WO2004007676A2 - Therapie combinee servant a traiter des tumeurs - Google Patents

Therapie combinee servant a traiter des tumeurs Download PDF

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Publication number
WO2004007676A2
WO2004007676A2 PCT/US2003/021783 US0321783W WO2004007676A2 WO 2004007676 A2 WO2004007676 A2 WO 2004007676A2 US 0321783 W US0321783 W US 0321783W WO 2004007676 A2 WO2004007676 A2 WO 2004007676A2
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WIPO (PCT)
Prior art keywords
compound
ciclopirox
cancer
antiproliferative agent
administered
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PCT/US2003/021783
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English (en)
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WO2004007676A3 (fr
Inventor
Margaret S. Lee
Curtis Keith
Benjamin A. Auspitz
Grant R. Zimmermann
M. James Nichols
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Combinatorx, Incorporated
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Priority to AU2003251875A priority Critical patent/AU2003251875A1/en
Publication of WO2004007676A2 publication Critical patent/WO2004007676A2/fr
Publication of WO2004007676A3 publication Critical patent/WO2004007676A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—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
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • 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
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring

Definitions

  • the invention relates to the treatment of neoplasms such as cancer.
  • Cancer is a disease marked by the uncontrolled growth of abnormal cells. Cancer cells have overcome the barriers imposed on normal cells, which have a finite lifespan, to grow indefinitely. As the growth of cancer cells continue, genetic alterations may persist until the cancerous cell has manifested itself to pursue a more aggressive growth phenotype. If left untreated, metastasis, the spread of cancer cells to distant areas of the body by way of the lymph system or bloodstream, may ensue, destroying healthy tissue.
  • Non-small cell lung cancer squamous cell carcinoma, adenocarcinoma, and large cell carcinoma
  • small cell lung cancer is the less common type, accounting for about 20% of all lung cancer.
  • Other cancers include brain cancer, breast cancer, cervical cancer, colon cancer, gastric cancer, kidney cancer, leukemia, liver cancer, lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, sarcoma, skin cancer, testicular cancer, and uterine cancer. These cancers, like lung cancer, are sometimes treated with chemotherapy.
  • Antiproliferative agents currently in use or in clinical trials include paclitaxel, docetaxel, tamoxifen, vinorelbine, gemcitabine, cisplatin, etoposide, topotecan, irinotecan, anastrozole, rituximab, trastuzumab, fiudarabine, cyclophosphamide, gentuzumab, carboplatin, interferon, and doxorubicin.
  • the most commonly used anticancer agent is paclitaxel, which is used alone or in combination with other chemotherapy drugs such as: 5-FU, doxorubicin, vinorelbine, cytoxan, and cisplatin.
  • the invention features a method for treating a patient who has a neoplasm by administering to the patient (a) a ciclopirox analog having the formula:
  • Ri is H, OH, NH 2 , a halide, or any branched or unbranched, substituted or unsubstituted C ⁇ -10 alkyl, C ⁇ io alkoxyalkyl, C 1-10 hydroxyalkyl, C ⁇ _ ⁇ o aminoalkyl, C O alkylaminoalkyl, C 4- ⁇ 0 cycloalkyl, C 5 . 8 aryl, or C 6 .
  • R 2 is H, OH, NH 2 , a halide, or any branched or unbranched, substituted or unsubstituted C MO alkyl, C 1-10 alkoxyalkyl, .io hydroxyalkyl, C ⁇ _ ⁇ 0 aminoalkyl, C 1-10 alkylaminoalkyl, C 4-10 cycloalkyl, C 5 _ 8 aryl, C 6 .
  • R is H, CH 3 , CH 3 CH 2 , (CH 3 ) 2 CH, (CH 3 CH 2 ) 2 CH, CH 3 0, CH 3 CH 2 0, (CH 3 ) 2 CHO, or (CH 3 CH 2 ) 2 CHO, and R 2 is cyclopentyl, cyclohexyl, CH 2 CH(CH3)CH 2 C(CH 3 )3, or
  • the compound is ciclopirox, rilopirox, or octopirox.
  • the invention also features a method for treating a patient who has a neoplasm by administering to the patient a functional ciclopirox analog and an antiproliferative agent simultaneously or within 14 days of each other in an amount sufficient to inhibit the neoplasm.
  • the functional ciclopirox analog is mimosine or geminin.
  • either the ciclopirox analog or the antiproliferative agent is approved by a national pharmaceutical regulatory agency, such as the United States Food and Drug Administration (USFDA), for administration to a human. More preferably, both the ciclopirox analog and the antiproliferative agent are approved by the pharmaceutical regulatory agency for administration to a human.
  • Preferred antiproliferative agents include paclitaxel, gemcitabine, doxorubicin, vinblastine, etoposide, 5-fluorouracil, and carboplatin.
  • Antiproliferative agents that can be administered in combination with ciclopirox or a ciclopirox analog for treating a neoplasm include those listed in Table 1. Table 1.
  • Platinum agents cisplatin carboplatinum oxaliplatin ZD-0473 (AnorMED) spiroplatinum, lobaplatin (Aeterna) carboxyphthalatoplatinum, satraplatin (Johnson Matthey) tetraplatin BBR-3464 (Hoffmann-La Roche) ormiplatin SM-11355 (Sumitomo) iproplatin AP-5280 (Access)
  • Antitumor dactinomycin (actinomycin D) amonafide antibiotics doxorubicin (adriamycin) azonafide deoxymbicin anthrapyrazole valrubicin oxantrazole daunombicin (daunomycin) losoxantrone epirubicin bleomycin sulfate (blenoxane) therarubicin bleomycinic acid idarubicin bleomycin A rubidazone bleomycin B plicamycinp mitomycin C porf ⁇ romycin MEN-10755 (Menarini) cyanomorpholinodoxorabicin GPX-100 (Gem Pharmaceuticals) mitoxantrone (novantrone) Ajitimitotic paclitaxel SB 408075 (GlaxoSrmthKlfne) agents docetaxel E7010 (Abbott) colchicine PG-TXL (Cell Therapeutic
  • TXD 258 (Aventis) PEG-paclitaxel (Enzon) epothilone B (Novartis) AZ10992 (Asahi)
  • Thymidylate pemetrexed (Eli Lilly) nolatrexed (Eximias) synthase inhibitors ZD-9331 (BTG) CoFactorTM (BioKeys)
  • DNA antagonists trabectedin (PharmaMar) mafosfamide (Baxter International) glufosfamide (Baxter International) apaziquone (Spectrum albumin + 32P (Isotope Solutions) Pharmaceuticals) thymectacin (NewBiotics) 06 benzyl guanine (Paligent) edotreotide (Novartis)
  • Histone tacedinaline Pfizer
  • pivaloyloxymethyl butyrate Tian
  • acetyltransferase SAHA Adijisawa
  • Depsipeptide Fujisawa
