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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
• • 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
  • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
  • A61K31/05—Phenols
• • 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
  • A61K31/12—Ketones
• • 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
• • 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
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• • 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
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/404—Indoles, e.g. pindolol
  • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
• • 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
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• This invention is in the field of the prevention and treatment of cancer. More specifically, this invention relates to the use of 5-lipoxygenase inhibitors or derivatives thereof in preventing and treating cancer.
• Arachidonic acid is a 20-carbon polyunsaturated fatty acid derived from dietary sources. Oxygenated AA metabolites participate in a variety of biologic and pathological processes including inflammation, bronchial asthma, and shock. Activation of AA metabolism is initiated by the release of AA from the phospholipid pool by the action of enzymes or other mediators. The released AA can be metabolized by either the lipoxygenase pathway where AA is converted by fatty acid lipoxygenases into hydroperoxy derivatives, giving rise to leukotrienes, or the cycloxygenase pathway where a fatty acid transforms AA rapidly to the prostaglandin PGG 2 , which in turn is further converted enzymatically.
• FLAP 5-lipoxygenase activating protein
• FLAP appears to be necessary for cellular leuketriene synthesis (U.S. Patent No. 5,182,367; Miller et al. (1990) Nature 343:278-281).
• FLAP appears to be involved in the translocation of 5-lipoxygenase from the cytosol to the membrane.
• Other enzymes involved with the sequential metabolism of the lipoxygenase product need to be in close relationship to the 5-lipoxygenase FLAP complex.
• FLAP and molecules of related structure may be essential to the activity of enzymes in the 5-lipoxygenase pathway as well as the other downstream enzymes required for leuketriene biosynthesis.
• Inhibitors of the AA 5-lipoxygenase pathway have shown promise in the treatment of inflammation, asthma, and shock, with minimal side effects in pre-clinical and clinical trials (Batt, Prog. Med. Che . 29:1-63 (1992); Larson, Ann. Pharmacother. 27:898-903 (1993)). However, their use for treating or preventing cancer has never been described.
• the present invention is directed to the use of inhibitors of 5-lipoxygenase functional activity for the treatment and prevention of epithelial cell-derived cancers.
• the present invention is also directed to the use of inhibitors of other enzymes in the lipoxygenase pathway involved in the metabolism of AA for use in the treatment and prevention of epithelial cell-derived cancers.
• the present invention relates to the use of lipoxygenase inhibitors in therapeutic applications, in particular to the prevention and treatment of epithelial cell-derived cancers.
• FIG. 1(a) classic SCLC cell lines NCI-H209, NCI-H345, and NCI-H510.
• Fig. Kb) variant SCLC cell lines NCI-N417 and NCI-H82.
• Fig. 1(c) NSCLC cell lines NCI-H23, A549, and NCI-H1155.
• Fig. 2 (a) classic SCLC cell lines NCI-H209 and NCI-H345.
• Fig. 2(b) variant SCLC cell lines NCI-N417 and NCI-H82.
• Fig. 2(c) NSCLC cell lines A549 and NCI- H1155.
• Fig. 3 (a) classic SCLC cell lines NCI-H209 and NCI-H345.
• Fig. 3 (b) variant SCLC cell lines NCI- N417 and NCI-H82.
• Fig. 3(c) NSCLC cell lines A549 and 5 NCI-H1155.
• FIG. 1 Structures of MK-886 and related structures: L-669,572, L-663,511, L-665,210, L-654,639, L-668,017 and MK-591.
• the present invention provides a method for 5 treating or preventing an epithelial cell-derived cancer in a subject in need of such treatment or prevention which comprises administering to the subject an amount of a 5- lipoxygenase inhibitor or derivative thereof, effective to treat or prevent the epithelial cell-derived cancer.
• the 0 present invention also provides a method for treating or preventing an epithelial cell derived cancer in a subject in need of such treatment by administering an effective amount of an inhibitor of other enzymes involved in the metabolism of arachidonic acid in the 5-lipoxygenase # pathway which comprises administering to the subject an amount of the inhibitor effective to treat or prevent a epithelial cell derived cancer.
• treatment includes partial or total inhibition of the cancer growth, as well as partial or total destruction of the cancer cells.
