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EP1656124A1 - Methodes et compositions pour le traitement du cancer - Google Patents

Methodes et compositions pour le traitement du cancer

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Publication number
EP1656124A1
EP1656124A1 EP03714956A EP03714956A EP1656124A1 EP 1656124 A1 EP1656124 A1 EP 1656124A1 EP 03714956 A EP03714956 A EP 03714956A EP 03714956 A EP03714956 A EP 03714956A EP 1656124 A1 EP1656124 A1 EP 1656124A1
Authority
EP
European Patent Office
Prior art keywords
cancer
agent
functionally related
pharmaceutically acceptable
cells
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.)
Withdrawn
Application number
EP03714956A
Other languages
German (de)
English (en)
Inventor
Adam Telerman
Robert Amson
Marius Tuijnder
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.)
Abionyx Pharma SA
Original Assignee
Cerenis SA
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 Cerenis SA filed Critical Cerenis SA
Publication of EP1656124A1 publication Critical patent/EP1656124A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the present invention relates to the use of various compounds including antihistaminic agents or stmcturally/functionally related compounds in the treatment and management of cancer.
  • Cancer is characterized primarily by an increase in the number of abnormal cells derived from a given normal tissue, invasion of adjacent tissues by these abnormal cells, or lymphatic or blood-borne spread of malignant cells to regional lymph nodes and to distant sites (metastasis).
  • Clinical data and molecular biologic studies indicate that cancer is a multi-step process that begins with minor preneoplastic changes, which may under certain conditions progress to neoplasia.
  • the neoplastic lesion may evolve clonally and develop an increasing capacity for invasion, growth, metastasis, and heterogeneity, especially under conditions in which the neoplastic cells escape the host's immune surveillance.
  • a first embodiment of the invention encompasses a method of inhibiting the growth of a cancer cell, which comprises contacting the cell with an antihistaminic agent or a structurally/functionally related compound, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or clathrate thereof. This method is particularly useful for the in compounds that are structurally or functionally related to the antihistaminic agents.
  • Another embodiment encompasses a method of treating cancer, which comprises administering to a patient in need of such treatment a therapeutically effective amount of an antihistaminic agent or a stmcturally/functionally related compound, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or clathrate thereof.
  • Another embodiment of the invention encompasses a method of managing cancer, which comprises administering to a patient in need of such treatment a therapeutically effective amount of an antihistaminic agent or a structurally/functionally related compound, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or clathrate thereof.
  • Cancers that can be treated or managed according to methods of the invention include blood borne and solid tumors, as well as primary and metastatic cancers.
  • cancers include, but are not limited to, leukemia, lymphoma, and cancer of the liver, lung, pancreas, stomach, thyroid, larygophamx, skin, uterus, breast, colon, cervix, ovary, testis, prostate and rectum.
  • Specific cancers are leukemia, melanoma, and cancer of breast, colon and lung.
  • antihistaminic agents or structurally/functionally related compounds can be used in the methods of the invention.
  • specific examples of the compounds include, but not limited to, perphenazine, sertralin, thioridazine, chlorpromazine, paroxetine, flupentixol, fluphenazine, hydroxyzine, promethazine, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates and clathrates thereof.
  • another embodiment of the invention encompasses a method of treating or managing cancer comprising administering to a patient in need of such treatment or management a therapeutically effective amount of an antihistaminic agent or a structurally/functionally related compound, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or clathrate thereof, and a therapeutically effective amount of a second anti-cancer agent.
  • the cancer is leukemia.
  • second anti-cancer agents examples include, but are not limited to, prednisone, vincristine, anthracycline, asparaginase, cytarabine, etoposide, cyclophosphamide, methotrexate, leucovorin, cytosine arabinose, corticosteroids, - , , , r ⁇ deoxyconformycin, 2-chlorodeoxyadenosine, hydroxyurea, 6-myelopurine, 6- thioguanine, melphalan, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates and clathrates thereof.
  • the cancer is melanoma.
  • second anti- cancer agents examples include, but are not limited to, dacarbazine, nitrosoureas carmustine, lomustine, cisplatin, interleukin-2, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates and clathrates thereof.
  • the cancer is breast cancer.
  • second anti-cancer agents that can be used in this method include, but are not limited to, cyclophosphamide, 5-fluorouracil, methotrexate, doxorubicin, tamoxifen, progestins, aromatase inhibitors, aminoglutethimide, letrozole, paclitaxel, docetaxel, navelbine, capecitabine, mitomycin C, prednisone, taxane, vinblastine, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates and clathrates thereof.
  • the cancer is colon cancer.
  • second anti-cancer agents examples include, but are not limited to, fluorouracil, folinic acid, levamisole, leucovorin, oxaliplatin, irinotecan, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates and clathrates thereof.
  • the cancer is lung cancer.
  • second anti- cancer agents that can be used in this method include, but are not limited to, cisplastin, topoisomerase inhibitors, carboplatin, vinorelbine, vincristine, vinblastine, docetaxel, oxaliplatin, paclitaxel, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates and clathrates thereof.
  • compositions and single unit dosage forms that can be used for the treatment or management of cancer, which comprise an antihistaminic agent or a stracturally/functionally related compound, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or clathrate thereof, and a second anti-cancer agent.
  • Pharmaceutical dosage forms include those suitable for oral, mucosal, parenteral, sublingual, transdermal, buccal or topical administration to a patient. Specific dosage forms are suitable for parenteral or oral administration.
  • kits that can be used for the treatment or management of cancer, which comprises a single unit dosage form of an antihistaminic agent or a stracturally/functionally related compound, or a , , , cic ⁇ , single unit dosage form of a second anti-cancer agent.
  • Another embodiment of the invention encompasses a method of determining whether a cancer patient will respond to a cancer treatment comprising testing for overexpression of TPT1 gene in cancer cells from the patient, wherein the cancer treatment is administration of an antihistaminic agent or a stracturally/functionally related compound, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or clathrate thereof.
  • Another embodiment of this invention encompasses a method of determining the effectiveness of a cancer treatment comprising: obtaining cancer cells from a patient being treated at a first time and at a second time; and determining if expression of TPT1 gene in cells obtained at the second time is less than the expression of TPT1 gene in cells obtained at the first time; wherein the first time is earlier than the second time.