  • Immuno- interferon dexosome therapy (Anosys) modulators oncophage (Antigenics) pentrix (Australian Cancer GMK (Progenies) Technology) adenocarcinoma vaccine (Biomira) ISF-154 (Tragen) CTP-37 (AVI BioPharma) cancer vaccine (Intercell) IRX-2 (Immuno-Rx) norelin (Biostar) PEP-005 (Peplin Biotech) BLP-25 (Biomira) synchrovax vaccines (CTL Immuno) MGV (Progenies) melanoma vaccine (CTL Immuno) ⁇ -alethine (Dovetail) p21 RAS vaccine (GemVax) CLL therapy (Vasogen)
  • Photodynamic talaporfin (Light Sciences) Pd-bacteriopheophorbide (Yeda) agents Theralux (Theratechnologies) lutetium texaphyrin (Pharmacyclics) motexaf ⁇ n gadolinium (Pharmacyclics) hypericin
  • Tyrosine Kinase imatinib Novartis kahalide F (PharmaMar) Inhibitors leflunomide (Sugen/Pharmacia) CEP-701 (Cephalon) ZD 1839 (AstraZeneca) CEP-751 (Cephalon) erlotinib (Oncogene Science) MLN518 (Millenium) canertinib (Pfizer) PKC412 (Novartis) squalamine (Genaera) phenoxodiol () SU5416 (Pharmacia) rrastuzumab (Genentech) SU6668 (Pharmacia ) C225 (ImClone) ZD4190 (AstraZeneca) rhu-Mab (Genentech) ZD6474 (AstraZeneca) MDX-H210 (Medarex) vatalanib (Novartis) 2C4 (Genentech) PKI166 (No
  • SR-27897 CCK A inhibitor, Sanofi-Synthelabo
  • BCX-1777 PNP inhibitor, BioCryst
  • tocladesine cyclic AMP agonist, Ribapharm
  • ranpirnase ribonuclease stimulant, Alfacell
  • alvocidib CDK inhibitor, Aventis
  • galarubicin RNA synthesis inhibitor, Dong-A
  • CapCellTM (CYP450 stimulant, Bavarian Nordic)
  • R-flurbiprofen (NF-kappaB inhibitor, Encore)
  • GCS-100 gal3 antagonist, GlycoGenesys
  • 3CPA NF-kappaB inhibitor, Active Biotech
  • G17DT immunogen (gastrin inhibitor, Aphton) seocalcitol (vitamin D receptor agonist, Leo) efaproxiral (oxygenator, Allos Therapeutics) 131-I-TM-601 (DNA antagonist, TransMolecular)
  • PI-88 heparanase inhibitor, Progen
  • ODC inhibitor eflornithine
  • tesmilifene histamine antagonist
  • YM minodronic acid osteoclast inhibitor
  • SR-31747 IL-1 antagonist, Sanofi-Synthelabo
  • PG2 hematopoiesis enhancer, Pharmagenesis
  • CCI-779 mTOR kinase inhibitor, Wyeth
  • ImmunolTM triclosan oral rinse, Endo
  • exisulind PDE V inhibitor, Cell Pathways
  • triacetyluridine uridine prodrug , Wellstat
  • CP-461 PDE V inhibitor, Cell Pathways
  • SN-4071 sarcoma agent, Signature BioScience
  • WX-UK1 plasmaogen activator inhibitor, PCK-3145 (apoptosis promotor, Procyon)
  • PBI-1402 PMN stimulant, ProMetic CHS-828 (cytotoxic agent, Leo)
  • trans-retinoic acid differentiated, NTH
  • bortezomib proteasome inhibitor, Millennium
  • MX6 apoptosis promotor, MAXIA
  • SRL-172 T cell stimulant, SR Pharrna
  • apomine apoptosis promotor, ILEX Oncology
  • TLK-286 glutthione S transferase inhibitor, urocidin (apoptosis promotor, Bioniche)
  • PT-100 growth factor agonist
  • Point brostallicin apoptosis promotor, Pharmacia
  • CDA-II apoptosis promotor, Everlife
  • the ciclopirox analog and the antiproliferative agent are administered with 5 days of each other, within 24 hours of each other, within one hour of each other, or simultaneously.
  • the ciclopirox analog and the antiproliferative are administered in the same pharmaceutical formulation.
  • the ciclopirox analog and the antiproliferative agent can be administered either by the same or different routes. Routes of administration include intravenous, intramuscular, subcutaneous, rectal, oral, topical, intravaginal, ophthalmic, or inhalation administration.
  • the ciclopirox analog is administered in an amount, frequency, and duration that measurably enhances the effectiveness of the antiproliferative agent.
  • ciclopirox analogs are administered in an amount between 0.01 and 2000 mg/day, 0.1 and 1000 mg/day, or 1.0 and 500 mg/day.
  • ciclopirox analogs can be administered as a 0.5% to 25% w/v topical formulation. Topical formulations of ciclopirox analogs are particularly useful for treating cancers of the skin and glands of the dermis and epidermis (i.e., sweat glands and sebaceous glands).
  • the two drugs can be provided together in a composition that contains a pharmaceutically acceptable carrier.
  • the ciclopirox analog is preferably present in the composition in amounts of 1.0 to 2000 mg, or more preferably 10 to 1000 mg.
  • bulk preparations suitable for reformulating into single doses may contain higher amounts.
  • the ciclopirox analog and the antiproliferative agent can be provided as components of a pharmaceutical pack.
  • the two ⁇ drugs can be formulated together or separately and in individual dosage amounts.
  • the structural or functional ciclopirox analogs can be administered in combination with two, three, four, or more antiproliferative agents, in amounts and frequencies sufficient to inhibit growth of the neoplasm.
  • the structural ciclopirox analog and each of the antiproliferative agents are administered at least once during a 28-day period.
  • the structural ciclopirox analog and/or any of the antiproliferative agents may be administered twice, three times, four times, or even daily (28 times) during a 28-day period, as required to inhibit growth of the neoplasm.
  • a method for treating a patient who has a neoplasm by administering to the patient a structural ciclopirox analog in an amount sufficient to inhibit the neoplasm.
  • the functional ciclopirox analog is ciclopirox, rilopirox, or octopirox.
  • the methods and compositions of the invention are particularly useful for treating neoplasms that are cancerous.
  • cancers of the lung e.g., non-small cell carcinoma
  • colon colon, ovary, and prostate.
  • an “antiproliferative agent” is meant a compound that, individually, inhibits the growth of a neoplasm.
  • Antiproliferative agents include, but are not limited to microtubule inhibitors, topoisomerase inhibitors, platins, alkylating agents, and anti-metabolites.
  • antiproliferative agents include paclitaxel, gemcitabine, doxorubicin, vinblastine, etoposide, 5-fluorouracil, carboplatin, altretamine, aminoglutethimide, amsacrine, anastrozole, azacitidine, bleomycin, busulfan, carmustine, chlorambucil, 2- chlorodeoxyadenosine, cisplatin, colchicine, cyclophosphamide, cytarabine, cytoxan, dacarbazine, dactinomycin, daunorubicin, docetaxel, estramustine phosphate, floxuridine, fludarabine, gentuzumab, hexamethylmelamine, hydroxyurea, ifosfamide, imatinib, interferon, irinotecan, lomustine, mechlorethamine, melphalen, 6-mercaptopurine, methotrexate, mit
  • neoplasm measurably slows, stops, or reverses the growth rate of the neoplasm or neoplastic cells in vitro or in vivo.
