US20040006045A1 - Methods for the treatment or prophylaxis of disease by inhibition of ornithine decarboxylase - Google Patents
Methods for the treatment or prophylaxis of disease by inhibition of ornithine decarboxylase Download PDFInfo
- Publication number
- US20040006045A1 US20040006045A1 US10/614,713 US61471303A US2004006045A1 US 20040006045 A1 US20040006045 A1 US 20040006045A1 US 61471303 A US61471303 A US 61471303A US 2004006045 A1 US2004006045 A1 US 2004006045A1
- Authority
- US
- United States
- Prior art keywords
- dfmo
- chitosan
- cancer
- disease
- inhibition
- 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.)
- Abandoned
Links
- 238000000034 method Methods 0.000 title claims abstract description 13
- 230000005764 inhibitory process Effects 0.000 title claims abstract description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract description 8
- 201000010099 disease Diseases 0.000 title claims abstract description 7
- 102000052812 Ornithine decarboxylases Human genes 0.000 title claims abstract description 5
- 108700005126 Ornithine decarboxylases Proteins 0.000 title claims abstract description 5
- 238000011282 treatment Methods 0.000 title claims description 8
- 238000011321 prophylaxis Methods 0.000 title 1
- 150000003839 salts Chemical class 0.000 claims description 25
- 206010028980 Neoplasm Diseases 0.000 claims description 24
- 229920001661 Chitosan Polymers 0.000 claims description 23
- 201000011510 cancer Diseases 0.000 claims description 17
- 102000004031 Carboxy-Lyases Human genes 0.000 claims description 10
- 108090000489 Carboxy-Lyases Proteins 0.000 claims description 10
- VLCYCQAOQCDTCN-UHFFFAOYSA-N eflornithine Chemical compound NCCCC(N)(C(F)F)C(O)=O VLCYCQAOQCDTCN-UHFFFAOYSA-N 0.000 claims description 10
- 230000002265 prevention Effects 0.000 claims description 9
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 claims description 6
- 208000004403 Prostatic Hyperplasia Diseases 0.000 claims description 6
- 230000003779 hair growth Effects 0.000 claims description 6
- 230000002401 inhibitory effect Effects 0.000 claims description 4
- 206010020112 Hirsutism Diseases 0.000 claims description 3
- 208000009621 actinic keratosis Diseases 0.000 claims description 3
- 208000015181 infectious disease Diseases 0.000 claims 1
- 229920000768 polyamine Polymers 0.000 description 17
- 241001465754 Metazoa Species 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 208000005623 Carcinogenesis Diseases 0.000 description 6
- 230000036952 cancer formation Effects 0.000 description 6
- 231100000504 carcinogenesis Toxicity 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 239000003112 inhibitor Substances 0.000 description 6
- 230000002113 chemopreventative effect Effects 0.000 description 5
- 239000006071 cream Substances 0.000 description 5
- 208000029742 colonic neoplasm Diseases 0.000 description 4
- 230000001815 facial effect Effects 0.000 description 4
- 230000012010 growth Effects 0.000 description 4
- 230000007794 irritation Effects 0.000 description 4
- 230000004060 metabolic process Effects 0.000 description 4
- KIDHWZJUCRJVML-UHFFFAOYSA-N putrescine Chemical compound NCCCCN KIDHWZJUCRJVML-UHFFFAOYSA-N 0.000 description 4
- ATHGHQPFGPMSJY-UHFFFAOYSA-N spermidine Chemical compound NCCCCNCCCN ATHGHQPFGPMSJY-UHFFFAOYSA-N 0.000 description 4
- 206010006187 Breast cancer Diseases 0.000 description 3
- 208000026310 Breast neoplasm Diseases 0.000 description 3
- 206010008263 Cervical dysplasia Diseases 0.000 description 3
- 206010009944 Colon cancer Diseases 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 230000010261 cell growth Effects 0.000 description 3
- 230000004663 cell proliferation Effects 0.000 description 3
- 208000007951 cervical intraepithelial neoplasia Diseases 0.000 description 3
- 210000001072 colon Anatomy 0.000 description 3
- 210000000245 forearm Anatomy 0.000 description 3
- 239000013038 irreversible inhibitor Substances 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 210000003491 skin Anatomy 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- VLCYCQAOQCDTCN-ZCFIWIBFSA-N α-difluoromethylornithine Chemical compound NCCC[C@@](N)(C(F)F)C(O)=O VLCYCQAOQCDTCN-ZCFIWIBFSA-N 0.000 description 3
- 206010008342 Cervix carcinoma Diseases 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 239000005700 Putrescine Substances 0.000 description 2