  • Figure 1 illustrates the effect of hydroxyzine dihydrochloride ("Atranine A”, Atarax ® ), brompheniramine maleate (Dimegan ® ), promethazine ("Atranine C”, Phenergan ® ) and dexchlorpheniramine maleate (Polaramine ® ) in myeloid leukemia K562 cells;
  • Figure 2 illustrates the effect of hydroxyzine, brompheniramine maleate, promethazine and dexchlorpheniramine maleate in premonocytie leukemia U937 cells;
  • Figure 3 illustrates the effect of hydroxyzine, brompheniramine maleate, promethazine and dexchlorpheniramine maleate in acute leukemia T cells derived from Jurkat cell line;
  • Figure 4 illustrates the effect of hydroxyzine, brompheniramine maleate, promethazine and dexchlorpheniramine maleate in breast ductal carconima cells derived from T47-D cell line;
  • Figure 5 illustrates the effect of hydroxyzine, brompheniramine maleate, promethazine and dexchlo ⁇ heniramine maleate in breast ductal carcinoma cells derived from MCF7 cell line; , promethazine and dexchlorpheniramine maleate in mammary gland carcinoma cells derived from BT20 cell line;
  • Figure 7 illustrates the effect of hydroxyzine, brompheniramine maleate, promethazine and dexchlorpheniramine maleate in immortalized, non-tumorigenic breast epithelium cells derived from 184B5 cell line;
  • Figures 8 and 9 illustrate the effect of hydroxyzine and promethazine in lymphocytes from healthy donors
  • Figure 10A illustrates that the growth of colorectal adenocarcinoma cells derived from LoVo cell line are unaffected by hydroxyzine and promethazine;
  • Figure 10B illustrates the effect of hydroxyzine and promethazine in immortalized, non-tumorigenic breast luminal epithelium cells derived from 184B5 cell line;
  • Figure 11 illustrates the antineoplastic activity of promethazine (Phenergan ® ) in U 937 cells injected in scid/scid mice;
  • Figure 12-14 illustrates the effect of the compounds of the present invention in inhibiting the growth of various cancer cell lines
  • Figure 15 illustrates the effect of the compounds of the present invention in inhibiting the growth of U937 cells
  • Figure 16 illustrates the effect of the compounds of the present invention at a concentration of 10 "5 M in inhibiting the viability of fresh leukemic cells ex vivo;
  • Figure 17 illustrates the effect of the compounds of the present invention at a concentration of 10 "6 M in inhibiting the viability of fresh leukemic cells ex vivo;
  • Figure 18 illustrates the effect of the compounds of the present invention in reducing the cell viability in various cancer cell lines
  • Figure 19 illustrates the curative effects of S60 and S59 in palpable tumors in U937 cells injected in scid/scid mice;
  • Figure 20 illustrates the curative effects of S64, hydroxyzine (Atarax ® ), promethazine, A37 and SQ42 in MDA-MB-231 cells injected in scid/scid mice;
  • Figure 21 illustrates the preventive effects of S60, S59 and promethazine in tumor development in U937 cells injected in scid/scid mice;
  • Figure 22 illustrates the up-regulation of TCTP expression in tissues from various cancerous organs and their respective normal counte ⁇ arts; compounds of the present invention.
  • Figure 24 illustrates the induction of caspase 3 and 7 activities by the compounds of the present invention in U937 cell line.
  • antihistaminic agent encompasses antagonists of histamine receptors.
  • structurally related compound encompasses compounds that possess structures similar to those of antihistaminic agents. Examples include, but are not limited to, derivatives, salts, metabolites, prodrugs, hydrates, solvates, or optical isomers of antihistaminic agents.
  • the tenn "functionally related compound”, as used herein, encompasses compounds that inhibit the expression of the TPT1 gene in humans, and inhibit or block the function of the protein encoded by the TPT1 gene. More broadly, the term also encompasses compounds that inhibit or block the formation or function of products resulting from a metabolic chain controlled directly or indirectly by the expression of TPT1 gene.
  • the term “inhibit” means induction of reduction in functional capacity or level of formation of a given molecule.
  • the phrase that a compound that "inhibits" the function or expression of a molecule means that the compound causes about 10 percent or more, specifically 30 percent or more, more specifically 60 percent or more, and most specifically 100 percent in reduction of functional capacity or level of product formation of the molecule.
  • the term "pharmaceutically acceptable salt(s)" refers to a non-toxic acid or base addition salt.
  • basic chemical moieties are capable of forming a wide variety of salts with various inorganic and organic acids.
  • the acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions.
  • Suitable organic acids include, but are not limited to, maleic, fumaric, benzoic, ascorbic, succinic, acetic, formic, oxalic, propionic, tartaric, salicylic, citric, gluconic, lactic, mandelic, cinnamic, oleic, tannic, aspartic, stearic, palmitic, glycolic, glutamic, gluconic, glucaronic, saccharic, isonicotinic, (i.e., l,l'-methylene-bis-(2-hydroxy-3-naphthoate) acids.
  • Suitable inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, sulfuric, phosphoric, or nitric acids.
  • Compounds that include an amine moiety can form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above.
  • Chemical moieties that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations.
  • Examples of such salts are alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium, lithium, zinc, potassium, or iron salts.
  • prodrug means a derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide the compound.
  • prodrugs include, but are not limited to, derivatives of the antihistaminic agents of the present invention that include biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues.
  • prodrugs include derivatives of the compounds of the present invention that include -NO, -NO , -ONO, or -ONO 2 moieties.
  • derivatives means a compound or chemical moiety wherein the degree of saturation of at least one bond has been changed (e.g., a single bond has been changed to a double or triple bond) or wherein at least one hydrogen atom is replaced with a different atom or a chemical moiety.
  • different atoms and chemical moieties include, but are not limited to, halogen, oxygen, nitrogen, sulfur, hydroxy, methoxy, alkyl, amine, amide, ketone, and aldehyde.
  • biohydrolyzable carbamate As used herein and unless otherwise indicated, the terms “biohydrolyzable carbamate,” “biohydrolyzable carbonate,” “biohydrolyzable ureide,” “biohydrolyzable phosphate” mean a carbamate, carbonate, ureide, or phosphate, respectively, of a compound that either: 1) does not interfere with the biological activity of the compound but can confer upon that compound advantageous properties in vivo, such as uptake, duration of action, or onset of action; or 2) is biologically inactive but is converted in vivo to the biologically active compound.