  • a slowing of the growth rate is by at least 20%, 30%, 50%, or even 70%, as determined using a suitable assay for determination of cell growth rates (e.g., a cell growth assay described herein).
  • a reversal of growth rate is accomplished by initiating or accelerating necrotic or apoptotic mechanisms of cell death in the neoplastic cells, resulting in a shrinkage of the neoplasm.
  • an effective amount is meant an amount of a compound, alone or in a combination according to the invention, required to inhibit the growth of a neoplasm in vivo.
  • the effective amount of active compound(s) used to practice the present invention for therapeutic treatment of neoplasms varies depending upon the manner of administration, the age, body weight, and general health of the subject. Ultimately, the attending physician or veterinarian will decide the appropriate amount and dosage regimen. Such amount is referred to as an "effective" amount.
  • a ciclopirox analog with an anti-proliferative agent for the treatment of neoplasms, allows for the administration of lower doses of each compound, providing similar efficacy and reduced toxicity, or increased efficacy with similar or reduced toxicity, compared to administration of either compound alone.
  • the combination of a ciclopirox analog with an anti-proliferative agent allows for the administration of similar doses of each compound, providing improved efficacy with similar or reduced toxicity, compared to the administration of either compound alone.
  • alkyl As used herein, the terms “alkyl,” “alkenyl,” and the prefix “alk-” are inclusive of both straight chain and branched chain groups and of cyclic groups, i.e., cycloalkyl and cycloalkenyl groups.
  • Cyclic groups can be monocyclic or polycyclic and preferably have from 3 to 20 ring carbon atoms, inclusive.
  • Exemplary cyclic groups include cyclopropyl, cyclopentyl, cyclohexyl, and adamantyl groups.
  • aromatic residue is meant an aromatic group having a ring system with conjugated ⁇ electrons (e.g., phenyl, or imidazole ).
  • the ring of the aryl group is preferably 5 to 10 atoms.
  • the aromatic ring may be exclusively composed of carbon atoms or may be composed of a mixture of carbon atoms and heteroatoms. Preferred heteroatoms include nitrogen, oxygen, sulfur, and phosphorous.
  • Aryl groups may optionally include monocyclic, bicyclic, or tricyclic rings, where each ring has preferably five or six members.
  • the aryl group may be substituted or unsubstituted.
  • substituents include alkyl, hydroxyl, alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halogen, fluoroalkyl, carboxyl, carboxyalkyl, amino, aminoalkyl, monosubstituted amino, disubstituted amino, and quaternary amino groups.
  • aryl means carbocyclic aromatic rings or ring systems. Examples of aryl groups include phenyl, naphthyl, biphenyl, fluorenyl, and indenyl groups.
  • heteroaryl means aromatic rings or ring systems that contain at least one ring hetero atom (e.g., O, S, N). Heteroaryl groups include furyl, thienyl, pyridyl, quinolinyl, tetrazolyl, and imidazo groups.
  • Heterocyclyl means non-aromatic rings or ring systems that contain at least one ring hetero atom (e.g., O, S, N). Heterocyclic groups include, for example, pyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiazolidinyl, and imidazolidinyl groups.
  • the aryl, heteroaryl, and heterocyclyl groups may be unsubstituted or substituted by one or more substituents selected from the group consisting of Ci.io alkyl, hydroxy, halo, nitro, C ⁇ _ ⁇ o alkoxy, Cj.io alkylthio, trihalomethyl, C ⁇ _ ⁇ o acyl, arylcarbonyl, heteroarylcarbonyl, nitrile, C ⁇ _ ⁇ 0 alkoxycarbonyl, oxo, arylalkyl (wherein the alkyl group has from 1 to 10 carbon atoms) and heteroarylalkyl (wherein the alkyl group has from 1 to 10 carbon atoms).
  • Compounds useful in the invention include those described herein in any of their pharmaceutically acceptable forms, including isomers such as diastereomers and enantiomers, salts, solvates, and polymorphs, thereof, as well as racemic mixtures of the compounds described herein.
  • ciclopirox enhances the antiproliferative activity of antiproliferative agents against cancer cells. Concentrations that exhibited maximal antiproliferative activity against cancer cells were not unacceptably toxic to normal cells. Thus, combinations of ciclopirox analogs and antiproliferatives are useful for the treatment of cancer and other neoplasms.
  • Ciclopirox Ciclopirox (6-cyclohexyl-l-hydroxy-4-methyl-2(lH)-pyridinone) is a synthetic antifungal agent having a broad spectrum of activity. It can be fungistatic and fungicidal against species including, for example, Candida albicans, Trichophyton spp., Epidermophyton spp., and Aspergillus spp. Antibacterial properties of ciclopirox have also been demonstrated against both Gram-positive and Gram-negative species (Abrams et al., Clin. DermatoL, 9: 471-477, 1992). Anti-inflammatory activity including the inhibition of prostaglandin and leukotriene synthesis in human polymorphonuclear cells has also been reported.
  • a 1% ciclopirox olamine cream is applied topically to treat the dermal fungal infections that cause tinea pedis, cutaneous candidiasis, and pityriasis versicolor.
  • Ciclopirox is also formulated (8%> w/v) as a medicinal nail lacquer for treating onychomycosis (nail fungus) of the fingernails or toenails.
  • Structural and functional analogs can replace ciclopirox in the therapeutic combinations of this invention.
  • Structural ciclopirox analogs are 2- pyridinones of general structure: wherein Ri is H, OH, NH 2 , a halide, or any branched or unbranched, substituted or unsubstituted C ⁇ - 10 alkyl, C MO alkoxyalkyl, Ci.io hydroxyalkyl, C O aminoalkyl, Ci.io alkylaminoalkyl, C -10 cycloalkyl, C 5-8 aryl, or C 6-2 o alkylaryl, and R 2 is H, OH, NH 2 , a halide, or any branched or unbranched, substituted or unsubstituted C ⁇ -10 alkyl, CM O alkoxyalkyl, Ci.io hydroxyalkyl, C O aminoalkyl, C O alkylaminoalkyl, C - ⁇ 0
  • Ri groups include H, CH 3 , CH 3 CH 2 , (CH 3 ) 2 CH, (CH 3 CH 2 ) 2 CH, CH 3 0,
  • R 2 groups include cyclopentyl, cyclohexyl, CH 2 CH(CH 3 )CH 2 C(CH 3 ) 3 , and
  • Functional ciclopirox analogs useful for combination therapy according to this invention, inhibit DNA initiation at origins of replication, are not purines or pyrimidines, and do not replace naturally occurring nucleotides during DNA synthesis.
  • Functional ciclopirox analogs include, for example, mimosine and geminin.
  • Inhibition of DNA initiation at origins of replication can be easily assessed using standard techniques. For example, replication intermediates isolated from cells cultured in the presence of the candidate ciclopirox analog can be assessed by 2D gel electrophoresis (Levenson et al., Nucleic Acid Res., 17: 3997-4004, 1993). This method takes advantage of the different electrophoretic properties of DNA fragments containing replication forks, replication bubbles, or termination structures. Fragments containing origins of replication are easily identified.
