saline
  • the cells (5 x 10 5 ) were suspended in 1 ml of ice cold 70% ethanol and they were frozen at -18°C for at least 24 h. They were suspended in PBS, centrifugated to remove ethanol (4°C, 10 min., 2000 rpm), transferred into FACS tubes and centrifuged (4°C, 5 min., 2000 rpm). The cell pellet was resuspended in R Ase buffer (5 x 10 2 cells in 500 ⁇ of RNAse solution). After incubation with RNAse buffer at 37°C for 60 min. each cell sample was treated with 50 ⁇ (50 mg/ml) of propidium iodide and incubated at 4°C for 30 min. The cells prepared according to the described protocol were subject to analysis.
  • Fig. 2 Interaction of vitamin D analogues PRI-2191 and PRI-2205 with anastrozole. The influence of combination of the compounds on cell cycle phases and apoptosis of MCF-7 human breast cancer cells. Results are represented as mean values of the results obtained in four repetitions of experiments.
  • Fig. 3 Interaction of vitamin D analogues PRI-2191 and PRI-2205 with anastrozole. The influence of combination of the compounds on cell cycle phases and apoptosis of SKBR-3 human breast cancer cells. Results are represented as mean values of the results obtained in fife repetitions of experiments.
  • Fig. 4 Interaction of vitamin D analogues PRI-2191 and PRI-2205 with anastrozole. The influence of combination of the compounds on cell cycle phases and apoptosis of T47D human breast cancer cells. Results are represented as mean values
  • vitamin D analogues enhance beneficial antineoplastic activity of anastrozole, therefore application of these compounds in combined therapy of breast cancer is reasonable.
  • mice in experimental groups control - 6; PRI-2191 - 6; PRI- 2205 - 6; anastrozole (An) - 7; An + PRI-2191 - 7; An + PRI-2205 - 7.
  • Anastrozole dosage 20( ⁇ g/kg/day, subcutaneously, every day (days 5-28 and day 31, 38).
  • PRI-2191 dosage 1 mg/kg/day, subcutaneously, once every two weeks, multiple administration, 3x a week (days: 10, 12, 14, 17, 19, 21, 24, 26, 28, 31,
  • PRI-2205 dosage 10 mg/kg/day, subcutaneously, once every two weeks, multiple administration, 3x a week (days: 10, 12, 14, 17, 19, 21, 24, 26, 28, 31 , 33, 35, 38, 40, 42, 45, 47).
  • FIG. 5 Masses of MCF-7 breast cancertumors in mice, treated with combination of anastrozole (200 ⁇ g/kg/day) and vitamin D analogues.
  • TGI 100-[(average mass of tumor in a treated group/average mass of tumor in a control) x 100)
  • %H 100-[(100-TGI An) x (100-TGI vit. D analogue)/! 00] Fig. 7.
  • body mass changes of mice with MCF-7 breast cancer (cancer cells were inoculated subcutaneously), treated with anastrozole (200 ⁇ g/kg/day, administered subcutaneously) in combination with vitamin D analogues administered subcutaneously 3x a week (PRI-2191: 1 mg/kg/day, PRI-2205: 10 mg/kg/day).
  • Anastrozole in combination with PRI-2191 analogue decreases MCF-7 tumor masses at statistically significant level, when comparing with the control group, starting measuring from day 19 to 42.
  • combination of anastrozole with PRI-2205 analogue causes statistically significant reduction of tumor growth in comparison with control, beginning from day 10 to last day of tumor size measurements, until day 47.
  • the PRI-2205 analogue used alone considerably inhibits tumor growth. In comparison with the control group, significant tumor growth inhibition was observed on days: 19, 21, 26, 28 and from day 35 to the last day of experiment.
  • Analogue PRI-2191 when used alone causes the decrease of MCF-7 tumor growth, but statistically relevant inhibition was observed on days: 10, 19, 24, 35, 38, and 42.
  • composition of capsule content is a composition of capsule content
  • Citric acid 0,01680 mg
  • the weighed amount of oil (about 80% of the total) was mixed for 15 minutes in nitrogen atmosphere.
  • the active substance dissolved in anhydrous ethanol with BHA and citric acid was added. It was stirred for 20 minutes in nitrogen atmosphere to the complete dissolution of ethanol phase in the oil phase, then the remaining part of the oil was added and stirred for 15 minutes.
  • Gelatin shell was prepared of the following composition:
  • the ingredients were dissolved in hot water, degassed, stirred for 30 minutes at the temperature of 65°C.
  • the whole together with the filling was transferred to capsulating apparatus, where at the temperature of about 60°C, it was dropped to paraffin cooled to about 0°C.
  • the capsules were then rinsed with tetrachloroethyelene and dried for 48 hours at the temperature of about 30°C.
  • Mean mass of a single capsule was 0.1275 g ⁇ 10%.
  • Mean mass of filling of the single capsule was about 0.080 g ⁇ 10%.
  • Capsules were packed to orange glass jars and closed with polyethylene stoppers.

Landscapes

  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne l'utilisation d'anastrozole et d'analogues de la vitamine D en polythérapie contre le cancer du sein. Les analogues de la vitamine D sont choisis dans un groupe comprenant le calcipotriol, le tacalcitol et le (1S,3R,5E,7E,22E,24S)-24-cyclopropyl-9,10-secochola- 5,7,10(19),22-tetraèn-l,3,24-triol (isomère 5,6-trans de calcipotriol).
PCT/PL2012/000012 2011-03-18 2012-03-16 Utilisation d'anastrozole et d'analogue de vitamine d dans polythérapie contre le cancer du sein Ceased WO2012128653A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PLPL394258 2011-03-18
PL394258A PL394258A1 (pl) 2011-03-18 2011-03-18 Terapia skojarzona nowotworów gruczolu sutkowego

Publications (1)

Publication Number Publication Date
WO2012128653A1 true WO2012128653A1 (fr) 2012-09-27

Family

ID=46045055

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/PL2012/000012 Ceased WO2012128653A1 (fr) 2011-03-18 2012-03-16 Utilisation d'anastrozole et d'analogue de vitamine d dans polythérapie contre le cancer du sein

Country Status (2)

Country Link
PL (1) PL394258A1 (fr)
WO (1) WO2012128653A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PL339112A1 (en) 2000-03-21 2001-09-24 Inst Farmaceutyczny Pharmacological agent exhibiting aniticarcinogenic effect, application of 1,25-diydoxycholecalcipherol analoques and method of treating neoplasms
PL378586A1 (pl) 2005-12-29 2007-07-09 Instytut Farmaceutyczny Zastosowanie analogów kalcypotriolu w leczeniu chorób nowotworowych
WO2009137104A1 (fr) * 2008-05-09 2009-11-12 Radius Health, Inc. Traitement combiné contre le cancer du sein comprenant un agent antioestrogène
WO2010143986A1 (fr) * 2009-06-10 2010-12-16 Instytut Farmaceutyczny Thérapie combinée du cancer colorectal

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PL339112A1 (en) 2000-03-21 2001-09-24 Inst Farmaceutyczny Pharmacological agent exhibiting aniticarcinogenic effect, application of 1,25-diydoxycholecalcipherol analoques and method of treating neoplasms
PL378586A1 (pl) 2005-12-29 2007-07-09 Instytut Farmaceutyczny Zastosowanie analogów kalcypotriolu w leczeniu chorób nowotworowych
WO2009137104A1 (fr) * 2008-05-09 2009-11-12 Radius Health, Inc. Traitement combiné contre le cancer du sein comprenant un agent antioestrogène
WO2010143986A1 (fr) * 2009-06-10 2010-12-16 Instytut Farmaceutyczny Thérapie combinée du cancer colorectal

Non-Patent Citations (14)

* Cited by examiner, † Cited by third party
Title
"F.A.C.M. Castelijins i wsp.", ACTA DERM. VENEREOL., vol. 79, 1999, pages 111
A. OPOLSKI: "Biological activity in vitro of side-chain modified analogues of calcitriol", CURRENT PHARMACEUTICAL DESIGN, vol. 6, 2000, pages 755 - 765
ANTICANCER RESEARCH 2006 JUL-AUG LNKD- PUBMED:16886680, vol. 26, no. 4A, July 2006 (2006-07-01), pages 2701 - 2705, ISSN: 0250-7005 *
BECKMAN M.J.; DELUCA H.F.: "Progress in Medicinal Chemistry", 1998, ELSEVIER SCIENCE PUBLISHERS, article "Modem view of vitamin D3 and its medicinal uses", pages: 1 - 56
D. FELDMAN: "Vitamin D", 2005, ELSEVIER SCIENCE PUBLISHERS
DATABASE MEDLINE [online] US NATIONAL LIBRARY OF MEDICINE (NLM), BETHESDA, MD, US; July 2006 (2006-07-01), PELCZYNSKA MARZENA ET AL: "Antiproliferative activity of vitamin D compounds in combination with cytostatics.", XP009161120, Database accession no. NLM16886680 *
FILIP B ET AL: "Antitumor properties of (5E,7E) analogs of vitamin D3", JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY, ELSEVIER SCIENCE LTD., OXFORD, GB, vol. 121, no. 1-2, 1 July 2010 (2010-07-01), pages 399 - 402, XP027142251, ISSN: 0960-0760, [retrieved on 20100701] *
J. WIETRZYK: "The antitumor effect of lowered doses of cytostatics combined with new analogs of vitamin D in mice", ANTICANCER RES., vol. 27, 2007, pages 3387 - 98, XP055061481
J. WIETRZYK: "Toxicity and antineoplastic effect of (24R)-1,24-dihydroxyvitamin D3 (PRI-2191", STEROIDS, vol. 69/10, 2004, pages 629 - 635, XP004588996, DOI: doi:10.1016/j.steroids.2004.05.015
L. BINDERUP; E. BRAMM, BIOCHEM. PHARMACOL., vol. 37, 1988, pages 889
M.J. CALVERLEY, TETRAHEDRON, vol. 43, 1987, pages 4609
PETERS D.C.; BALFOUR J.A.; TACALCITOL., DRUGS, vol. 54, 1997, pages 265 - 271
PETERS G.J. I WSP., PHARMACOL THER, vol. 87, 2000, pages 227 - 253
SKEHAN ET AL., J. NATL. CANCER INST., vol. 82, 1990, pages 1107 - 1112

Also Published As

Publication number Publication date
PL394258A1 (pl) 2012-09-24

Similar Documents

Publication Publication Date Title
JP5762390B2 (ja) 乳癌の治療に使用されるアロマターゼ阻害薬による副作用の低減
AU2002322346B2 (en) Method of treating hyperproliferative diseases using active vitamin D analogues
KR100849919B1 (ko) 에스트로겐 대체 요법으로 치료중인 여성의 호르몬결핍증을 치료하기 위한 에스트로겐 및 안드로겐의 조합
KR20040061000A (ko) 활성 비타민 ｄ 유사체를 사용하는 과다증식성 질환의 치료
KR20090060306A (ko) 비타민 ｄ 화합물 및 추가 치료제, 및 그를 함유하는 조성물을 투여하는 것을 포함하는, 암을 치료하는 방법
US20060003950A1 (en) Method of treating prostatic diseases using a combination of vitamin D analogues and other agents
CN109803647A (zh) α-丁酮酸、α-酮戊二酸和2-羟基丁酸用于刺激毛发生长
CA2762458C (fr) Nouvelles utilisations therapeutiques de l'inecalcitol
JP2004535439A (ja) 活性なビタミンｄ類縁体を使用する悪性関連高カルシウム血症の治療方法
ES2398640T3 (es) Formulaciones de análogos 14-epi de la vitamina D
US20120101057A1 (en) Combined therapy of colorectal carcinoma
ES2399328T3 (es) Uso de 2-metilen-19-nor-20(S)-1a,25-dihidroxivitamina D3 para la profilaxis de enfermedades óseas
CN112386601B (zh) 维生素d补充制剂及其应用
CN100386083C (zh) 用维生素d类化合物制备治疗骨髓发育不良综合症药物的方法
CN113577051A (zh) 一种维拉帕米在制备保护软骨细胞缓解骨关节炎的产品中的应用
WO2012128653A1 (fr) Utilisation d'anastrozole et d'analogue de vitamine d dans polythérapie contre le cancer du sein
UA110211C2 (uk) Нові склади 14-eпi-аналогів вітаміну d
JPH1112175A (ja) 白血病治療剤
HK40127583A (zh) 用於治疗多囊卵巢综合征的组合物
US20080293647A1 (en) Combined Use Of Vitamin D Derivatives And Anti-Proliferative Agents For Treating Bladder Cancer
UA112845C2 (uk) Склад 14-eпi-аналогів вітаміну d
RU2575819C2 (ru) Новые составы 14-эпи-аналогов витамина d
RU2575792C2 (ru) Составы 14-эпи-аналогов витамина d
HK40008352A (en) Alpha-ketobutyrate, alpha-ketoglutarate, and 2-hydroxybutyrate for stimulating hair growth

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12719471

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 12719471

Country of ref document: EP

Kind code of ref document: A1