• prevention includes either preventing the onset of clinically evident cancer altogether or preventing the onset of a preclinically evident stage of cancer in individuals at risk, also intended to encompassed by this definition is the prevention of initiation for malignant cells or to arrest or reverse the progression of premalignant cells to malignant cells.
• the epithelial cell- derived cancer includes basal cell carcinoma, adenocarcinoma, colon cancer, prostate cancer, renal cell carcinoma, and other known cancers that effect epithelial cells throughout the body.
• the epithelial cell-derived cancer is lung cancer or breast cancer.
• subject for purposes of treatment includes any human or animal subject who has any one of the known epithelial cell-derived cancers, and preferably is a human subject.
• the subject is any human or animal subject, and preferably is a human subject who is at risk for obtaining an epithelium cell-derived cancer.
• the subject may be at risk due to exposure to carcinogenic agents, being genetically predisposed to have the cancer, and the like.
• Inhibitors of the 5-lipoxygenase pathway in the metabolism of arachidonic acid used in the prevention and treatment of epithelial cell derived cancers may inhibit enzyme activity through a variety of mechanisms.
• the inhibitor may block or reverse the association of the enzyme with the membrane or inhibit the ° translocation of specific enzymes such as 5-lipoxygenase via a protein such as FLAP.
• the inhibitors used in the methods described herein may block the enzyme activity directly by acting as a substrate for the enzyme or by depriving the enzyme of necessary cofactors. 5
• the methods provided herein relate to the use of
• the 5-lipoxygenase inhibitor is 2-(12-Hydroxydodeca-5, 10-diynyl)-3,5,6-
• Derivatives are intended to encompass any compounds which are structurally related to AA861, NDGA or MK886 or which possess the substantially equivalent
• inhibitors may include, but are not limited to, derivatives which act as co-factor antagonist, better enzymatic substrates or inhibitors of activating peptide function.
• a derivative of MK886 may have the general formula:
• R 1 is C ⁇ -C 6 alkyl or OH or RCO- in which R 2 is H or C,-C 6 alkyl or quinoline or a long chain hydrocarbon possessing 1-32 carbon atoms and 0-6 double bonds.
• long chain hydrocarbons include, but are not limited to, linoleic acid (18:2) or oleic acid (18:1).
• R 3 is C,-C 6 alkyl or R 4 S- or R 5 SO- or R 6 S0 2 - and which R 4 or R 5 or R 6 may be C,-C 6 alkyl or quinoline or a long chain hydrocarbon possessing 1-32 carbon atoms and 0-6 double bonds.
• Examples of long chain hydrocarbon include, but are not limited to, linoleic acid (18:2) or oleic acid (18:1).
• R 3 examples include, but are not limited to, ° t-butyl thio, cyclic propyl methylthio, phenyl sulfonyl, phenyl, methyl, phenylthiol.
• MK886 intended to be encompassed by this invention include, but are not limited to, L- 669,572, 3-[1-(p-cholorobenzyl)-5-isopropyl-3-cyclo- 5 propylmethylthioindole-2-yl]-2,2-dimethylpropanoic acid; L-663,511 3-[1-(p-cholorobenzyl)-5-isopropyl-3- phenysulfonylindol-2-yl)-2,2-dimethylpropanoic acid, L- 665,210, 3-[l-(p-chlorobenzyl) -5-isopropyl-3- phenysulfonylindol-2-yl)-2,2-dimethylpropanoic aid; L-654- 0 639, 3 [l-(p-chlorobenzyl)-5-methoxy-3-methylindol-2-yl]- 2,2-dimethylpropanoic acid;
• the MK886 5 derivative is 3-(1-(4-chlorobenzyl)-3-(1-butyl-thio)-5- (quinolin-2-yl-methoxy)-indol-2-yl) -2,2-dimethyl propanoic acid) (MK-591) (Tagari, et al. (1993) Agents Action 40:62- 71).
• hydroxyurea derivatives are also used as inhibitors of 5-lipoxygenase in the prevention and treatment of epithelial cell derived cancers.
• hydroxyurea derivatives include, but are not limited to, (N-(l- benzo(b)thien-2-ylethyl)-N-hydroxyurea) (zileuton) (Tagari, et al. (1993) Agents Action 40:62-71 herein 5 incorporated by reference.