  • biohydrolyzable carbamates include, i uii u , , , ainm ⁇ aci ⁇ s, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyether amines.
  • biohydrolyzable ester means an ester of a compound that either: 1) does not interfere with the biological activity of the compound but can confer upon that compound advantageous properties in vivo, such as uptake, duration of action, or onset of action; or 2) is biologically inactive but is converted in vivo to the biologically active compound.
  • biohydrolyzable esters include, but are not limited to, lower alkyl esters, alkoxyacyloxy esters, alkyl acylamino alkyl esters, and choline esters.
  • biohydrolyzable amide means an amide of a compound that either: 1) does not interfere with the biological activity of the compound but can confer upon that compound advantageous properties in vivo, such as uptake, duration of action, or onset of action; or 2) is biologically inactive but is converted in vivo to the biologically active compound.
  • biohydrolyzable amides include, but are not limited to, lower alkyl amides, amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides.
  • the present invention is based, in part, on the discovery that certain antihistaminic agents and compounds of related structures or functions exhibit strong and selective anti- cancer activity against various tumors.
  • certain genes are overexpressed during the tumor phase in comparison with the reversion phase.
  • One of these overexpressed genes is translationally controlled tumor protein, or TPT1 , which encodes histamine releasing factor.
  • TPT1 translationally controlled tumor protein
  • the present invention relates to the use of compounds that inhibit or prevent the expression of the TPT1 gene, inhibit or block the function of the protein encoded by i g . ivi , uuuus or prevent the formation of products controlled by the TPT1 gene, e.g., products resulting from a metabolic chain controlled directly or indirectly by the expression of TPT1 gene.
  • products controlled by the TPT1 gene e.g., products resulting from a metabolic chain controlled directly or indirectly by the expression of TPT1 gene.
  • One such product is histamine.
  • This invention encompasses methods of treating cancer, which comprise administering to a patient (e.g. , a human) in need of such treatment a therapeutically effective amount of an antihistaminic agent or a stracturally/functionally related compound, or a pharmaceutically acceptable salt, prodrug, hydrate, solvate or clathrate thereof.
  • the invention also encompasses a method of managing cancer, which comprises administering to a patient in need of such management a prophylactically effective amount of an antihistaminic agent or a stracturally/functionally related compound, or a pharmaceutically acceptable salt, prodrug, hydrate, solvate or clathrate thereof.
  • the term "managing” encompasses preventing the recurrence of cancer in a patient who had suffered from cancer, lengthening the time a patient who had suffered from cancer remains in remission, preventing the occurrence of cancer in patients at risk of suffering from cancer (e.g., patients who had been exposed to high amounts of radiation or carcinogenic materials, such as asbestos; patients infected with virases associated with the occurrence of cancer, such as, but not limited to, HIV and Kaposi's sarcoma-associated he ⁇ sviras; and patients with genetic predispositions to cancer, such as those suffering from Downs syndrome), and preventing the occurrence of malignant cancer in patients suffering from pre-malignant or non-malignant cancers.
  • cancer e.g., patients who had been exposed to high amounts of radiation or carcinogenic materials, such as asbestos; patients infected with virases associated with the occurrence of cancer, such as, but not limited to, HIV and Kaposi's sarcoma-associated he ⁇ sviras
  • therapeutically effective amount refers to an amount that provides a therapeutic benefit in the treatment, prevention, or management of cancer.
  • the specific amount that is therapeutically effective can be readily determined by ordinary medical practitioner, and may vary depending on factors know in the art, such as the type of cancer, the patient's history and age, the stage of cancer, the administration of other anti-cancer agents, including radiation therapy.
  • Methods of the invention can be used to treat and manage patients suffering from primary and metastatic cancer. They further encompass methods of treating patients who , v ⁇ treated for cancer.
  • the invention encompasses first-line, second-line, third-line and further lines cancer treatments.
  • Cancers that can be treated and managed using methods of the invention include but are not limited to, cancers of the bladder, bone or blood, brain, breast, cervix, chest, colon, endrometrium, esophagus, eye, head, kidney, liver, lymph nodes, lung, mouth, neck, ovaries, pancreas, prostate, rectum, stomach, testis, throat, and uterus.
  • cancers include, but are not limited to: AIDS associated leukemia and adult T-cell leukemia lymphoma; anal carcinoma; astrocytoma; biliary tract cancer; cancer of the bladder, including bladder carcinoma; brain cancer, including glioblastomas and medulloblastomas; breast cancer, including breast carcinoma; cervical cancer; choriocarcinoma; colon cancer including colorectal carcinoma; endometrial cancer; esophageal cancer; Ewing's sarcoma; gastric cancer; gestational trophoblastic carcinoma; glioma; hairy cell leukemia; head and neck carcinoma; hematological neoplasms, including acute and chronic lymphocytic and myelogeneous leukemia; hepatocellular carcinoma; Kaposi's sarcoma; kidney cancer; multiple myeloma; intraepithelial neoplasms, including Bowen's disease and Paget's disease; liver cancer; lung cancer including small cell
  • the compounds of the present invention are used to inhibit the growth of a cancer cell, wherein the cancer is leukemia, lymphoma, melanoma, or cancer of the liver, lung, pancreas, stomach, thyroid, larygopharnx, skin, uterus, breast, colon, cervix, ovary, testis, prostate or rectum. More specifically, the compounds of the j v uu.w ⁇ o g e g w , wnerein me cancer is leukemia, melanoma, or cancer of breast, colon or lung.
  • the compounds used in methods and compositions of the invention include a wide variety of compounds, the suitability of which can be readily determined by those of ordinary skill using methods disclosed herein and known in the art.
  • the compounds of this invention would encompass antihistaminic agents and compounds that are structurally or functionally related to the antihistaminic agents.
  • Preferred compounds of the invention are antihistaminic agents.