- 208000000453 Skin Neoplasms Diseases 0.000 description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 244000309464 bull Species 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 201000010881 cervical cancer Diseases 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 230000004734 cutaneous carcinogenesis Effects 0.000 description 2
- 210000004209 hair Anatomy 0.000 description 2
- 210000003780 hair follicle Anatomy 0.000 description 2
- 208000014081 polyp of colon Diseases 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 201000000849 skin cancer Diseases 0.000 description 2
- 229940063673 spermidine Drugs 0.000 description 2
- PFNFFQXMRSDOHW-UHFFFAOYSA-N spermine Chemical compound NCCCNCCCCNCCCN PFNFFQXMRSDOHW-UHFFFAOYSA-N 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 208000035984 Colonic Polyps Diseases 0.000 description 1
- 230000006820 DNA synthesis Effects 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- ZRKWMRDKSOPRRS-UHFFFAOYSA-N N-Methyl-N-nitrosourea Chemical compound O=NN(C)C(N)=O ZRKWMRDKSOPRRS-UHFFFAOYSA-N 0.000 description 1
- 101150100692 ODC gene Proteins 0.000 description 1
- 229940122060 Ornithine decarboxylase inhibitor Drugs 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 1
- 108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 230000006819 RNA synthesis Effects 0.000 description 1
- 108700005075 Regulator Genes Proteins 0.000 description 1
- 230000035508 accumulation Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 231100000360 alopecia Toxicity 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 125000005219 aminonitrile group Chemical group 0.000 description 1
- 239000000090 biomarker Substances 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 1
- 229960000590 celecoxib Drugs 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000004736 colon carcinogenesis Effects 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000004748 mammary carcinogenesis Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 230000035407 negative regulation of cell proliferation Effects 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 239000002818 ornithine decarboxylase inhibitor Substances 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 210000001236 prokaryotic cell Anatomy 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229940063675 spermine Drugs 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- MLKXDPUZXIRXEP-MFOYZWKCSA-N sulindac Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 description 1
- 229960000894 sulindac Drugs 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 230000005748 tumor development Effects 0.000 description 1
- 230000005740 tumor formation Effects 0.000 description 1
- 239000000717 tumor promoter Substances 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q7/00—Preparations for affecting hair growth
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
- A61K8/44—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q7/00—Preparations for affecting hair growth
- A61Q7/02—Preparations for inhibiting or slowing hair growth
Definitions
- the present invention relates to methods of treatment or prevention of disease using salts of 2-difluoromethyl-2,5-diaminopentanoic acid (DFMO) with chitosan.
- DFMO 2-difluoromethyl-2,5-diaminopentanoic acid
- DFMO 2-difluoromethyl-2,5-diaminopentanoic acid
- DFMO has been studied and continues to be studied as a cancer prevention agent, especially in skin, cervical and colon cancer.
- Love R R Carbone, P P Verma, A K, Gilmore D, Carey P, Tutsch K D. Pomplun M, and Wilding G. Randomized Phase I chemoprevention dose-seeking study of alpha-difluoromethylornithine. J. Natl. Cancer Inst., 85:732-736, 1993; Nishioka K, Melgarejo A B, Lyon R R and Mitchell M F. Polyamines as biomarkers of cervical intraepithelial neoplasia. J. Cell.
- DFMO has also been found useful in conditions unrelated to cancer. ODC inhibitors have been associated with control of hair growth. Studies in mice have suggested that the ODC gene is an important regulatory gene for the mouse hair follicle. (Soler A P, Gilliard G, Megosh L C, O'Brien T G. J Modulation of murine hair follicle function by alterations in omithine decarboxylase activity. Invest Dermatol 1996 May; 106(5):1108-13.) The FDA, to control facial hair growth in women, has recently approved DFMO. (Current DFMO salts, when used topically, cause burning, irritation and inflammation.) DFMO may have use in controlling male facial hair growth as well and may constitute a methodology to supplant or reduce the use of razors to remove facial hair in men.