• inhibitors of other enzymes that metabolize arachidonic acid downstream of 5-lipoxygenase may also be used to prevent or treat epithelial cell derived cancers in a 0 subject in need of such treatment in a method which comprises administering to the subject an amount effective to prevent or treat the epithelial cell derived cancer.
• Such inhibitors may effect the activity of the enzyme 5 either directly by acting as a substrate inhibitor or by depriving the enzyme of a cofactor.
• the inhibitor may also act by targeting proteins such as FLAP which are responsible for the translocation of the enzymes to the membrane where the enzymes are activated.
• the compounds utilized in the methods of the present invention may be present in the form of free bases or pharmaceutically acceptable acid addition salts thereof. Examples of suitable acids for salt formation are: methanesulfonic, sulfuric, hydrochloric, phosphoric, acetic, citric, lactic, ascorbic, maleic, and the like.
• the administration for the above methods may be affected by means known to those skilled in the art such as oral, rectal, topical (including aerosol), intranasal, intravenous, subcutaneous, intramuscular, intrabronchial, intracavitary, or intraperitoneal routes of administration. If the cancer is localized, local administration rather than system administration is preferred. Formulation in a lipid vehicle may be used to enhance bioavailability.
• the compound may be combined with a sterile aqueous solution which is preferably isotonic with the blood of the recipient.
• a sterile aqueous solution which is preferably isotonic with the blood of the recipient.
• Such formulations may be prepared by dissolving solid active ingredient in water containing physiologically compatible substances such as sodium chloride, glycine, and the like, and having a buffered pH compatible with physiological conditions to produce an aqueous solution, and rendering said solution sterile.
• the formulations may be present in unit or multi-dose containers such as sealed ampoules or vials.
• the formulation may be presented as capsules, tablets, powders, granules or a suspension, with conventional additives such as lactose, mannitol, corn starch or potato starch; with binders such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins; with disintegrators such as corn starch, potato starch or sodium carboxymethyl-cellulose; and with lubricants such as talc or magnesium stearate.
• the compound may be formulated with acid-stable, base- labile coatings known in the art which begin to dissolve in the high pH small intestine. Formulation to enhance local pharmacologic effects and reduce systemic uptake are preferred.
• Formulations suitable for parenteral administration conveniently comprise a sterile aqueous preparation of the active compound which is preferably made isotonic. Preparations for injections may also be formulated by suspending or emulsifying the compounds in non-aqueous solvent, such as vegetable oil, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol.
• non-aqueous solvent such as vegetable oil, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol.
• Formulations for topical use include known gels, creams, oils, and the like.
• the compounds may be formulated with known aerosol exipients, such as saline, and administered using commercially available nebulizers.
• Formulation in a fatty acid source may be used to enhance biocompatibility. Aerosol delivery is the preferred method of delivery for epithelial cancers of the lung for prevention application.
• the active ingredient may be formulated into suppositories using bases which are solid at room temperature and melt or dissolve at body temperature.
• bases include coca butter, glycerinated gelatin, hydrogenated vegetable oil, polyethylene glycols of various molecular weights, and fatty esters of polyethylene stearate.
• the dosage form and amount can be readily established by reference to known cancer treatment or prophylactic regiments.
• the dosage for the inhibitors or derivatives thereof may be from about 0.1 ng/kg to about 450 g/kg, most preferred is about 0.5 ng/kg to about 100 mg/kg, and most preferably is about 1 ng/kg to about 10 mg/kg.
• the serum concentration of the inhibitor may be from about 1 ⁇ g/ml to about 20 ⁇ g/ml.
• the actual dose will depend upon whether the administration is for treatment or prophylactic purposes, the route of administration, the location of the cancer, as well as the phar acokinetic properties of the individual treated.
• the dosage will generally be lower if the compounds are administered locally rather than systemically, and for prevention rather than for treatment. Such treatments may be administered as often as necessary and for the period of time judged necessary by the treating physician.
• the dosage regime or therapeutically effective amount of the inhibitor to be administrated may need to be optimized for each individual.
• the administration of the present invention may be for either prevention or treatment purposes.
• the methods and compositions used herein may be used alone or in conjunction with additional therapies known to those skilled in the art in the prevention or treatment of cancer.
• the methods and compositions described herein may be used as adjunct therapy.
• the 5-lipoxygenase inhibitor may be administered alone or in conjunction with other antineoplastic agents or other growth inhibiting agents or other drugs or nutrients.