  • Combination therapy may be performed alone or in conjunction with another therapy (e.g., surgery, radiation, chemotherapy, biologic therapy). Additionally, a person having a greater risk of developing a neoplasm (e.g., one who is genetically predisposed or one who previously had a neoplasm) may receive prophylactic treatment to inhibit or delay neoplastic , formation.
  • the duration of the combination therapy depends on the type of disease or disorder being treated, the age and condition of the patient, the stage and type of the patient's disease, and how the patient responds to the treatment.
  • Combination therapy may be provided wherever chemotherapy is performed: at home, the doctor's office, a clinic, a hospital's outpatient department, or a hospital. Treatment generally begins at a hospital so that the doctor can observe the therapy's effects closely and make any adjustments that are needed. The duration of the combination therapy depends on the kind of cancer being treated, the age and condition of the patient, the stage and type of the patient's disease, and how the patient's body responds to the treatment. Drug administration may be performed at different intervals (e.g., daily, weekly, or monthly) and the administration of each agent can be determined individually. Combination therapy may be given in on-and-off cycles that include rest periods so that the patient's body has a chance to build healthy new cells and regain its strength.
  • the combination therapy can be used to treat cancer, to slow the spreading of the cancer, to slow the cancer's growth, to kill or arrest cancer cells that may have spread to other parts of the body from the original tumor, to relieve symptoms caused by the cancer, or to prevent cancer in the first place.
  • Combination therapy can also help people live more comfortably by eliminating cancer cells that cause pain or discomfort.
  • each component of the combination can be controlled independently.
  • one compound i.e., the ciclopirox analog
  • the second compound i.e., the antiproliferative agent
  • Combination therapy may be given in on-and-off cycles that include rest periods so that the patient's body has a chance to recovery from any as yet unforeseen side effects.
  • the compounds may also be formulated together such that one administration delivers both compounds.
  • cancers and other neoplasms include, without limitation, leukemias (e.g., acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (Hodgkin's disease, non-Hodgkin's disease), Waldenstrom's macroglobulinemia, heavy chain disease, and solid tumors such as sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma
  • each compound of the combination may be by any suitable means that results in a concentration of the compound that, combined with the other component, is anti-neoplastic upon reaching the target region.
  • the compound may be contained in any appropriate amount in any suitable carrier substance, and is generally present in an amount of 1-95% by weight of the total weight of the composition.
  • the composition may be provided in a dosage form that is suitable for the oral, parenteral (e.g., intravenously, intramuscularly), rectal, cutaneous, nasal, vaginal, inhalant, skin (patch), or ocular administration route.
  • the composition may be in the form of, e.g., tablets, capsules, pills, powders, granulates, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, creams, plasters, drenches, osmotic delivery devices, suppositories, enemas, injectables, implants, sprays, or aerosols.
  • the pharmaceutical compositions may be formulated according to conventional pharmaceutical practice (see, e.g., Remington: The Science and Practice of Pharmacy (20th ed.), ed. A.R. Gennaro, Lippincott Williams & Wilkins, 2000 and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York).
  • compositions according to the invention may be formulated to release the active compound substantially immediately upon administration or at any predetermined time or time period after administration.
  • controlled release formulations which include (i) formulations that create a substantially constant concentration of the drug within the body over an extended period of time; (ii) formulations that after a predetermined lag time create a substantially constant concentration of the drug within the body over an extended period of time; (iii) formulations that sustain drug action during a predetermined time period by maintaining a relatively, constant, effective drug level in the body with concomitant minimization of undesirable side effects associated with fluctuations in the plasma level of the active drug substance (sawtooth kinetic pattern); (iv) formulations that localize drug action by, e.g., spatial placement of a controlled release composition adjacent to or in the diseased tissue or organ; and (v) formulations that target drug action by using carriers or chemical derivatives to deliver the drug to a particular target cell type.
  • Administration of compounds in the form of a controlled release formulation is especially preferred in cases in which the compound, either alone or in combination, has (i) a narrow therapeutic index (i.e., the difference between the plasma concentration leading to harmful side effects or toxic reactions and the plasma concentration leading to a therapeutic effect is small; in general, the therapeutic index, TI, is defined as the ratio of median lethal dose (LD 50 ) to median effective dose (ED 50 )); (ii) a narrow absorption window in the gastro-intestinal tract; or (iii) a very short biological half-life so that frequent dosing during a day is required in order to sustain the plasma level at a therapeutic level.
  • a narrow therapeutic index i.e., the difference between the plasma concentration leading to harmful side effects or toxic reactions and the plasma concentration leading to a therapeutic effect is small
  • the therapeutic index, TI is defined as the ratio of median lethal dose (LD 50 ) to median effective dose (ED 50 )
  • a narrow absorption window in the gastro-intestinal tract or
  • controlled release is obtained by appropriate selection of various formulation parameters and ingredients, including, e.g., various types of controlled release compositions and coatings.
  • the drug is formulated with appropriate excipients into a pharmaceutical composition that, upon administration, releases the drug in a controlled manner. Examples include single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, nanoparticles, patches, and liposomes.
  • Formulations for oral use include tablets containing the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients.
  • excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates, or alginic acid); binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, carboxymethylcellulose sodium, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose
  • the tablets may be uncoated or they may be coated by known techniques, optionally to delay disintegration and absorption in the gastrointestinal tract and thereby providing a sustained action over a longer period.
  • the coating may be adapted to release the active drug substance in a predetermined pattern (e.g., in order to achieve a controlled release formulation) or it may be adapted not to release the active drug substance until after passage of the stomach (enteric coating).
  • the coating may be a sugar coating, a film coating (e.g., based on hydroxypropyl methylcellulose, methylcellulose, methyl hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, acrylate copolymers, polyethylene glycols and/or polyvinylpyrrolidone), or an enteric coating (e.g., based on methacrylic acid copolymer, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, shellac, and/or ethylcellulose).
  • a film coating e.g., based on hydroxypropyl methylcellulose, methylcellulose, methyl hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, acrylate copolymers, polyethylene glycols and/or polyvinylpyrrolidone
  • an enteric coating e.g.,
  • a time delay material such as, e.g., glyceryl monostearate or glyceryl distearate may be employed.
  • the solid tablet compositions may include a coating adapted to protect the composition from unwanted chemical changes, (e.g., chemical degradation prior to the release of the active drug substance).
  • the coating may be applied on the solid dosage form in a similar manner as that described in Encyclopedia of Pharmaceutical Technology, supra.
  • the two drugs may be mixed together in the tablet, or may be partitioned.
  • the first drug is contained on the inside of the tablet, and the second drug is on the outside, such that a substantial portion of the second drag is released prior to the release of the first drug.
  • Formulations for oral use may also be presented as chewable tablets, or as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example, peanut oil, liquid paraffin, or olive oil.
  • Powders and granulates may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, e.g., a mixer, a fluid bed apparatus or a spray drying equipment.