- U.S. Pat. No. 4,330,559, May 18, 1982, Bey, et al. discloses the use of DFMO to treat benign prostatic hypertrophy.
- U.S. Pat. No. 4,399,151, Aug. 16, 1983, Sjoerdsma, et al. discloses the use of 2-(difluoromethyl)-2,5-diaminopentanoic acid (DFMO) for inhibiting the growth of protozoa.
- DFMO 2-(difluoromethyl)-2,5-diaminopentanoic acid
- U.S. Pat. No. 4,405,530, Sep. 20, 1983, Gerhart discloses the preparation of fluorinated amino-nitriles. These patents do not disclose the use of salts of DFMO with chitosan.
- agents that inhibit ornithine decarboxylase would have significant utility over a wide range of disorders or conditions associated with an increase polyamine metabolism.
- agents that inhibit ornithine decarboxylase would have utility in preventing and/or treating colon polyps, benign prostatic hypertrophy (BPH), or hirsutism.
- BPH benign prostatic hypertrophy
- Such agents may also provide a means to decrease the need for daily shaving of facial hair in males.
- the present invention discloses methods for the use of salts of DFMO with chitosan.
- These salts of DFMO with chitosan have utility in treating or preventing a variety of conditions related to the aforementioned mechanisms of action of DFMO, namely ODC inhibition.
- a salt of DFMO with chitosan is administered to a warmblooded animal in need thereof to inhibit ODC.
- a salt of DFMO with chitosan is administered to a warm blooded animal to prevent and or treat the following conditions: aging of the skin, cancer, HIV, alopecia, solar keratosis, benign prostatic hypertrophy, prostate cancer, breast cancer, cervical cancer, and other such conditions in which polyamine metabolism requires modulation.
- a salt may be administered along with any other agent to enhance its therapeutic effectiveness.
- this invention is generally directed to therapeutic uses of salts of DFMO with chitosan.
- Such salts of DFMO with chitosan when administered to a warm-blooded animal in need thereof, have utility in the prevention or treatment of conditions enumerated above in warm-blooded animals, including humans.
- treat or “treatment” means that the symptoms associated with one or more conditions mentioned above are alleviated or reduced in severity or frequency and the term “prevent” means that subsequent occurrences of such symptoms are avoided or that the frequency between such occurrences is prolonged.
- salts of DFMO with chitosan have good characteristics that are such as to render them particularly suitable both for use in pharmaceutical formulations and for preparative applications.
- the example illustrates the complete absence of the well known irritation side effects of DFMO when a cream containing 20 % salt of DFMO with chitosan is applied topically to the forearm of healthy volunteers.
- a cream containing 20% salt of DFMO with chitosan was applied to the forearm of 10 healthy individuals twice daily for a two-week period in an outpatient clinic. No patients complained of burning, irritation, scaling or redness after the cream. Patients returned to the clinic after having used the cream for two weeks for a visual inspection of the forearm area. The examining physician noted no redness, irritation or scaling in the area where the cream had been applied.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Dermatology (AREA)
- Epidemiology (AREA)
- Birds (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Methods to prevent or treat conditions or diseases treatable by inhibition of ornithine decarboxylase are disclosed.
Description
- This is a divisional of U.S. patent application Ser. No. 09/919,692 filed on Jul. 31, 2001, the entire disclosure and contents of which are incorporated by reference.
- 1. Field of the Invention
- The present invention relates to methods of treatment or prevention of disease using salts of 2-difluoromethyl-2,5-diaminopentanoic acid (DFMO) with chitosan.
- 2. Technical Field
- This patent relates to the therapeutic use of salts of 2-difluoromethyl-2,5-diaminopentanoic acid (DFMO) with chitosan. DFMO, in vitro and in vivo, is an inhibitor of omithine decarboxylase, an enzyme that is involved in polyamine formation in organisms.