  • antihistaminic agents that can be used for the pmpose of this invention include, but are not limited to: alkylamines such as acrivastine, brompheniramine, chlo ⁇ heniramine and tripolidine; ethanolamine derivatives such as carbinoxamine, clemastine, diphenhydramine, dimenhydrinate and doxylamine; ethyleneamine derivatives such as mepyramine-type compounds, pyrilamine and tripelennamine; phenothiazine derivatives such as dimethiothiazine, hydroxyethylpromethazine, isothipendyl, mequitazine, methdilazine, oxomemazine, promethazine, propiomazine, thiazinamium and trimeprazine; piperidine derivatives such as astemizole, fexofenadine, levocabastine, loratadine, tefenadine and mizolastine;
  • Examples of other structurally and functionally related compounds include, but are not limited to: dopamine antagonists such as, but not limited to, chlo ⁇ romazine, thioxanthenes including thioridazine; selective serotonin uptake inhibitors such as, but not limited to, clomipramine, nefazodone, paroxetine, sertraline, fluoxetine, fluvoxamine and citalopram; antidepressants such as, but not limited to, amitryptiline, doxepin, nortryptiline, venlafaxine trazodone, nefazodone, mianserine and minalcitran; other compounds such as flupentixol, fluphenazine, clemastine, fumarate, pyrimethamine, maprotiline, pe ⁇ henazine, cyproheptadine, ketotifen, imipramine, levomepromazine, promazine, chlo ⁇
  • Specific compounds include, but are not limited to, hydroxyzine, promethazine, pe ⁇ henazine, sertraline, thioridazine, chlo ⁇ romazine, paroxetine, flupentixol, , , , clathrates thereof.
  • the antihistaminic agent is not polaramine.
  • This invention encompasses the use of the compounds of this invention in combination with one or more second anti-cancer agents, or pharmaceutically acceptable salts, prodrugs, hydrates, solvates or clathrates thereof.
  • the compounds of this invention can be administered simultaneously or sequentially with antineoplastic agents such as antimetabolites, alkylating agents, spindle poisons and/or intercalating agents, and proteins such as interferons.
  • Examples of particular second anti-cancer agents include, but are not limited to: acivicin; aclarabicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthracycline; anthramycin; aromatase inhibitors; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride
  • Still other anti-cancer drugs include, but are not limited to: 20-epi-l,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrabicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing mo ⁇ hogenetic protein- 1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-
  • axinastatin 2 axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; bufhionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; car
  • B itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lom ⁇ tr ⁇ xol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol
  • N-substituted benzamides N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphte ⁇ in; nartograstim; nedaplatin; nemorabicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues; paclitaxel derivatives; palauamine; palmitoylrh
  • squalamine stem cell inhibitor; stem-cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl
  • second anti-cancer agents that can be used to treat leukemia include, but are not limited to, prednisone, vincristine, anthracycline, asparaginase, cytarabine, etoposide, cyclophosphamide, methofrexate, leucovorin, cytosine arabinose, corticosteroids, daunorabicin, idarubicin, 6-thioguanine, chlorambucil, fludarabine, interferon ⁇ , deoxyconformycin, 2-chlorodeoxyadenosine, hydroxyurea, 6-myelopurine,
  • 6-thioguanine and/or melpharan 6-thioguanine and/or melpharan.
  • Examples of the second anti-cancer agents that can be used to treat melanoma include, but are not limited to, dacarbazine, nitrosoureas carmustine, lomustine, cisplatin and/or interleukin-2; examples of the second anti-cancer agents that can be used to treat breast cancer include, but are not limited to, cyclophosphamide, 5-fluorouracil, methofrexate, doxorabicin, tamoxifen, progestins, aromatase inhibitors, aminoglutethimide, letrozole, paclitaxel, docetaxel, navelbine, capecitabine, mitomycin
  • Examples of the second anti-cancer agents that can be used to treat colon cancer include, but are not limited to, fluorouracil, folinic acid, levamisole, leucovorin, oxaliplatin or irinotecan.
  • Examples of the second anti-cancer agents that can be used to treat lung cancer include, but are not limited to, cisplastin, topoisomerase inhibitors, carboplatin, vinorelbine, vincristine, vinblastine, docetaxel, oxaliplatin or paclitaxel.
  • the compounds of this invention and second anti-cancer agents can be administered to patients simultaneously or sequentially by the same or different routes of administration.
  • treatment of tumors on the skin or on exposed mucosal tissue may be more effective if one or both active ingredients are administered topically, transdermally or mucosally (e.g., by nasal, sublingual, buccal, rectal, or vaginal administration).
  • Treatment of tumors within the body, or prevention of cancers that may spread from one part of the body to another, may be more effective if one or both of the active ingredients are administered parenterally or orally.
  • parenteral administration may be preferred for the acute treatment of a disease
  • transdermal or subcutaneous routes of administration may be employed for chronic treatment or prevention of a disease.
  • Preferred routes of administration for the anti-cancer agents are known to those of ordinary skill in the art.
  • This invention encompasses pharmaceutical compositions comprising an antihistaminic agent or a stracturally/functionally related compound, or a pharmaceutically acceptable salt, prodrug, hydrate, solvate or clathrate thereof, and a second anti-cancer agent, or a pharmaceutically acceptable salt, prodrug, hydrate, solvate or clathrate thereof.
  • the compounds of this invention and second anti-cancer agents that can be inco ⁇ orated into such compositions are disclosed herein (e.g., in Section 4.1., above).
  • compositions are single unit dosage fom s suitable for oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intraarterial), or transdermal administration to a patient.
  • mucosal e.g., nasal, sublingual, vaginal, buccal, or rectal
  • parenteral e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intraarterial
  • transdermal administration e.g., transdermal administration to a patient.
  • dosage forms include, but are not limited to: tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; ointments; cataplasms (poultices); pastes; powders; dressings; creams; plasters; solutions; patches; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (e.g.
  • aqueous or non-aqueous liquid suspensions oil-in-water emulsions, or a water-in-oil liquid emulsions
  • solutions and elixirs
  • liquid dosage forms suitable for parenteral administration to a patient and sterile solids (e.g., crystalline or amo ⁇ hous ( -- -" ⁇ r administration to a patient.
  • composition, shape, and type of dosage forms of the invention will typically vary depending on their use.
  • a dosage form used in the acute treatment of a disease may contain larger amounts of one or more of the active ingredients it comprises than a dosage form used in the chronic treatment of the same disease.
  • a parenteral dosage form may contain smaller amounts of one or more of the active ingredients it comprises than an oral dosage form used to treat the same disease.
  • Typical pharmaceutical compositions and dosage forms comprise one or more excipients.