• the 5- lipoxygenase inhibitor or derivatives thereof and the inhibitor of other downstream enzymes involved in the metabolism of arachidonic acid may be administered in combination with each other.
• molecular methods may be used to inhibit the 5-lipoxygenase.
• antisense constructs generated by methods known to those skilled in the art can be used to target the messenger RNA of the 5-lipoxygenase enzyme.
• All books, articles or patents reference herein are incorporated by reference.
• the present invention is described in the following Experimental Details section, which sets forth specific examples to aid in an understanding of the invention, and should not be construed to limit in any way the invention as defined in the claims which follow thereafter.
• Example 1 Materials and Methods Cell lines: The following cell lines were used: classic small cell lung cancer (SCLC) cell lines NCI-H209, NCI-H345, and NCI-H510; variant SCLC cell lines NCI-N417 and NCI-H82; large cell carcinoma cell line NCI-H1155; adeno carcinoma cell line NCI-H23; and bronchioalveolear carcinoma cell line A549, breast cancer cell line MCF-7 (American Type Tissue Culture Rockville MD; ATCC) and a colon cancer cell line NCI-H630 (ATCC) .
• SCLC classic small cell lung cancer
• NCI-N417 and NCI-H82 variant SCLC cell lines NCI-N417 and NCI-H82
• large cell carcinoma cell line NCI-H1155 adeno carcinoma cell line NCI-H23
• bronchioalveolear carcinoma cell line A549 breast cancer cell line MCF-7 (American Type Tissue Culture Rockville MD; ATCC) and a colon cancer cell line
• All cells were grown in RPMI-1640, supplemented with 5% fetal bovine serum (FBS) , penicillin and streptomycin (Gibco, Grand Island, NY) , and were maintained in a 5% C0 2 atmosphere at 37°C. All cell lines were free of mycoplasma contamination.
• FBS fetal bovine serum
• penicillin and streptomycin Gibco, Grand Island, NY
• Biochemical compounds General lipoxygenase inhibitor Nordihydroguaiaretic acid (NDGA) and 5- lipoxygenase inhibitor AA861, are readily commercially available and were purchased from Biomol Research Laboratories (Plymouth Meeting, PA) .
• 5-lipoxygenase inhibitor MK886 and MK-591 were obtained from Merck Frost. MK886 may be synthesized as described in Gillard, J. , et al. Can. J. Phvsiol. Pharmacol. 67:456-464 (1989)). ° Growth studies: A modification (Promega
• AA861 was tested in a dose range of 0.5-10 ⁇ M on three classic SCLC cell lines, two variant SCLC cell lines, and three NSCLC cell lines.
• the effect of AA861 on the in vitro growth of the specific lung cancer cell lines 0 is presented in Figures 1(a), 1(b), and 1(c).
• AA861 significantly inhibited growth on all of the SCLC cell lines, and two out of three of the NSCLC cell lines.
• a bronchioalveolear carcinoma, A549 was repeatedly resistant to AA861. The reason for this resistance is 5 unclear.
• NDGA also was tested on four SCLC cell lines and two NSCLC cell lines, and the results are presented in Figures 2(a), 2(b), and 2(c).
• NDGA inhibited the growth of all of the lung cancer cell lines tested. MK886 also was tested on four SCLC cell lines and two NSCLC cell 0 lines, and the results are presented in Figures 3(a), 3(b), and 3(c). MK886 showed similar inhibition results as NDGA. AA861 inhibited growth of MCF-7 cells relative to controls (absence of AA861) to 70% and H630 to 50%. NDGA inhibited growth of MCF-7 cells relative to controls 5 80% and H630 cells 50% relative to controls. MK886 inhibited growth of MCF7 cells 100% relative to controls.
• the therapeutic potential of the 5-lipoxygenase inhibitor, NDGA was assessed in a heterotransplant animal model. Using conventional methodology small cell lung cancer cells (cell line NCI-209) were transplanted into nude mice. Experimental animals received a 0.1% solution
• 25 derivatives thereof may be also be tested in the heterotransplant model. Suggested serum concentration of the inhibitor in experimental animals may be from about 1 ⁇ g/ml to about 20 ⁇ g/ml. In addition to treatment models, in vivo models of cancer prevention may also be assessed for the therapeutic potential of the inhibitors or

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