- In both eukaryotic and prokaryotic cells, the decarboxylation of omithine to putrescine, a reaction catalyzed by omithine decarboxylase (ODC), is the first step in the biosynthesis of the polyamines known as spermidine and spermine. The polyamines, which are found in animal tissues and microorganisms, are known to play an important role in cell growth and proliferation. The onset of cell growth and proliferation is associated with a marked increase in ODC activity and an increase in the levels of putrescine and the polyamines. Although the exact mechanism of the role of the polyamines in cell growth and proliferation is not known, it appears that the polyamines may facilitate macromolecular processes such as DNA, RNA, or protein synthesis. (Tabor H, Tabor C W, Cohn M S, Hafner E W. Streptomycin resistance produces an absolute requirement for polyamines for growth on an Escherichia coli strain unable to synthesize spermidine. J Bacteriolol 1981; 147: 702-4; Mamont P S, Bohelen, P, McCann P P, Bey P, Schuber R, Tardif C. Alpha-methyl omithine, a potent competitive inhibitor of omithine decarboxylase, blocks proliferation of rat hepatoma cells in culture. Proc Natl Acad Sci USA 1976; 73: 1626-30.)
- The association between high levels of the polyamines and rapid proliferation was discovered more than a quarter of a century ago. (Bachrach U and Weinstein A. Effect of aliphatic polyamines on growth and macromolecular syntheses in bacteria. J. Gen. Microbiol., 60: 159-165 1970.) Subsequent studies showed that activation of the enzyme ODC was important for carcinogenesis and subsequent tumor development in animal and tumor models. (Weeks C E, Harmann A L, Nelson F R, Slaga T J. Alpha difluoromethylomithine, an irreversible inhibitor of omithine decarboxylase, inhibits tumor promoter-induced polyamine accumulation and carcinogenesis in mouse skin. Proc Natl Acad Sci USA 1982; 79:6028-32.)
- It is currently known that increased intracellular polyamine concentrations are related to human neoplastic conditions. (Verma, A K Inhibition of tumor promotion by DL-alpha-difluoromethylomithine, specific irreversible inhibitor of ornithine decarboxylase. Basic Life Sci., 52:195-204, 1990). A further example of this relationship between high polyamine concentrations and neoplasms involves colonic polyps and cancers compared to surrounding normal colon mucosa. (Hixson, L J, Garewal, H S, McGee D., Sloan D, Fennerty, M B, Sampliner R E and Gerner E W Omithine decarboxylase and polyamines in colorectal neoplasia and adjacent mucosa. Cancer Epidemiol. Biomark. Prev. 2;369-374, 1993; Rozhin J, Wilson P S, Bull A W, and Nigro, N D. Omithine decarboxylase activity in the rat and human colon. Cancer Res. 44: 3226-3230, 1984.)
- Other groups have reported that polyamine metabolism was necessary for carcinogenesis, especially in epithelial tissues. ODC inhibitors have been found to inhibit or suppress tumor formation in models of bladder, breast, colon and skin carcinogenesis. (Verma, A K Inhibition of tumor promotion by DL-alpha-difluoromethylomithine, specific irreversible inhibitor of omithine decarboxylase. Basic Life Sci., 52:195-204, 1990; Nigro N D, Bull A W and Boyd, M E. Inhibition of intestinal carcinogenesis in rats: effect of difluoromethylomithine for colon cancer prevention. J. Natl Cancer Inst. 77: 1309-1313, 1986; Thompson H J, and Ronan Am. Effect of DL-2-difluoromethylomrithine and endocrine manipulation on the induction of mammary carcinogenesis by 1-methyl-1-nitrosourea. Carcinogenesis (Lond.), 7: 20032006, 1986.)
- It is thought, however, that the mechanism of cancer prevention by ODC inhibitors such as DFMO may involve more than just inhibition of cell proliferation. Animal studies show that DFMO may act at later stages in models of chemical carcinogenesis. These stages involve the transition of non-invasive tumors to invasive cancers. (Slaga, T J. Multistage skin carcinogenesis: a useful model for the study of the chemoprevention of cancer. Acta Pharmacol. Toxicol., 55 (Suppl. 2): 107-124, 1984.)