  • Suitable excipients are well known to those skilled in the art of pharmacy, and non-limiting examples of suitable excipients are provided herein. Whether a particular excipient is suitable for inco ⁇ oration into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art including, but not limited to, the way in which the dosage form will be administered to a patient.
  • oral dosage forms such as tablets may contain excipients not suited for use in parenteral dosage forms. The suitability of a particular excipient may also depend on the specific active ingredients in the dosage fonn.
  • the decomposition of some active ingredients may be accelerated by some excipients such as lactose, or when exposed to water.
  • Active ingredients that comprise primary or secondary amines are particularly susceptible to such accelerated decomposition. Consequently, this invention encompasses pharmaceutical compositions and dosage forms that contain little, if any, lactose other mono- or di-saccharides.
  • lactose-free means that the amount of lactose present, if any, is insufficient to substantially increase the degradation rate of an active ingredient.
  • Lactose-free compositions of the invention can comprise excipients that are well known in the art and are listed, for example, in the U.S. Pharmacopeia (USP) 25-NF20 (2002).
  • lactose-free compositions comprise active ingredients, a binder/filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts.
  • Prefened lactose-free dosage forms comprise active ingredients, microcrystalline cellulose, pre-gelatinized starch, and magnesium stearate.
  • water e.g., 5%
  • water e.g., 5%
  • water and heat accelerate the decomposition of some compounds.
  • the effect of water on a formulation can be of great significance since moisture and/or humidity are commonly encountered during manufacture, handling, packaging, storage, shipment, and use of formulations.
  • Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.
  • Pharmaceutical compositions and dosage forms that comprise lactose and at least one active ingredient that comprises a primary or secondary amine are preferably anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected.
  • anhydrous phannaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions are preferably packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.
  • the invention further encompasses pharmaceutical compositions and dosage forms that comprise one or more compounds that reduce the rate by which an active ingredient will decompose.
  • Such compounds which are refened to herein as
  • antioxidants include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.
  • the amounts and specific types of active ingredients in a dosage form may differ depending on factors such as, but not limited to, the route by which it is to be administered to patients. > > >
  • compositions of the invention that are suitable for oral administration can be presented as discrete dosage forms, such as, but are not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g., flavored syrups).
  • dosage forms contain predetermined amounts of active ingredients, and may be prepared by methods of pharmacy well known to those skilled in the art. See generally, Remington 's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA (1990).
  • Typical oral dosage forms of the invention are prepared by combining the active ingredients in an intimate admixture with at least one excipient according to conventional pharmaceutical compounding techniques.
  • Excipients can take a wide variety of forms depending on the form of preparation desired for administration.
  • excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents.
  • excipients suitable for use in solid oral dosage forms include, but are not limited to, starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents.
  • tablets and capsules represent the most advantageous oral dosage unit fomis, in which case solid excipients are employed. If desired, tablets can be coated by standard aqueous or nonaqueous techniques. Such dosage forms can be prepared by any of the methods of pharmacy. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid earners, finely divided solid earners, or both, and then shaping the product into the desired presentation if necessary.
  • a tablet can be prepared by compression or molding.
  • Compressed tablets can be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as powder or granules, optionally mixed with an excipient.
  • Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • excipients that can be used in oral dosage forms of the invention include, but are not limited to, binders, fillers, disintegrants, and lubricants.
  • Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, com starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar . ., , cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pynolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos.
  • microcrystalline cellulose and mixtures thereof.
  • Suitable forms of microcrystalline cellulose include, but are not limited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICEL RC-581, AVICEL-PH- 105 (available from FMC Co ⁇ oration, American Viscose Division, Avicel Sales, Marcus Hook, PA), and mixtures thereof.
  • An specific binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL RC-581.
  • Suitable anhydrous or low moisture excipients or additives include AVICEL-PH-103TM and Starch 1500 LM.
  • fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.
  • the binder or filler in pharmaceutical compositions of the invention is typically present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.
  • Disintegrants are used in the compositions of the invention to provide tablets that disintegrate when exposed to an aqueous environment. Tablets that contain too much disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients should be used to form solid oral dosage forms of the invention.
  • the amount of disintegrant used varies based upon the type of formulation, and is readily discernible to those of ordinary skill in the art.
  • Typical pharmaceutical compositions comprise from about 0.5 to about 15 weight percent of disintegrant, preferably from about 1 to about 5 weight percent of disintegrant.
  • Disintegrants that can be used in pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.
  • the invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, com oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof.
  • hydrogenated vegetable oil e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, com oil, and soybean oil
  • zinc stearate ethyl oleate, ethyl laureate, agar, and mixtures thereof.
  • Additional lubricants include, for example, a syloid silica gel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore, MD), a coagulated aerosol of synthetic silica (marketed by Degussa Co. of Piano, TX), CAB-O-SIL (apyrogenic silicon dioxide product sold by Cabot Co. of Boston, MA), and mixtures thereof. If used at all, lubricants are typically used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are inco ⁇ orated.
  • AEROSIL 200 a syloid silica gel
  • a coagulated aerosol of synthetic silica marketed by Degussa Co. of Piano, TX
  • CAB-O-SIL apyrogenic silicon dioxide product sold by Cabot Co. of Boston, MA
  • lubricants are typically used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are inco ⁇ orated.
  • Active ingredients of the invention can be administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which is inco ⁇ orated herein by reference.
  • Such dosage forms can be used to provide slow or controlled-release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions.
  • Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active ingredients of the invention.
  • the invention thus encompasses single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled-release.
  • controlled-release pharmaceutical products have a common goal of improving drag therapy over that achieved by their non-controlled counte ⁇ arts.
  • the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time.
  • Advantages of controlled-release formulations include , , paueni compliance.
  • controlled-release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and can thus affect the occurrence of side (e.g., adverse) effects.
  • Controlled-release formulations are designed to initially release an amount of drag (active ingredient) that promptly produces the desired therapeutic effect, and gradually and continually release of other amounts of drag to maintain this level of therapeutic or prophylactic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drag must be released from the dosage form at a rate that will replace the amount of drag being metabolized and excreted from the body.
  • Controlled-release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.