  • Controlled release compositions for oral use may, e.g., be constructed to release the active drag by controlling the dissolution and/or the diffusion of the active drug substance.
  • Dissolution or diffusion controlled release can be achieved by appropriate coating of a tablet, capsule, pellet, or granulate formulation of compounds, or by incorporating the compound into an appropriate matrix.
  • a controlled release coating may include one or more of the coating substances mentioned above and/or, e.g., shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol palmitostearate, ethylcellulose, acrylic resins, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone, polyethylene, polymethacrylate, methylmethacrylate, 2- hydroxymethacrylate, methacrylate hydrogels, 1,3 butylene glycol, ethylene glycol methacrylate, and/or polyethylene glycols.
  • shellac beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, gly
  • the matrix material may also include, e.g., hydrated metylcellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, and/or halogenated fluorocarbon.
  • a controlled release composition containing one or more of the compounds of the claimed combinations may also be in the form of a buoyant tablet or capsule (i.e., a tablet or capsule that, upon oral administration, floats on top of the gastric content for a certain period of time).
  • a buoyant tablet formulation of the compound(s) can be prepared by granulating a mixture of the drug(s) with excipients and 20-75% w/w of hydrocolloids, such as hydroxyethylcellulose, hydroxypropylcellulose, or hydroxypropylmethylcellulose. The obtained granules can then be compressed into tablets. On contact with the gastric juice, the tablet forms a substantially water-impermeable gel barrier around its surface. This gel barrier takes part in maintaining a density of less than one, thereby allowing the tablet to remain buoyant in the gastric juice. Liquids for Oral Administration
  • Powders, dispersible powders, or granules suitable for preparation of an aqueous suspension by addition of water are convenient dosage forms for oral administration.
  • Formulation as a suspension provides the active ingredient in a mixture with a dispersing or wetting agent, suspending agent, and one or more preservatives.
  • Suitable dispersing or wetting agents are, for example, naturally-occurring phosphatides (e.g., lecithin or condensation products of ethylene oxide with a fatty acid, a long chain aliphatic alcohol, or a partial ester derived from fatty acids) and a hexitol or a hexitol anhydride (e.g., polyoxyethylene stearate, polyoxyethylene sorbitol monooleate, polyoxyethylene sorbitan monooleate, and the like).
  • Suitable suspending agents are, for example, sodium carboxymethylcellulose, methylcellulose, sodium alginate, and the like.
  • the pharmaceutical composition may also be administered parenterally by injection, infusion or implantation (intravenous, intramuscular, subcutaneous, or the like) in dosage forms, formulations, or via suitable delivery devices or implants containing conventional, non-toxic pharmaceutically acceptable carriers and adjuvants.
  • injection, infusion or implantation intravenous, intramuscular, subcutaneous, or the like
  • suitable delivery devices or implants containing conventional, non-toxic pharmaceutically acceptable carriers and adjuvants.
  • compositions for parenteral use may be provided in unit dosage forms (e.g., in single-dose ampoules), or in vials containing several doses and in which a suitable preservative may be added (see below).
  • the composition may be in form of a solution, a suspension, an emulsion, an infusion device, or a delivery device for implantation, or it may be presented as a dry powder to be reconstituted with water or another suitable vehicle before use.
  • the composition may include suitable parenterally acceptable carriers and/or excipients.
  • the active drug(s) may be incorporated into microspheres, microcapsules, nanoparticles, liposomes, or the like for controlled release.
  • the composition may include suspending, solubilizing, stabilizing, pH-adjusting agents, and/or dispersing agents.
  • the pharmaceutical compositions according to the invention may be in the form suitable for sterile injection.
  • the suitable active drug(s) are dissolved or suspended in a parenterally acceptable liquid vehicle.
  • acceptable vehicles and solvents that may be employed are water, water adjusted to a suitable pH by addition of an appropriate amount of hydrochloric acid, sodium hydroxide or a suitable buffer, 1,3-butanediol, Ringer's solution, and isotonic sodium chloride solution.
  • the aqueous formulation may also contain one or more preservatives (e.g., methyl, ethyl or n-propyl p-hydroxybenzoate).
  • preservatives e.g., methyl, ethyl or n-propyl p-hydroxybenzoate.
  • a dissolution enhancing or solubilizing agent can be added, or the solvent may include 10- 60% w/w of propylene glycol or the like.
  • Controlled release parenteral compositions may be in form of aqueous suspensions, microspheres, microcapsules, magnetic microspheres, oil solutions, oil suspensions, or emulsions.
  • the active drug(s) may be incorporated in biocompatible carriers, liposomes, nanoparticles, implants, or infusion devices.
  • Biodegradable/bioerodible polymers such as polygalactin, poly(isobutyl cyanoacrylate), poly(2-hydroxyethyl-L-glutamnine) and, poly(lactic acid).
  • Biocompatible carriers that may be used when formulating a controlled release parenteral formulation are carbohydrates (e.g., dextrans), proteins (e.g., albumin), lipoproteins, or antibodies.
  • Materials for use in implants can be non-biodegradable (e.g., polydimethyl siloxane) or biodegradable (e.g., poly(caprolactone), poly(lactic acid), poly(glycolic acid) or poly(ortho esters)).
  • suitable dosage forms for a composition include suppositories (emulsion or suspension type), and rectal gelatin capsules (solutions or suspensions).
  • the active drug(s) are combined with an appropriate pharmaceutically acceptable suppository base such as cocoa butter, esterified fatty acids, glycerinated gelatin, and various water-soluble or dispersible bases like polyethylene glycols and polvoxyethylene sorbitan fatty acid esters.
  • an appropriate pharmaceutically acceptable suppository base such as cocoa butter, esterified fatty acids, glycerinated gelatin, and various water-soluble or dispersible bases like polyethylene glycols and polvoxyethylene sorbitan fatty acid esters.
  • Various additives, enhancers, or surfactants may be incorporated.
  • compositions for Inhalation are provided.
  • typical dosage forms include nasal sprays and aerosols.
  • the active ingredient(s) are dissolved or dispersed in a suitable vehicle.
  • suitable vehicles and excipients are selected in accordance with conventional pharmaceutical practice in a manner understood by the persons skilled in the art of formulating pharmaceuticals.
  • compositions may also be administered topically on the skin for percutaneous absorption in dosage forms or formulations containing conventionally non-toxic pharmaceutical acceptable carriers and excipients including microspheres and liposomes.
  • the formulations include creams, ointments, lotions, liniments, gels, hydrogels, solutions, suspensions, sticks, sprays, pastes, plasters, and other kinds of transdermal drug delivery systems.
  • the pharmaceutically acceptable carriers or excipients may include emulsifying agents, antioxidants, buffering agents, preservatives, humectants, penetration enhancers, chelating agents, gel-forming agents, ointment bases, perfumes, and skin protective agents.
  • emulsifying agents are naturally occurring gums (e.g., gum acacia or gum tragacanth) and naturally occurring phosphatides (e.g., soybean lecithin and sorbitan monooleate derivatives).
  • antioxidants are butylated hydroxy anisole (BHA), ascorbic acid and derivatives thereof, tocopherol and derivatives thereof, butylated hydroxy anisole, and cysteine.
  • preservatives are parabens, such as methyl or propyl p- hydroxybenzoate, and benzalkonium chloride.
  • humectants are glycerin, propylene glycol, sorbitol, and urea.
  • Examples of penetration enhancers are propylene glycol, DMSO, triethanolamine, N,N- dimethylacetamide, N,N-dimethylformamide, 2-pyrrolidone and derivatives thereof, tetrahydrofurfuryl alcohol, and AZONETM.
  • Examples of chelating agents are sodium EDTA, citric acid, and phosphoric acid.
  • Examples of gel forming agents are CARBOPOLTM, cellulose derivatives, bentonite, alginates, gelatin and polyvinylpyrrolidone.
  • ointment bases are beeswax, paraffin, cetyl palmitate, vegetable oils, sorbitan esters of fatty acids (Span), polyethylene glycols, and condensation products between sorbitan esters of fatty acids and ethylene oxide (e.g., polyoxyethylene sorbitan monooleate (TWEENTM)).
  • Span sorbitan esters of fatty acids
  • TWEENTM polyoxyethylene sorbitan monooleate
  • compositions described above for topical administration on the skin may also be used in connection with topical administration onto or close to the part of the body that is to be treated.
  • the compositions may be adapted for direct application or for introduction into relevant orifice(s) of the body (e.g., rectal, urethral, vaginal or oral orifices).
  • the composition may be applied by means of special drug delivery devices such as dressings or alternatively plasters, pads, sponges, strips, or other forms of suitable flexible material.
  • a controlled release percutaneous and/or topical composition may be obtained by using a suitable mixture of the above- mentioned approaches.
  • the active drug is present in a reservoir which is totally encapsulated in a shallow compartment molded from a drug-impermeable laminate, such as a metallic plastic laminate, and a rate- controlling polymeric membrane such as a microporous or a non-porous polymeric membrane (e.g., ethylene-vinyl acetate copolymer).
  • a rate- controlling polymeric membrane such as a microporous or a non-porous polymeric membrane (e.g., ethylene-vinyl acetate copolymer).
  • the active drug substance may either be dispersed in a solid polymer matrix or suspended in a viscous liquid medium such as silicone fluid.
  • a thin layer of an adhesive polymer is applied to achieve an intimate contact of the transdermal system with the skin surface.
  • the adhesive polymer is preferably a hypoallergenic polymer that is compatible with the active drag.
  • a reservoir of the active drug is formed by directly dispersing the active drug in an adhesive polymer and then spreading the adhesive containing the active drug onto a flat sheet of substantially drug-impermeable metallic plastic backing to form a thin drug reservoir layer.
  • a matrix dispersion-type system is characterized in that a reservoir of the active drug substance is formed by substantially homogeneously dispersing the active drug substance in a hydrophilic or lipophilic polymer matrix and then molding the drag-containing polymer into a disc with a substantially well- defined surface area and thickness.
  • the adhesive polymer is spread along the circumference to form a strip of adhesive around the disc.
  • the reservoir of the active substance is formed by first suspending the drug solids in an aqueous solution of water- soluble polymer, and then dispersing the drug suspension in a lipophilic polymer to form a plurality of microscopic spheres of drug reservoirs.
  • each compound of the claimed combinations depends on several factors, including: the administration method, the neoplasm to be treated, the severity of the neoplasm, whether the neoplasm is to be treated or prevented, and the age, weight, and health of the patient to be treated.
  • the compound in question may be administered orally in the form of tablets, capsules, elixirs or syrups, or rectally in the form of suppositories.
  • Parenteral administration of a compound is suitably performed, for example, in the form of saline solutions or with the compound incorporated into liposomes.
  • a solubilizer such as ethanol can be applied.
  • the correct dosage can be determined by examining the efficacy of the compound in cell proliferation assays.
  • the ciclopirox analog is usually provided in a 0.5%-25% w/v solution, cream, or gel.
  • the 2-pyridinone analog is normally dosed at about 0.01-2000 mg/kg/day.
  • the antiproliferative agents are usually given by the same routes of administration that are known to be effective for delivering each particular antiproliferative agent.
  • the antiproliferative agents are dosed in amounts and frequencies equivalent to or less than those that result in effective monotherapy using the antiproliferative agent.
  • Ciclopirox either alone or in combination with known antiproliferative agents were assessed for antiproliferative activity against tumor cell lines.
  • Alamar Blue dye was used to measure the metabolic potential of the tumor cells and can be taken as an indirect measure of the number of viable cells in the well. Alamar Blue dye is a non-fluorescent dye that is reduced, by living cells, to a red fluorescent product that can be easily quantified.
  • tumor cells were treated with a combination of ciclopirox and a known antiproliferative agent. In each case, ciclopirox enhanced the efficacy of the antiproliferative agent.
  • DMEM Dulbecco's Modified Eagle Medium
  • Human colorectal carcinoma HCT116 (ATCC# CCL-247) cells were grown at 37 ⁇ 0.5°C and 5% CO 2 , in McCoys 5A medium supplemented with 10% FBS, 2 mM glutamine, 1% penicillin, and 1% streptomycin.
  • Human prostatic carcinoma cell line DU145 (ATCC# HTB-81) was grown at 37 ⁇ 0.5°C and 5% CO 2 , in Minimum essential medium Eagle supplemented with 10% FBS, 2 mM glutamine, 1% penicillin, and 1% streptomycin.
  • Human ovarian adenocarcinoma SKON-3 was grown at 37 ⁇ 0.5°C and 5% C0 2 , in McCoys 5 A medium supplemented with 10% FBS, 2 mM glutamine, 1% penicillin, and 1% streptomycin.
  • the anti-proliferation assays were performed in 384 well plates. Initially, 6.6 ⁇ l of 10X stock solutions from the combination matrices were added at 40 ⁇ l of culture media. The tumor cells were liberated from the culture flask using a solution of 0.25% trypsin. Cells were diluted in culture media such that 3000 cells were delivered in 20 ⁇ l of media into each assay well. Assay plates were incubated for 90-95 hours. Twenty five microliters of 20% Alamar Blue, in culture media, were added to each assay well following the incubation period. Alamar Blue metabolism was quantified by the amount of fluorescence intensity 3.5 - 5.0 hours after addition.
  • Quantification using the LJL Analyst AD reader (LJL Biosystems), was taken in the middle of the well with high attenuation, a 100 msec read time, an excitation filter at 530 nm, and an emission filter at 575 nm. For some experiments, quantification was performed using a Wallac Victor 2 reader. Measurements were taken at the top of the well with stabilized energy lamp control, a 100 msec read time, an excitation filter at 530 nm, and an emission filter at 590 nm. No significant differences between plate readers were measured.
  • %I [(avg. untreated wells - treated well)/(avg. untreated wells)] x 100
  • the average untreated well value (avg. untreated wells) is the arithmetic mean of 40 wells from the same assay plate treated with vehicle alone.
  • the data shown is the average of four 10x10 matrices, except Examples 6 and 7, which are the average of two 10x10 matrices.
  • Example 1 Antiproliferative Activity of Ciclopirox and Paclitaxel Against Non-Small Cell Lung Carcinoma
  • the results from a hand pipetted non-linear dilution series of paclitaxel and ciclopirox combination on A549 cell growth are shown in Table 2.
  • the IC 50 of paclitaxel alone is approximately 15 nM.
  • 500 nM ciclopirox the efficacy of paclitaxel is enhanced, having an IC 50 of less than 1 nM, more than a 10-fold reduction.
  • the data demonstrate that, in this assay, paclitaxel maximally inhibits neoplastic cell proliferation by about 85% at concentrations of 2 ⁇ M.
  • the addition of 100 nM ciclopirox reduces the paclitaxel concentration required for maximal growth inhibition to 0.10 ⁇ M, a 20-fold reduction.
  • Example 2 Antiproliferative Activity of Ciclopirox and Gemcitabine Against Non-Small Cell Lung Carcinoma
  • Example 3 Antiproliferative Activity of Ciclopirox and Doxorubicin Against Non-Small Cell Lung Carcinoma
  • Example 4 Antiproliferative Activity of Ciclopirox and Vinblastine Against Non-Small Cell Lung Carcinoma
  • the results from a 2-fold dilution series of vinblastine and ciclopirox combination on A549 cell growth are shown in Table 5.
  • the IC 50 of vinblastine is reduced from greater than 10 nM, when administered alone, to about 0.2 nM with the addition of 470 nM ciclopirox.
  • Example 5 Antiproliferative Activity of Ciclopirox and Etoposide Against Non-Small Cell Lung Carcinoma
  • Example 6 Antiproliferative Activity of Ciclopirox and 5-Flurouracil Against Non-Small Cell Lung Carcinoma
  • the results from a 2-fold dilution series of 5-fluorouracil and ciclopirox combination on A549 cell growth are shown in Table 7.
  • the IC 50 of 5- fluorouracil is reduced by about 4-fold, from about 5 ⁇ M to about 1.25 ⁇ M, when administered in combination with 60 nM ciclopirox.
  • Example 7 Antiproliferative Activity of Ciclopirox and Carboplatin 10 Against Non-Small Cell Lung Carcinoma
  • Example 8 Antiproliferative Activity of Ciclopirox and Paclitaxel Against Colorectal Carcinoma
  • the results from a 2-fold dilution series of paclitaxel and ciclopirox combination on HCTl 16 colorectal carcinoma cell growth is shown in Table 9.
  • the efficacy of paclitaxel is enhanced, having an IC 50 of about 0.2 nM.
  • the results from a 2-fold dilution series of paclitaxel and ciclopirox combination on SK0V3 ovarian adenocarcinoma cell growth is shown in Table 10.
  • the IC 50 of paclitaxel alone, against SKOV3 cells, is about 20 nM.
  • the IC 50 of paclitaxel is reduced by 8-12 fold with the addition of 6 nM ciclopirox.
  • the therapeutic index is a relative measure of the effectiveness of an antiproliferative agent compared to its toxicity.
  • the TI of an antiproliferative agent is expressed as a ratio of the dose required to achieve a particular anti-proliferative effect or endpoint (effective dose) to the dose that produces the maximum acceptable level of toxicity (maximum tolerable dose).
  • the TI may be used as an index of the safety margin of a particular therapy. A therapy having a low TI must be monitored more carefully than one having a high TI.
  • Patients receiving a low TI therapy are more prone to toxicity in the event of small overdosing or slight alterations in physiologic parameters that may result from normal interindividual variability.
  • Therapies having a large TI are generally regarded as safer because larger deviations in dosage or interindividual variability are possible without producing unacceptable toxicity.
  • antiproliferative agents have low therapeutic indices. The difference between the dose required for effective antiproliferative therapy and that which causes unacceptable toxicity to the patient is small. The maximum dose of many antiproliferative agents is limited by the adverse effects caused by toxicity to non-neoplastic tissues. The cells of the bone marrow are often the most susceptible to intoxication. The dosage, frequency, and duration of antiproliferative therapy is frequently modified in response to deterioration of hematologic parameters such as an excessive loss of red blood cells, indicative of anemia, or a panleukopenia. Accordingly, there is a need for techniques that increase the TI of antiproliferative agents.
  • BMMCs human bone marrow mononuclear cells
  • Cryopreserved human BMMCs (BioWhitaker, Inc., catalog# 2M-125C) were thawed and prepared according to the manufacturer's instructions. Bone marrow colony forming assays were performed using a commercially available methylcellulose kit (Stem Cell Technologies; catalog# 04464). Briefly, 6 x 10 4 BMMCs were added to each methylcellulose aliquot provided in the kit. Ciclopirox and gemcitabine were diluted in DMSO to generate lOx stock solutions in culture medium (Iscoves DMEM containing 2% FBS) and added to the methylcellulose aliquots. DMSO was used for an untreated control.
  • the anti-proliferative effect demonstrated with the tumor cell lines used herein can be similarly demonstrated using other cancer cell lines, such as MCF7 mammary adenocarcinoma, PA-1 ovarian teratocarcinoma, HT29 colorectal adenocarcinoma, HI 299 large cell carcinoma, U-2 OS osteogenic sarcoma, U-373 MG glioblastoma, Hep-3B hepatocellular carcinoma, BT-549 mammary carcinoma, T-24 bladder cancer, C-33A cervical carcinoma, HT-3 metastatic cervical carcinoma, SiHa squamous cervical carcinoma, CaSki epidermoid cervical carcinoma, NCI-H292 mucoepidermoid lung carcinoma, NCI-2030, non small cell lung carcinoma, HeLa, epithelial cervical adenocarcinoma, KB epithelial mouth carcinoma, HT1080 epithelial fibrosarcoma, Saos-2 epithelial osteogenic sarcoma, PC3 epi
  • the specificity can be tested by using cells such as NHLF lung fibroblasts, NHDF dermal fibroblasts, HMEC mammary epithelial cells, PrEC prostate epithelial cells, HRE renal epithelial cells, NHBE bronchial epithelial cells, CoSmC Colon smooth muscle cells, CoEC colon endothelial cells, NHEK epidermal keratinocytes, and bone marrow cells as control cells.
  • cells such as NHLF lung fibroblasts, NHDF dermal fibroblasts, HMEC mammary epithelial cells, PrEC prostate epithelial cells, HRE renal epithelial cells, NHBE bronchial epithelial cells, CoSmC Colon smooth muscle cells, CoEC colon endothelial cells, NHEK epidermal keratinocytes, and bone marrow cells as control cells.

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Abstract

L'invention concerne un procédé servant à traiter un patient atteint d'un cancer ou d'un autre type de tumeur, ce qui consiste à administrer à ce patient (i) ciplopirox ou des analogues structuraux ou fonctionnels de ce dernier et, éventuellement, (ii) un agent antiprolifératif simultanément ou à deux semaines d'écart, en quantités suffisantes pour inhiber la croissance de la tumeur.
PCT/US2003/021783 2002-07-15 2003-07-14 Therapie combinee servant a traiter des tumeurs WO2004007676A2 (fr)

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005058320A1 (fr) * 2003-12-19 2005-06-30 Novartis Ag Combinaison de (a) n-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridyl)-2-pyrimidine-amine et (b) au moins un inhibiteur de formation de l'hypusine et son utilisation
US7141589B2 (en) * 2001-08-23 2006-11-28 The United States Of America As Represented By The Department Of Health And Human Services Methods of inhibiting formation of vascular channels and methods of inhibiting proliferation
KR20100003192A (ko) * 2008-06-30 2010-01-07 산요 시키소 가부시키가이샤 컬러필터용 안료분산체
WO2010048712A1 (fr) * 2008-10-31 2010-05-06 University Health Network Ciclopirox et cytarabine pour le traitement de troubles leucémiques
ITTO20100539A1 (it) * 2010-06-23 2011-12-24 Alessandro Quattrone Composti per il trattamento di tumori che portano oncoproteine myc deregolate
US8334307B2 (en) 2010-06-01 2012-12-18 Biotheryx Inc. Hydroxypyridone derivatives, pharmaceutical compositions thereof, and their therapeutic use for treating proliferative diseases
US20150342942A1 (en) * 2010-06-01 2015-12-03 Biotheryx, Inc. Methods of treating hematologic malignancies using 6-cyclohexyl-1-hydroxy-4-methyl-2(1h)-pyridone
WO2016077346A1 (fr) 2014-11-11 2016-05-19 The University Of Kansas Procédés de traitement du cancer de la vessie avec le ciclopirox, le ciclopirox olamine ou un promédicament à base de ciclopirox
WO2016089760A1 (fr) * 2014-12-02 2016-06-09 Ignyta, Inc. Combinaisons pour le traitement du neuroblastome
US10231965B2 (en) 2014-02-20 2019-03-19 Ignyta, Inc. Molecules for administration to ROS1 mutant cancer cells
US10398693B2 (en) 2017-07-19 2019-09-03 Ignyta, Inc. Pharmaceutical compositions and dosage forms
US10869864B2 (en) 2015-12-18 2020-12-22 Ignyta, Inc. Combinations for the treatment of cancer
US11007191B2 (en) 2017-10-17 2021-05-18 Ignyta, Inc. Pharmaceutical compositions and dosage forms

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5756118A (en) * 1991-10-16 1998-05-26 Richardson-Vicks Inc. Enhanced skin penetration system for improved topical delivery of drugs
US5846984A (en) * 1996-01-19 1998-12-08 The Trustees Of Columbia University In The City Of New York Use of ciclopirox or a pharmaceutically acceptable salt thereof for inhibiting neuronal cell damage or neuronal cell death
US6277892B1 (en) * 1991-10-16 2001-08-21 Schering-Plough Healthcare Products, Inc. Enhanced skin penetration system for improved topical delivery of drugs

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5756118A (en) * 1991-10-16 1998-05-26 Richardson-Vicks Inc. Enhanced skin penetration system for improved topical delivery of drugs
US6277892B1 (en) * 1991-10-16 2001-08-21 Schering-Plough Healthcare Products, Inc. Enhanced skin penetration system for improved topical delivery of drugs
US5846984A (en) * 1996-01-19 1998-12-08 The Trustees Of Columbia University In The City Of New York Use of ciclopirox or a pharmaceutically acceptable salt thereof for inhibiting neuronal cell damage or neuronal cell death

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7141589B2 (en) * 2001-08-23 2006-11-28 The United States Of America As Represented By The Department Of Health And Human Services Methods of inhibiting formation of vascular channels and methods of inhibiting proliferation
WO2005058320A1 (fr) * 2003-12-19 2005-06-30 Novartis Ag Combinaison de (a) n-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridyl)-2-pyrimidine-amine et (b) au moins un inhibiteur de formation de l'hypusine et son utilisation
KR20100003192A (ko) * 2008-06-30 2010-01-07 산요 시키소 가부시키가이샤 컬러필터용 안료분산체
WO2010048712A1 (fr) * 2008-10-31 2010-05-06 University Health Network Ciclopirox et cytarabine pour le traitement de troubles leucémiques
US8334307B2 (en) 2010-06-01 2012-12-18 Biotheryx Inc. Hydroxypyridone derivatives, pharmaceutical compositions thereof, and their therapeutic use for treating proliferative diseases
US20150342942A1 (en) * 2010-06-01 2015-12-03 Biotheryx, Inc. Methods of treating hematologic malignancies using 6-cyclohexyl-1-hydroxy-4-methyl-2(1h)-pyridone
US9273005B2 (en) 2010-06-01 2016-03-01 Biotheryx, Inc. Hydroxypyridone derivatives, pharmaceutical compositions thereof, and their therapeutic use for treating proliferative diseases
WO2011161631A3 (fr) * 2010-06-23 2012-03-22 Alessandro Quattrone Composés destinés à traiter des tumeurs portant des oncoprotéines myc dérégulées
ITTO20100539A1 (it) * 2010-06-23 2011-12-24 Alessandro Quattrone Composti per il trattamento di tumori che portano oncoproteine myc deregolate
US10231965B2 (en) 2014-02-20 2019-03-19 Ignyta, Inc. Molecules for administration to ROS1 mutant cancer cells
US10682348B2 (en) 2014-02-20 2020-06-16 Ignyta, Inc. Molecules for administration to ROS1 mutant cancer cells
US10561651B2 (en) 2014-02-20 2020-02-18 Ignyta, Inc. Methods for treating neuroblastoma
WO2016077346A1 (fr) 2014-11-11 2016-05-19 The University Of Kansas Procédés de traitement du cancer de la vessie avec le ciclopirox, le ciclopirox olamine ou un promédicament à base de ciclopirox
CN107206012A (zh) * 2014-11-11 2017-09-26 堪萨斯大学 用环吡酮、环吡酮胺或环吡酮前药治疗膀胱癌的方法
WO2016089760A1 (fr) * 2014-12-02 2016-06-09 Ignyta, Inc. Combinaisons pour le traitement du neuroblastome
US10357490B2 (en) 2014-12-02 2019-07-23 Ignyta, Inc. Combinations for the treatment of neuroblastoma
US10085979B2 (en) 2014-12-02 2018-10-02 Ignyta, Inc. Combinations for the treatment of neuroblastoma
KR20170094259A (ko) * 2014-12-02 2017-08-17 이그니타, 인코포레이티드 신경모세포종의 치료를 위한 병용
KR102595599B1 (ko) 2014-12-02 2023-11-02 이그니타, 인코포레이티드 신경모세포종의 치료를 위한 병용
US10869864B2 (en) 2015-12-18 2020-12-22 Ignyta, Inc. Combinations for the treatment of cancer
US10398693B2 (en) 2017-07-19 2019-09-03 Ignyta, Inc. Pharmaceutical compositions and dosage forms
US11253515B2 (en) 2017-07-19 2022-02-22 Ignyta, Inc. Pharmaceutical compositions and dosage forms
US11007191B2 (en) 2017-10-17 2021-05-18 Ignyta, Inc. Pharmaceutical compositions and dosage forms

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