- DFMO has been studied and continues to be studied as a cancer prevention agent, especially in skin, cervical and colon cancer. (Love R R, Carbone, P P Verma, A K, Gilmore D, Carey P, Tutsch K D. Pomplun M, and Wilding G. Randomized Phase I chemoprevention dose-seeking study of alpha-difluoromethylornithine. J. Natl. Cancer Inst., 85:732-736, 1993; Nishioka K, Melgarejo A B, Lyon R R and Mitchell M F. Polyamines as biomarkers of cervical intraepithelial neoplasia. J. Cell. Biochem., 23 (Suppl.): 87-95, 1995; Mitchell M F, Tortolero-Luna G, Lee J J, Hittelman W N, Lotan R, Wharton J T, Hong, W K and Nishioka, K. Phase I dose de-escalation trial of alpha-difluoromethylornithine in patients with grade 3 cervical intraepithelial neoplasia. Clin. Cancer Res., 4:303-310, 1998; Meyskens F I, Emerson S S, Pelot D, Meshkinpour H, Shassetz R, Einspahr J, Alberts D S, and Gerner, E W Dose de-escalation chemoprevention trial of alphadifluoromethylomithine in patients with colon polyps. J. Natl. Cancer Inst., 86:1122-1130, 1994.)
- While high doses of DFMO in humans can cause some problems with hearing (reversible upon discontinuation of DFMO), at the doses used for chemoprevention of cancer (0.50 g/m2/day) such concerns have been found to be groundless. (Meyskens F L, Gerner E, Emerson S, Pelot D, Durbin T, Doyle K and Lagerber W. A randomized double-blind placebo controlled Phase IIb trial of difluoromethylornithine for colon cancer prevention. J. Natl. Cancer Inst., 90: 1212-1218, 1998).
- DFMO has also been found useful in conditions unrelated to cancer. ODC inhibitors have been associated with control of hair growth. Studies in mice have suggested that the ODC gene is an important regulatory gene for the mouse hair follicle. (Soler A P, Gilliard G, Megosh L C, O'Brien T G. J Modulation of murine hair follicle function by alterations in omithine decarboxylase activity. Invest Dermatol 1996 May; 106(5):1108-13.) The FDA, to control facial hair growth in women, has recently approved DFMO. (Current DFMO salts, when used topically, cause burning, irritation and inflammation.) DFMO may have use in controlling male facial hair growth as well and may constitute a methodology to supplant or reduce the use of razors to remove facial hair in men.
- Review of Prior Art
- U.S. Pat. No. 4,330,559, May 18, 1982, Bey, et al. discloses the use of DFMO to treat benign prostatic hypertrophy. U.S. Pat. No. 4,399,151, Aug. 16, 1983, Sjoerdsma, et al. discloses the use of 2-(difluoromethyl)-2,5-diaminopentanoic acid (DFMO) for inhibiting the growth of protozoa. U.S. Pat. No. 4,405,530, Sep. 20, 1983, Gerhart, discloses the preparation of fluorinated amino-nitriles. These patents do not disclose the use of salts of DFMO with chitosan.
- U.S. Pat. No. 4,413,141, Nov. 1, 1983 Bey, et al. discloses 2-(difluoromethyl)-2,5-diaminopentanoic acid (DFMO) and the methods for the preparation and use thereof U.S. Pat. No. 4,499,072, Feb. 12, 1985, Sunkara, et al. discloses the use of DFMO as an ODC inhibitor along with interferon in treating diseases. U.S. Pat. No. 4,720,489, Jan. 19, 1988, Shander, discloses the use of DFMO as an ornithine decarboxylase inhibitor to modify hair growth. These patents do not disclose the use of salts of DFMO with chitosan.
- U.S. Pat. No. 5,648,394 Jul. 15, 1997, Boxall, et al. discloses the use of DFMO as a topical composition for inhibiting hair growth but does not teach the use salts of DFMO with chitosan. WO9814188, May 04, 1998, Love et al. teaches the use of preparations comprising a single enantiomer or defined ratio of enantiomers of alphadifluoromethylornithine (DFMO) for treating, preventing, controlling the growth of and/or reducing the risk of developing estrogen independent breast cancer or tumor and for administering DFMO alone or in combination with taxol. However, this patent does not teach the use of salts of DFMO with chitosan. U.S. Pat. No. 5,851,537, Dec. 22, 1998, Alberts et al. discloses the use of topical application of DFMO to prevent skin cancer but does not teach the salts of DFMO with chitosan. WO0069434, Nov. 23, 2000, Love discloses the use of Celecoxib, a COX-2 specific nonsteroidal antiinflammatory agent, in combination with DFMO for the prevention and/or treatment of cancers. However, this patent does not teach the salts of DFMO with chitosan. U.S. Pat. No. 6,166,079, Dec. 26, 2000, Follen et al. discloses the use of DFMO for the treatment or prevention of cervical intraepithelial neoplasia. U.S. Pat. No. 6,258,845, Jul. 10, 2001, Gerner, et al. discloses the use of DFMO and sulindac combination in cancer chemoprevention. These patents do not teach the use of salts of DFMO with chitosan.