  • Parenteral dosage forms can be administered to patients by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Because their administration typically bypasses patients' natural defenses against contaminants, parenteral dosage forms are preferably sterile or capable of being sterilized prior to administration to a patient. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions.
  • Suitable vehicles that can be used to provide parenteral dosage forms of the invention are well known to those skilled in the art. Examples include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium
  • Chloride Injection Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection
  • water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol
  • non-aqueous vehicles such as, but not limited to, com oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
  • Transdermal, topical, and mucosal dosage forms of the invention include, but are not limited to, ophthalmic solutions, sprays, aerosols, creams, lotions, ointments, gels, solutions, emulsions, suspensions, or other fonns known to one of skill in the art. See, e.g., Remington 's Pharmaceutical Sciences, 16 th and 18 th eds., Mack Publishing, Easton PA (1980 & 1990); and Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger, Philadelphia (1985).
  • transdermal dosage fonns include "reservoir type” or “matrix type” patches, which can be applied to the skin and worn for a specific period of time to permit the penetration of a desired amount of active ingredients.
  • Suitable excipients e.g. , carriers and diluents
  • other materials that can be used to provide transdermal, topical, and mucosal dosage forms encompassed by this invention are well known to those skilled in the pharmaceutical arts, and depend on the particular tissue to which a given pharmaceutical composition or dosage form will be applied.
  • excipients include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane- 1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof to form lotions, tinctures, creams, emulsions, gels or ointments, which are non-toxic and pharmaceutically acceptable.
  • Moisturizers or humectants can also be added to pharmaceutical compositions and dosage forms if desired. Examples of such additional ingredients are well known in the art. See, e.g. , Remington 's Pharmaceutical Sciences, 16 th and 18 th eds., Mack Publishing, Easton PA (1980 & 1990).
  • penetration enhancers can be used to assist in delivering the active ingredients to the tissue.
  • Suitable penetration enhancers include, but are not limited to: acetone; various alcohols such as ethanol, oleyl, and tetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethyl acetamide; dimethyl formamide; ⁇ n gra ⁇ es (Povidone, Polyvidone); urea; and various water-soluble or insoluble sugar esters such as Tween 80 (polysorbate 80) and Span 60 (sorbitan monostearate).
  • the pH of a pharmaceutical composition or dosage form, or of the tissue to which the pharmaceutical composition or dosage form is applied may also be adjusted to improve delivery of one or more active ingredients.
  • the polarity of a solvent earner, its ionic strength, or tonicity can be adjusted to improve delivery.
  • Compounds such as stearates can also be added to phannaceutical compositions or dosage forms to advantageously alter the hydrophilicity or lipophilicity of one or more active ingredients so as to improve delivery.
  • stearates can serve as a lipid vehicle for the formulation, as an emulsifying agent or surfactant, and as a delivery-enhancing or penetration-enhancing agent.
  • Different salts, hydrates or solvates of the active ingredients can be used to further adjust the properties of the resulting composition.
  • kits In some cases, active ingredients of the invention are preferably not administered to a patient at the same time or by the same route of administration. This invention therefore encompasses kits which, when used by the medical practitioner, can simplify the administration of appropriate amounts of active ingredients to a patient.
  • kits of the invention comprises a single unit dosage form of an antihistaminic agent or a stracturally/functionally related compound, or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, or clathrate thereof, and a single unit dosage form of a second anti-cancer agent, or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, or clathrate thereof.
  • Kits of the invention can further comprise devices that are used to administer the active ingredients. Examples of such devices include, but are not limited to, syringes, drip bags, patches, and inhalers.
  • Kits of the invention can further comprise pharmaceutically acceptable vehicles that can be used to administer one or more active ingredients.
  • the kit can comprise a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a particulate-free sterile solution that is suitable for parenteral administration.
  • Examples of pharmaceutically acceptable vehicles include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited , ⁇ u ui c u , nj e __ o , e _ _ , exu ⁇ se Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, com oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
  • aqueous vehicles such as, but not limited , ⁇ u ui c u , nj e __ o , e _ _ , exu ⁇ se Sodium Chloride Injection, and Lactated Ringer's
  • this invention encompasses a method of determining whether a cancer patient will respond to a cancer treatment comprising testing for overexpression of TPTl gene in cancer cells from the patient, wherein the cancer treatment is administration of an antihistaminic agent or a stracturally/functionally related compound, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or clathrate thereof.
  • TPTl gene can be monitored using techniques well_known in the art.
  • One such technique is to monitor the cellular level of the product of TPTl gene, namely TCTP, based on electrophoresis methods.
  • the intensity of the band conesponding to TCTP can be quantified using various techniques including, but not limited to, densitometry, fluorometry, spectrometry and luminometry. Using the quantification, it is possible to determine whether TCTP is present at a higher level in cancer cells than in normal cells.
  • the tenn "overexpression” means that a higher level of TCTP is present in cancer cells as compared with nonnal cells.
  • "overexpression” would result in about 20 percent or more, specifically about 50 percent or more, more specifically about 100 percent or more, and most specifically about 200 percent or more TCTP formation in cancer cells as compared with normal cells.
  • a cancer treatment is effective in a patient receiving the treatment by monitoring the decreased expression of TPTl gene as c ⁇ i ci j ⁇ ⁇ gi . , _ _ e ntio to a method of determining the effectiveness of a cancer treatment comprising: obtaining cancer cells from a patient being treated at a first time and at a second time; and determining if expression of TPTl gene in cells obtained at the second time is less than the expression of TPTl gene in cells obtained at the first time; wherein the first time is earlier than the second time.
  • cytotoxic activity of the following four compounds were tested: hydroxyzine dihydrochlori.de (Atrax ® , Atranine A, designated as “A”); brompheniramine maleate (Dimegan ® , Atranine B, designated as “B”); promethazine (Phenergan ® , Atranine C, designated as “C”); and dexchlo ⁇ heniramine maleate (Polaramine ® , Atranine D, designated as "D").
  • KS revertant of K562 that exhibits reduced tumorigenicity
  • US4 revertant of U937 that exhibits reduced tumorigenicity
  • Jurkat T lymphocyte, acute leukemia of T cells
  • T47-D breast cancer, ductal carcinoma
  • MCF7 breast cancer, ductal carcinoma
  • BT20 breast cancer, carcinoma of the mammary glands
  • LoVo colorectal adenocarcinoma
  • MCF10A breast, immortalized , non-tumorigenic luminal epithelium cells; and T and B cells freshly isolated from three healthy donors. va u e nes were per orme accor ng o e ionowing procedures.
  • All leukemic cell lines were grown and used in logarithmic phase. After one day of treatment, the cells were isolated, counted and diluted in a regular growth medium to provide the cell density of about 75 x 10 3 cells/ml for reading on plates at 48 hours after the treatment, and 9.375 cells/ml for reading at 144 hours after the treatment.
  • the blood from healthy donors was collected on citrate and diluted 1 : 1 with 0.15M NaCl.
  • the dilution (6 ml) was loaded onto 3ml of lymphoprep ® (Nycomed), and the mixture was centrifuged at 800 g for 30 minutes at room temperature.
  • the white cells were isolated and washed with RPMI 1640 and 10% FBS.
  • the white cells were diluted to provide 450,000 cells/ml in RPMI1640/10% FSB medium.
  • the tests for the compounds of this invention were perfom ed according to the same procedures described in Section 5.1.1.
  • Adherent Cells of Breast and Colon The cells were grown on their respective propagation medium and seeded 24 hours before the compounds are added. The cells were trypsinized, and 50,000 cells/well and 10,000 cells/well were seeded in order to read the plates at 48 hours and 144 hours after being treated by the compounds, respectively.
  • the medium was replaced by 10 ml each of series dilution of the compounds, consisting of: control, which contained no compound of this u , u on; : , u on; an : , ⁇ ⁇ ut ⁇ om ⁇ ne starting concentrations for these dilutions were: 50 mg/ml for compound A; 10 mg/ml for compound B; 25 mg/ml for compound C; and 5 mg/ml for compound D.
  • the dilution was made using the growth medium.
  • a tested compound is regarded as being active in cytotoxicity where the percentage of surviving cells after the treatment with the compound is less than 30%.
  • Figures 8 A, 8B and 9 show the results obtained from these tests using the lymphocytes from three different healthy donors. As shown in these figures, the surviving cell counts from these lymphocytes at 48 hours after the treatment with compound A or C, even at 1 : 1,000 dilution level, are substantial. This result shows that compounds A and C exhibit a differential effect on the healthy and cancerous cells. In order to demonstrate that this phenomenon is not arising from a general cytotoxicity of compounds A and C, assays were canied out on LoVo cancer cells, which are resistant to the cytopathic effect of the parvo virus HI . Figure 10A shows that LoVo cancer cells are totally resistant to the antihistamines. This result indicates that the cytotoxicity of compounds A and C are not non-specific.
  • ATRA Trans Retinoic Acid
  • ARA-C cytarabine
  • scid/scid mice As a positive control, ARA-C (cytarabine), which is a known antimitotic agent, was administered to six scid/scid mice at a concentration of 100 mg/kg. The administration of ARA-C resulted in tumor development in none of the six mice tested ( Figure HE).
  • U937 cells were treated with various dilutions of hydroxyzine, brompheniramine and promethazine for 24 hours as denoted in Figure 23A.
  • Starting concentrations were: 50 mg/ml for hydrazine ("A”); 10 mg/ml for brompheniramine ("B”); and 25 mg/ml for promethazine ("C”).
  • the proteins were isolated from these cells and loaded onto a gel for western blot analysis.
  • a specific anti-TCTP (anti-HRF) antibody was used to visualize the location of TCTP.
  • anti-HRF anti-HRF
  • U937 cells were treated with various concentrations of hydroxyzine and promethazine for 24 hours.
  • the proteins were isolated from these cells and loaded onto a gel for a western blot analysis.
  • a specific anti-PARP antibody was used to visualize the location of PARP.
  • the results showed that hydroxyzine and promethazine, as well as staurosporine (positive control), cleave PARP, indicating the induction of apoptosis.
  • a test was developed in a multi-well plate. Two leukemic cell lines, namely K562 and U937, and three breast cancer cell lines, namely MDA-DB231, BT20 and MCF7 were used for this test.
  • the cells were seeded at low density and were left for 24 hours to recover and reach a new logarithmic phase of growth.
  • Various concentrations of the compounds being tested ranging from 2xl0 "9 M to 2xl0 "4 M, were added in triplicate. The mixture was incubated for 6 days, during which approximately 4 doublings of the cell population occuned, to allow the cells to reach subconfluence.
  • the viability of the cultured cells after the treatment by the compounds was determined by quantifying the level of ATP since the level of ATP is directly proportional to the number of viable cells present in the culture.
  • the ATP level was quantified by using CellTiter-GloTM (Promega) luminescent test for cell viability.
  • group I encompassing the compounds exhibiting powerful cytotoxic effects at log-5 M
  • group II encompassing the compounds exhibiting cytotoxic effects at log-5 M, but with a less degree than that of compounds in group I
  • group III encompassing the compounds that are highly toxic at log-4 M, but less toxic at log-5 M.
  • the compounds that can be classified as group I are pe ⁇ henazine, sertraline, thioridazine, chlo ⁇ romazine, paroxetine and flupentixol. Their cytotoxic effects are shown in Figure 12.
  • the compounds of group II include fluphenazine, loratadine, clemastine, fumarate, pyrimethamine, clomipramine and nortryptiline. Their cytotoxic effects are shown in Figure 13.
  • the compounds of group III include maprotiline, i ⁇ iic ttuiuc, u ⁇ , _ , xa e, u , a me, lmip , levomepromazine, promazine, chlo ⁇ rothixene, haloperidol, nefazodone and chloroquine. Their cytotoxic effects are shown in Figure 14.
  • Figure 15 shows the effects of hydroxyzine, S64, SQ42, S60, S59, A37 and i41 on the growth of U937 cells.
  • Figures 15A through 15C conespond to the effects shown by these compounds at varying concentrations ranging from 10 "4 to 10 "6 M. The number is representation of cell death in excess of the usual death of 20-30 % observed in the negative control.
  • An assay in a multi-well plate was designed to assess the cytopathic effect of various antihistaminic or structurally/functionally related compounds.
  • the compounds tested were SQ42, S64, A37, S59, S60 and S26.
  • the compounds were prepared in their respective vehicle solution at a concentration of 1 x 10 "2 M. Following sterilization by filtration, the compounds were diluted to yield the concentrations as denoted in Figure 18.
  • Colon cancer cell lines consisting of DLD-1, SW1116, HCT-15, CACO-2, COLO-205, COLO-320-HSR, LOVO, SW-1463, SW-620, LS-180, SW-900, SW-948, SW-403, SW-48 and SW-837;
  • Lung cancer cell lines consisting of NCI-H-446, WI38, H-69-AR, NCI-H-209, NCI-H-510A, CALU-1, A549, A427, CALU-6, CALU-3, DMS-53, NCI-H-358, NCI-H- 520 and NCI-H-292; and
  • the first protocol is u ⁇ u ⁇ c co ⁇ t vii .
  • This protocol cancerous cells are inoculated to the animals, and the inoculated animals were left without any further treatment until the development of tumors.
  • the compounds of this invention were administered daily to the animals.
  • Figure 19 illustrates the curative effects of compounds S60 and S59 in U937 cells.
  • Figure 19A is the result obtained from a negative control, wherein the animals were treated with excipient only. Eight out of 10 mice tested rapidly developed tumors. In a positive control, wherein the animals were treated with ARA-C, no tumor development was observed (Figure 19B). As shown in Figures 19C and 19D, compounds S60 and S59 cause a delay in the tumor growth in U937 cells.
  • Figure 20 illustrates the curative effects of the compounds of this invention in MDA-MB-231 cell line.
  • the major tumor development commences around day 30.
  • Figure 20A illustrates the result obtained from second control, wherein the animals were treated with excipient only. Eight out of 10 mice developed tumors.
  • the compounds of this invention cause the decrease in tumor growth, at least at the higher concentration that was tested.
  • S64 at a concentration of 2.5 mg/kg, appears to cause a regression of the tumor volume ( Figure 20C).
  • promethazine either at a concentration of 11.25 mg/kg or 22.5 mg/kg ( Figure 20E).
  • Figure 20C the same is also true for certain animals treated with promethazine, either at a concentration of 11.25 mg/kg or 22.5 mg/kg.
  • Figure 20E For all other compounds tested, a general decrease in tumor growth was observed. In the case of compounds A37 and SQ42, higher dosage caused the death of certain test animals, but the general trend of decreased tumor growth remained the same with the surviving animals.
  • the second protocol was designed to test the preventive effects of the compounds of this invention on tumorigenesis.
  • the animals have been treated with various compounds of the present invention on day 1. After more than 24 hours, tumoral cells were inoculated. The administration of the compounds of this invention was maintained daily. The cell line used for this test was U937.
  • compounds S49, S60 and promethazine caused a decrease in tumor growth in U937 cell line compared to the negative control. The death of certain animals tested. However, it does appear that these compounds also cause the decrease in tumor growth.
  • TCTP expression in tissues from various normal and cancerous organs was analyzed using a western blot analysis.
  • the normal and cancerous tissues tested were obtained from liver, lung, pancreas, stomach, thyroid, laryngopharynx, skin, uterus, breast, cervix, ovary, testis, prostate and rectum.
  • the proteins were isolated from these tissues and loaded onto a gel for western blot analysis.
  • a specific anti-TCTP (anti-HRF) antibody was used to visualize the location of TCTP.
  • Figure 23 shows that down regulation of TCTP is exhibited in all cells treated with these antihistamines.
  • the level of actin in equal loading of extract was visualized by anti-actin antibody (Santa Craz Biotechnology). As shown in Figure 23, no substantial difference between the level of actin in treated and untreated cells was observed. This result shows that these antihistamines selectively act on the TCTP expression.
  • the conversion of prefluorescent caspase substrate rhodamine 110-Z-DEVD to fluorescent product was determined by monitoring the fluorescence of the mixture. The fluorescence was measured on a fluorimeter at 499 nm excitation and 521 nm emission.

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Abstract

Méthodes de traitement et de surveillance du cancer, qui consistent à administrer un agent antihistaminique ou un composé structurellement / fonctionnellement apparenté à ce composé, éventuellement en combinaison avec un ou plusieurs agents anticancéreux supplémentaires. Des compositions pharmaceutiques, dont des formes posologiques unitaires, et des kits utiles pour traiter et surveiller le cancer sont également décrits. Une méthode permettant de déterminer l'efficacité d'un traitement contre le cancer est en outre décrite.
EP03714956A 2003-03-12 2003-03-12 Methodes et compositions pour le traitement du cancer Withdrawn EP1656124A1 (fr)

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WO2012080509A1 (fr) * 2010-12-17 2012-06-21 Institut National De La Sante Et De La Recherche Medicale (Inserm) Acides nucléiques ciblant tctp pour emploi dans le traitement de cancers chimiorésistants ou hormonorésistants
US20150328193A1 (en) * 2012-12-17 2015-11-19 The Brigham And Women's Hospital, Inc. Treatment of mtor hyperactive related diseases and disorders
US9925202B2 (en) 2013-03-04 2018-03-27 Brigham And Women's Hospital, Inc. Treatment of lymphangioleiomyomatosis
AU2016208673B2 (en) 2015-01-19 2021-04-01 Belina Pharma Ab Antihistamine for use in treatment of breast cancer
WO2017000084A1 (fr) * 2015-06-30 2017-01-05 上海交通大学 Utilisation de la prométhazine pour la préparation d'un produit de lutte contre le cancer du foie et/ou le cancer colorectal et/ou le cancer du poumon
IL300476B2 (en) * 2015-06-30 2024-07-01 Eiger Group Int Inc Use of chloroquine and clemizole compounds for treatment of inflammatory and cancerous conditions
CN106361752A (zh) * 2016-08-31 2017-02-01 清华大学深圳研究生院 氟哌噻吨的新用途
IL322309A (en) 2017-05-24 2025-09-01 Novartis Ag IL2 antibody grafted proteins and methods of use in cancer treatment
FR3071726B1 (fr) * 2017-09-29 2020-09-04 Univ Paris Sud Agents inhibant la proteine tctp pour le traitement de maladies proliferatives et de maladies infectieuses
WO2019204154A1 (fr) * 2018-04-18 2019-10-24 Reyoung Corporation Compositions et méthodes pour le traitement du cancer du foie
CN114432446B (zh) * 2020-11-05 2023-07-04 南湖实验室 抗组胺药在制备抗肿瘤药物中的应用
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