- Administration of agents that inhibit ornithine decarboxylase would have significant utility over a wide range of disorders or conditions associated with an increase polyamine metabolism. For example, in addition to the prevention and/or treatment of different types of cancer or precancer conditions, such agents would have utility in preventing and/or treating colon polyps, benign prostatic hypertrophy (BPH), or hirsutism. Such agents may also provide a means to decrease the need for daily shaving of facial hair in males.
- Accordingly, there is a need in the art for methods related to the use of such ODC inhibition agents to prevent and/or treat conditions associated with increased polyamine metabolism. The present invention fulfills this need, and provides further related advantages.
- Briefly stated, the present invention discloses methods for the use of salts of DFMO with chitosan. These salts of DFMO with chitosan have utility in treating or preventing a variety of conditions related to the aforementioned mechanisms of action of DFMO, namely ODC inhibition. Thus in one embodiment, a salt of DFMO with chitosan is administered to a warmblooded animal in need thereof to inhibit ODC. In yet a further embodiment, a salt of DFMO with chitosan is administered to a warm blooded animal to prevent and or treat the following conditions: aging of the skin, cancer, HIV, alopecia, solar keratosis, benign prostatic hypertrophy, prostate cancer, breast cancer, cervical cancer, and other such conditions in which polyamine metabolism requires modulation. Such a salt may be administered along with any other agent to enhance its therapeutic effectiveness. Other aspects of the present invention will become evident upon reference to the following detailed description.
- As mentioned above, this invention is generally directed to therapeutic uses of salts of DFMO with chitosan. Such salts of DFMO with chitosan, when administered to a warm-blooded animal in need thereof, have utility in the prevention or treatment of conditions enumerated above in warm-blooded animals, including humans.
- The term “treat” or “treatment” means that the symptoms associated with one or more conditions mentioned above are alleviated or reduced in severity or frequency and the term “prevent” means that subsequent occurrences of such symptoms are avoided or that the frequency between such occurrences is prolonged.
- It has now surprisingly been found that salts of DFMO with chitosan have good characteristics that are such as to render them particularly suitable both for use in pharmaceutical formulations and for preparative applications.
- The example illustrates the complete absence of the well known irritation side effects of DFMO when a cream containing 20% salt of DFMO with chitosan is applied topically to the forearm of healthy volunteers.
- This example is given to illustrate the present invention, but not by way of limitation. Accordingly, the scope of this invention should be determined not by the embodiments illustrated, but rather by the appended claims and their legal equivalents.
- A cream containing 20% salt of DFMO with chitosan was applied to the forearm of 10 healthy individuals twice daily for a two-week period in an outpatient clinic. No patients complained of burning, irritation, scaling or redness after the cream. Patients returned to the clinic after having used the cream for two weeks for a visual inspection of the forearm area. The examining physician noted no redness, irritation or scaling in the area where the cream had been applied.
Claims (5)
1. A method for the treatment of a disease or a condition which is treatable by inhibition of ornithine decarboxylase, which comprises administration of a therapeutically active or nithine decarboxylase-inhibiting amount of a salt of 2-difluoromethyl-2,5-diaminopentanoic acid with chitosan.
2. A method for the prevention of a disease or a condition which is preventable by inhibition of omithine decarboxylase, which comprises administration of a therapeutically active omithine decarboxylase-inhibiting amount of a salt of 2-difluoromethyl-2,5-diaminopentanoic acid with chitosan.
3. The method as defined by claim 1 , wherein a salt of 2-difluoromethyl-2,5-diaminopentanoic acid with chitosan is administered to treat a disease or condition selected from the group consisting of cancer, benign prostatic hypertrophy, protozoal in fections, actinic keratosis, and hirsutism.
4. The method as defined by claim 2 , wherein a salt of 2-difluoromethyl-2,5-diaminopentanoic acid with chitosan is administered to prevent a condition or disease selected from the group consisting of cancer, benign prostatic hypertrophy, HIV, prozoal infections, actinic keratosis, and hirsutism.
5. A method wherein a salt of 2-difluoromethyl-2,5-diaminopentanoic acid with chitosan is administered topically to prevent hair growth.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US10/614,713 US20040006045A1 (en) | 2000-08-01 | 2003-07-07 | Methods for the treatment or prophylaxis of disease by inhibition of ornithine decarboxylase |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US22242000P | 2000-08-01 | 2000-08-01 | |
| US09/919,692 US6630511B2 (en) | 2000-08-01 | 2001-07-31 | Water-soluble salts of 2-difluoromethyl-2,5-diaminopentanoic acid (DFMO) |
| US10/614,713 US20040006045A1 (en) | 2000-08-01 | 2003-07-07 | Methods for the treatment or prophylaxis of disease by inhibition of ornithine decarboxylase |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US09/919,692 Division US6630511B2 (en) | 2000-08-01 | 2001-07-31 | Water-soluble salts of 2-difluoromethyl-2,5-diaminopentanoic acid (DFMO) |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US20040006045A1 true US20040006045A1 (en) | 2004-01-08 |
Family
ID=26916774
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US09/919,692 Expired - Fee Related US6630511B2 (en) | 2000-08-01 | 2001-07-31 | Water-soluble salts of 2-difluoromethyl-2,5-diaminopentanoic acid (DFMO) |
| US10/614,713 Abandoned US20040006045A1 (en) | 2000-08-01 | 2003-07-07 | Methods for the treatment or prophylaxis of disease by inhibition of ornithine decarboxylase |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US09/919,692 Expired - Fee Related US6630511B2 (en) | 2000-08-01 | 2001-07-31 | Water-soluble salts of 2-difluoromethyl-2,5-diaminopentanoic acid (DFMO) |
Country Status (1)
| Country | Link |
|---|---|
| US (2) | US6630511B2 (en) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6630511B2 (en) * | 2000-08-01 | 2003-10-07 | Rolland F. Hebert | Water-soluble salts of 2-difluoromethyl-2,5-diaminopentanoic acid (DFMO) |
| US7045550B2 (en) * | 2001-08-07 | 2006-05-16 | Wisconsin Alumni Research Foundation | Polyamines and analogs for protecting cells during cancer chemotherapy and radiotherapy |
| JP2005517004A (en) * | 2002-02-07 | 2005-06-09 | ウィスコンシン アルムニ リサーチ ファンデーション | Polyamine compounds and compositions for use in connection with cancer treatment |
| US20030199584A1 (en) * | 2002-04-11 | 2003-10-23 | Ahluwalia Gurpreet S. | Reduction of hair growth |
| US20040141935A1 (en) * | 2003-01-21 | 2004-07-22 | Peter Styczynski | Reduction of hair growth |
| CA2543148A1 (en) * | 2003-10-21 | 2005-04-28 | Netech Inc. | Mucous membrane bulging humor composition comprising chitosan derivative containing saccharide chain for use in condoscopic surgery |
| US20050249685A1 (en) * | 2004-04-27 | 2005-11-10 | Natalia Botchkareva | Reduction of hair growth |
| BRPI0519218A2 (en) * | 2004-12-22 | 2009-01-06 | Gillette Co | hair growth reduction |
| WO2006069192A1 (en) * | 2004-12-22 | 2006-06-29 | The Gillette Company | Reduction of hair growth with survivin inhibitors |
| CA2590328A1 (en) * | 2004-12-22 | 2006-06-29 | The Gillette Company | Reduction of hair growth |
| US7618956B2 (en) * | 2005-05-31 | 2009-11-17 | The Gillette Company | Reduction of hair growth |
| US20170273926A1 (en) | 2016-03-24 | 2017-09-28 | Orbus Therapeutics, Inc. | Compositions and methods for use of eflornithine and derivatives and analogs thereof to treat cancers, including gliomas |
| CN117530943A (en) | 2016-10-06 | 2024-02-09 | 奥巴斯治疗股份有限公司 | Preparations for administering eflornithine |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4720489A (en) * | 1984-10-15 | 1988-01-19 | Douglas Shander | Hair growth modification with ornithine decarboxylase inhibitors |
| US5851537A (en) * | 1996-02-02 | 1998-12-22 | Cancer Technologies, Inc. | Topical application of α-DFMO for preventing skin cancer |
| US6277411B1 (en) * | 1996-11-01 | 2001-08-21 | Ilex Oncology, Inc. | Pharmaceutical formulation containing DFMO for the treatment of cancer |
| US6630511B2 (en) * | 2000-08-01 | 2003-10-07 | Rolland F. Hebert | Water-soluble salts of 2-difluoromethyl-2,5-diaminopentanoic acid (DFMO) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4413141A (en) * | 1977-07-11 | 1983-11-01 | Merrell Toraude Et Compagnie | 2-(Difluoromethyl)-2,5-diaminopentanoic acid |
| US4499072A (en) * | 1982-11-29 | 1985-02-12 | Merrell Dow Pharmaceuticals Inc. | Process for treating diseases with ODC inhibitors |
-
2001
- 2001-07-31 US US09/919,692 patent/US6630511B2/en not_active Expired - Fee Related
-
2003
- 2003-07-07 US US10/614,713 patent/US20040006045A1/en not_active Abandoned
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4720489A (en) * | 1984-10-15 | 1988-01-19 | Douglas Shander | Hair growth modification with ornithine decarboxylase inhibitors |
| US5851537A (en) * | 1996-02-02 | 1998-12-22 | Cancer Technologies, Inc. | Topical application of α-DFMO for preventing skin cancer |
| US6277411B1 (en) * | 1996-11-01 | 2001-08-21 | Ilex Oncology, Inc. | Pharmaceutical formulation containing DFMO for the treatment of cancer |
| US6630511B2 (en) * | 2000-08-01 | 2003-10-07 | Rolland F. Hebert | Water-soluble salts of 2-difluoromethyl-2,5-diaminopentanoic acid (DFMO) |
Also Published As
| Publication number | Publication date |
|---|---|
| US20020019338A1 (en) | 2002-02-14 |
| US6630511B2 (en) | 2003-10-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20040006045A1 (en) | Methods for the treatment or prophylaxis of disease by inhibition of ornithine decarboxylase | |
| AU783758B2 (en) | Use of creatine or creatine compounds for skin preservation | |
| EP0910331B1 (en) | Oxa diacids and related compounds for treating skin conditions | |
| CA1262335A (en) | Hair growth modification | |
| Rebora | The management of rosacea | |
| US6333356B1 (en) | Compounds for treating skin conditions | |
| AU606325B2 (en) | Treatment of skin disorders | |
| RU2160103C2 (en) | Apoptosis-modulation composition containing factor influencing intracellular level of methional or malonic dialdehyde | |
| EP2702982B1 (en) | Composition for topical application for preventing hair loss and stimulating hair growth | |
| JPS63502437A (en) | Oxygenated cholesterol-containing compositions and their use for the local treatment of diseases | |
| IL159205A0 (en) | Carbocyclic hydrazino inhibitors of copper-containing amine oxidases | |
| KR101005715B1 (en) | Topical formulations containing nonsteroidal anti-inflammatory agents that exhibit chemoprophylactic activity | |
| JPH07309751A (en) | Remedy for inflammatory or hormonal alopecia | |
| US20020034484A1 (en) | Vitamin/metal salt compositions for reducing hair loss and/or promoting hair regrowth | |
| JP4243353B2 (en) | Zinc salt of conjugated linoleic acid for the treatment of skin diseases | |
| US6734210B2 (en) | Therapeutically improved salts of azelaic acid | |
| Gollnick et al. | Azelaic acid for the treatment of acne: comparative trials | |
| EP2881107B1 (en) | Compositions and method for the stimulation of the female and male sexual response | |
| Abramovits et al. | Treatment of warty dyskeratoma with tazarotenic acid | |
| Blankenship | Drugs and alopecia. | |
| Chaudhary et al. | A review on treatment options for acne vulgaris | |
| JPH04342515A (en) | Hair cosmetic | |
| JPH0328402B2 (en) | ||
| Gupta et al. | FC045 Pharmacoeconomic analysis of oral therapies for onychomycosis in the US | |
| Derumeaux et al. | FC047 Clindamycin 1%/tretinoin 0.025% gel versus clindamycin 1% lotion in acne vulgaris |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |