WO1993011668A1 - Procedes et compositions destines a reduire la multiresistance aux medicaments - Google Patents

Procedes et compositions destines a reduire la multiresistance aux medicaments Download PDF

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Publication number
WO1993011668A1
WO1993011668A1 PCT/US1992/010563 US9210563W WO9311668A1 WO 1993011668 A1 WO1993011668 A1 WO 1993011668A1 US 9210563 W US9210563 W US 9210563W WO 9311668 A1 WO9311668 A1 WO 9311668A1
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Prior art keywords
approximately
human
fatty acid
composition
acid
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PCT/US1992/010563
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English (en)
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John S. Coon
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Rush-Presbyterian-St. Luke's Medical Center
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Priority to CA002125279A priority Critical patent/CA2125279A1/fr
Priority to JP5511010A priority patent/JPH07502274A/ja
Priority to EP19930900961 priority patent/EP0616493A4/fr
Publication of WO1993011668A1 publication Critical patent/WO1993011668A1/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
    • A61K31/74—Synthetic polymeric materials
    • A61K31/785—Polymers containing nitrogen
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • 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
    • A61K31/74—Synthetic polymeric materials
    • A61K31/765—Polymers containing oxygen
    • 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
    • A61K31/74—Synthetic polymeric materials
    • A61K31/765—Polymers containing oxygen
    • A61K31/77—Polymers containing oxygen of oxiranes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to the use of resistance modification agents in vivo to reverse multidrug resistance in human or animal tumor cells. More particularly, the present invention relates to the use of certain non-ionic surfactants comprising certain amphipathic esters of fatty acids as resistance modification agents.
  • Mdrl protein a cell membrane drug efflux transporter
  • P- glycoprotein a cell membrane drug efflux transporter
  • RMAs resistance modification agents
  • metabolic poisons such as azide
  • RMAs a highly effective RMA
  • verapamil appear to work as competitive antagonists of a drug binding site on the Mdrl protein.
  • Many of these agents also have toxicity which limits their usefulness in vivo. Consequently, there is a need to develop alternate pharmacological strategies for reversing multidrug resistance to provide RMAs with improved activity and lower overall toxicity.
  • Decreased intracellular drug accumulation through overexpression of the drug efflux Mdrl protein is important to, but apparently not the only factor, in the multidrug resistance phenotype. Altered intracellular drug distribution and binding, among other possibilities, also seem to play a role.
  • the mechanism of reversing doxorubicin resistance using verapamil appears to be more related to altered intracellular distribution of doxorubicin than increased accumulation in the cell, as detailed in Schuurhuis, G.J., et al., "Quantitative dete ⁇ nination of factors contributing to doxorubicin resistance in multidrug resistant cells," /. Natl. Cancer Inst., 81:1887-1892, 1989.
  • doxorubicin is concentrated almost exclusively in the nucleus in drug sensitive cells, and mainly in the cytoplasm in drug resistant cells. With the addition of verapamil, doxorubicin is localized mainly in the nucleus in drug resistant cells. Thus, high affinity binding of drugs to Mdrl does not appear to be sufficient for optimal efflux, suggesting the existence of additional, rate limiting steps which may be susceptible to pharmacological intervention.
  • Certain non-ionic amphipathic surfactants such as
  • Tween 80 and Cremophor EL have evidenced RMA activity.
  • RMA activity See Riehm H., et al. "Potentiation of drug effect by Tween 80 in Chinese hamster cells resistant to actinomycin D and Danomycin” Cancer Res. Vol. 32, pgs. 1195-1200, 1972 and Woodcock, D. B., et al., "Reversal of the multidrug resistance phenotype with
  • Cremophore EL a common vehicle for water-insoluble vitamins and drugs
  • Tween 80 potentiates drug toxicity in both parental and multidrug resistant cells, calling into question the specificity of the Tween 80 effect on multidrug resistance. An effect on drug efflux has not been demonstrated.
  • Cremophor EL is a complicated mixture of polyoxyethylated esters of triglycerides of mainly ricinoleic acid (castor oil), the composition and active component of which have not been identified. Use of Cremophor EL in vivo is complicated by adverse histamine release in some patients.
  • compositions that reverse multidrug resistance in vivo.
  • the composition should have a low occurrence of adverse side-effects.
  • the compositions should inhibit drug efflux by a mechanism different from antagonistic competition for a drug binding site on the Mdrl protein, thereby broadening the pharmacological repertoire which may be employed to reverse multidrug resistance.
  • the present invention comprises certain compositions that exhibit substantial RMA activity in cancers.
  • a composition is a non-ionic amphipathic surfactant, known by the trade name SOLUTOL® HS 15 (BASF Corporation, Parsippany, New Jersey).
  • SOLUTOL® HS 15 BASF Corporation, Parsippany, New Jersey.
  • This composition increases the cytotoxicity of chemotherapeutic drugs in multidrug resistant cell lines, but not in drug sensitive cell lines, indicating that the potentiating effect is not due to the additive toxicity of the agent itself.
  • the agent also promotes chemotherapeutic agent accumulation in multidrug resistant cells thereby potentiating the effect of the chemotherapeutic agent.
  • the present invention also comprises a method for reversing multidrug resistance in human or animal cancer cells and a composition for eliminating multidrug resistant human or animal cancer cells.
  • One composition that is an aspect of the present invention is a particular fraction of SOLUTOL® HS 15 collected by reverse phase liquid chromatography. It has been found that the RMA activity in the SOLUTOL® HS 15 resides in a narrow fraction from the reverse phase liquid chromatography.
  • the present invention also includes a class of compounds which are ethoxylated fatty acids which exhibit strong
  • RMA activity These compounds have been found to be a fatty acid with between approximately 8 and 60 carbon atoms and between approximately 4 to 100 ethoxy units.
  • the fatty acid component of the present invention can be unsaturated and can have one or more hydroxyl group. In general, the fatty acids without the ethoxy units have little or no RMA activity.
  • the present invention also includes compositions and methods for reducing the resistance of certain microorganisms to chemotherapeutic agents. It has been determined that certain microorganisms contain p-glycoprotein-like pumping mechanisms that are similar to those found in mammalian cells and it is believed that these mechanisms may be important in resistance to antmicrobial agents.
  • Another embodiment of the present invention are the polyoxyethylene/polyoxypropylene copolymers with the following general formula:
  • a is an integer such that the hydrophobe represented by (C 3 H 6 O) has a molecular weight of about 1200 to 9000, preferably 1750 to 4000, and b is an integer such that the hydrophile portion represented by (C2H4O) constitutes approximately 10% to 50% by weight of the compound.
  • Another embodiment of the present invention are the polyoxyethylene/polyoxypropylene copolymers with the following general formula:
  • the mean aggregate molecular weight of the portion of the octablock copolymer represented by the polyoxypropylene is between approximately 4500 and 7000 daltons; a is a number such that the portion represented by polyoxyethylene constitutes between approximately 10% to 20% of the compound by weight, and; b is a number such that the polyoxypropylene portion of the total molecular weight of the octablock copolymer constitutes between approximately 80% and 90% of the compound by weight.
  • Yet another embodiment of the present invention are the polyoxyethylene/polyoxypropylene copolymers with the following general formula: (C 2 H 4 ⁇ ) a (C 3 H- ⁇ ) b ⁇ C 3 9 H ⁇ 6O) h (C,H.O).
  • the mean aggregate molecular weight of the portion of the octablock copolymer represented by the polyoxypropylene is between approximately 4500 and 7000 daltons; a is a number such that the portion represented by polyoxyethylene constitutes between approximately 10% to 40% of the compound by weight, and; b is a number such that the polyoxypropylene portion of the total molecular weight of the octablock copolymer constitutes between approximately 60% and 90% of the compound by weight.
  • Figure 1 shows fractionation of SOLUTOL® HS 15 using reverse phase liquid chromatography.
  • the present invention comprises methods and compositions for reducing or eliminating multidrug resistance in cancers in humans or animals.
  • a non-ionic amphipathic ester of a fatty acid is administered to a patient in which a human or animal cancer exhibits multidrug resistance to the chemotherapeutic agent.
  • the method and composition of the present invention may be employed with particular efficacy where multidrug resistance to any chemotherapeutic agent has been conferred upon a cancer.
  • multidrug resistance means resistance or acquired or natural resistance of tumor or other cells to chemotherapeutic agents.
  • the multidrug resistance can be mediated by P-glycoprotein or can be mediated by other mechanisms.
  • the present invention includes a method of treating a human or animal with a cancer that exhibits multidrug resistance to reduce or eliminate the multidrug resistance which includes administering to the human or animal an effective amount of a non-ionic amphipathic ester of a fatty acid.
  • a preparation that exhibits the desired biologic activity is SOLUTOL® HS 15. This preparation is a mixture of various compounds with surfactant activities.
  • the fatty acid component of the present invention can be unsaturated and can be hydroxylated and still exhibit activity.
  • the fatty acid can be branched.
  • the preferred fatty acids are straight chained.
  • the fatty acids without the ethoxy units have little or no RMA activity.
  • the preferred compounds are fatty acids which have ethoxy units esterified on the carboxy group.
  • the fatty acids have between 8 and 60 carbon atoms and between approximately 4 to 100 ethoxy units. If the fatty acid is hydroxylated the ethoxy units may be esterified at the hydroxyl group.
  • the ethoxy units can be attached to the carboxyl group and/or the hydroxyl group if a hydroxyl group is present.
  • the more preferred compounds have a fatty acid with between 12 and 50 carbons with the most preferred compounds with between 15 and 25 carbon atoms and between approximately 15 and 60 ethoxy units with the most preferred compounds having between approximately 15 and 20 carbon atoms.
  • the preferred compounds have between approximately 4 and 100 ethoxy units, with the more preferred compounds having between 15 and 60 ethoxy units and the most preferred compounds having between 25 and 50 ethoxy units.
  • Preferred fatty acids are selected from the group consisting of stearic acid, 12-hydroxystearic acid, oleic acid, palmitic acid, and ricinoleic acid.
  • the preferred number of ethoxy units are between approximately 5 and 50 units.
  • Non-ionic amphipathic surfactants exhibit membrane surface activity and are characterized by having a hydrophilic head and hydrophobic tail.
  • non-ionic amphipathic esters of fatty acids inhibit the formation of such protein polymers, and thereby inhibit drug efflux.
  • the ester of the present invention has a hydrophilic head, which comprises polyethylene glycol, and a hydrophobic tail comprising a fatty acid.
  • the fatty acid component of the ester of the composition of the present invention can be selected from a wide range of fatty acids. It may advantageously possess at least one hydroxyl group outside of the carboxyl group. Such fatty acids can easily be esterified with themselves, as is well known in the art, to produce polymers of the fatty acid.
  • the RMA can be formed not just from esters of a fatty acid monomer with polyethylene glycol, but such polymers of hydroxylated fatty acids also can be esterified with polyethylene glycol to form the RMA.
  • the non-ionic amphipathic ester comprises polyethylene glycol ester of 12-hydroxystearic acid.
  • a formulation is a component of a commercially available preparation from BASF Corporation (Parsippany, New Jersey) under the trade name SOLUTOL® HS 15.
  • the ester may be administered to a patient either alone or in combination with a treatment program of at least one chemotherapeutic agent to which the human cancer is resistant.
  • chemotherapeutic agent typically includes, but is not limited to, doxorubicin, vincristine, vinblastine, Taxol, colchicine, VP-16 and actinomycin D.
  • the present invention is useful for reducing resistance to platinum compounds by promoting accumulation of these compounds.
  • At least one effective dose of the RMA of the present invention is administered for every dose of chemotherapeutic agent that is administered in treatment.
  • an effective dose of the RMA may be administered at least daily throughout the period between administration of successive doses of chemotherapeutic agent.
  • the treatment period typically lasts about four weeks, depending upon the cancer being treated and the chemotherapeutic agents being used.
  • the RMA may be continuously infused throughout said period.
  • the administration of the RMA may also commence prior to a session of chemotherapy, and continue throughout and after the chemotherapy session.
  • the amount of the RMA per dose will depend on which particular non-ionic amphipathic fatty acid ester is employed according to the present invention. However it is preferable that the maximum dosage that may be tolerated with negligible toxic symptoms in vivo be used. At least some non- ionic amphipathic esters of fatty acids, such as SOLUTOL® HS 15, are tolerated extremely well in vivo, and may be employed with no acute toxicity at dosages which achieve equivalent or superior reversal of multidrug resistance to common chemotherapeutic agents as compared to dosages of the prototypical RMA verapamil which produce marked toxicity.
  • the RMA of the present invention can be administered either intravenously or orally. It may be administered separately from the chemotherapeutic agent, as may be dictated by the chemotherapy, in which case the amount of time between commencing administration of the RMA and administration of the chemotherapeutic agent should not be substantial, e.g. typically within 24 hours, or as the chemotherapy permits.
  • An exemplary treatment regimen comprises oral or intravenous administration of the chemotherapeutic agent, followed by continuous administration of the RMA throughout the period until the next session of chemotherapy, either by continuous infusion or oral time release capsules.
  • a typical dose for a human of the SOLUTOL® HS 15 is between approximately 1 mg/kg and 250 mg/kg.
  • a more preferred dose of SOLUTOL® HS 15 is between approximately 5 mg/kg and 100 mg/kg. If a purified esterified fatty acid is used to treat a human with multidrug resistant cancer, the preferred dose is between approximately 1 mg/kg and 200 mg/kg with the more preferred dose between approximately 15 mg/kg and 60 mg/kg.
  • the RMA of the present invention may be administered in combination with the chemotherapeutic agent, comprising continuous infusion or daily oral consumption of time release capsules of the RMA commencing prior to the chemotherapy session, and continuing throughout and after the session, by way of example.
  • the RMA may be infused together through the same needle with the chemotherapeutic agent, or combined in a single oral capsule, as the chemotherapeutic agent permits, in which cases the RMA of the present invention may be used as an emulsifier of the agent, since non-ionic amphipathic esters of fatty acids commonly possess emulsifying characteristics.
  • Preparation of an emulsion of the chemotherapeutic agent with the RMA will depend on the particular agents used.
  • the RMA and the chemotherapeutic agent are combined and heated above room temperature to a range in which both the RMA and the chemotherapeutic agent are still stable, but in which the RMA becomes fluid, about 50° to 80° C.
  • Sterile water is heated to the same temperature and then added with vigorous agitation in a proper amount to achieve a viscosity appropriate for administration.
  • Other components may be added to the emulsion as necessary to prepare it either for intravenous or oral administration, as is well known in the art.
  • the RMA of the present invention can be administered together with other RMAs, such as verapamil.
  • the RMA of the present invention and a second RMA can be infused separately or concurrently, or combined into one time release capsule for oral consumption, in effective doses typically administered in treatment using each RMA alone, as permitted by the toxicity of the second RMA.
  • the method and composition of the present invention provide an important new means of overcoming multidrug resistance in human cancers.
  • the method and composition have an efficacy equal to or better then best resistance modification agents known to the inventor.
  • the agent used in the method and composition of the present invention has a lower toxicity than other RMAs and fewer side effects than other potential RMAs.
  • the agent operates by a different mechanism on the complex phenotype of multidrug resistance, and thus can be combined with other RMAs to provide a more potent means of reversing multidrug resistance.
  • SOLUTOL® HS 15 The structure of SOLUTOL® HS 15 is dissimilar to that of verapamil or other typical RMAs.
  • the markedly greater potency of SOLUTOL® HS 15 than verapamil for reversing VP-16 or colchicine resistance relative to the ability of each to reverse vinblastine or doxorubicin resistance supports the hypothesis that SOLUTOL® HS 15 operates by a MDR-reversing mechanism different from competition for the drug-binding site on Mdrl protein found in verapamil.
  • Colchicine is known to interact weakly with the identified drug-binding site on the Mdrl protein, since colchicine does not compete for vinblastine binding.
  • SOLUTOL® HS 15 is a highly potent RMA for both colchicine and vinblastine, it may inhibit a second event necessary for efflux after drag binding, namely actual transport through the membrane. It is likely that SOLUTOL® HS 15, as a surfactant, inhibits formation of Mdrl protein polymers which may be necessary to achieve drag efflux.
  • RMA of the present invention Another important advantage of the RMA of the present invention is the fact that the compounds which are contemplated as part of the present invention are highly effective against the multidrug resistance against the anticancer drag VP-16.
  • the prior art RMAs, such as verapamil, are not effective against VP-16 multidrug resistance. (See Schested, M, et al. "Relationship of VP-16 to the Classical Multidrug Resistance Phenotype", Cancer Research, Vol. 52, pgs. 2874-2879, 1992.)
  • the RMAs of the present invention have been found to be effective in reducing multidrug resistance against a broad spectrum of anticancer drags.
  • microorganisms contain membrane proteins which are similar in structure and function to the P-glycoprotein that is expressed by the MDR1 gene in mammals. It is contemplated as part of the present invention that the methods and compositions that make up the present invention can be used to make certain microorganisms more susceptible to therapeutic drags. For example, it is likely that the present invention will reverse chloroquine resistance in malaria.
  • Another embodiment of the present invention relates to the blood brain barrier. It has been reported that the P- glycoprotein pump exists in brain capillary endothelium. (See Tasuta, T., et al., Functional Involvement of P-glycoprotein in brain capillary endothelium. (See Tasuta, T., et al., Functional Involvement of P-glycoprotein in brain capillary endothelium. (See Tasuta, T., et al., Functional Involvement of P-glycoprotein in
  • the brain is a pharmacologic sanctuary in that many drags administered systemically have Umited access to the tissue parenchyma.
  • endothelial cells forming the capillary tube are joined by continuous tight junctions that prevent many substances from entering the organ.
  • Nutrients needed for brain cells are selectively transported from the blood through specific channels or transporters in the capillary endothelial cells.
  • the brain is a rigorously isolated compartment that is protected by a blood-brain barrier.
  • Hydrophobic antitumor agents such as Vinca alkaloid and adriamycin (ADM) cannot enter the brain, although other hydrophobic molecules such as nicotine and ethanol readily pass through the blood-brain barrier. Therefore, some mechanisms of the barrier that selectively block the penetration of lipid-soluble antitumor agents into the brain could exist.
  • the presence of P- glycoprotein in the capillary endothelium has been reported in both brain and testis but not in the other tissues. This suggests the functional involvement of P-glycoprotein in the blood-brain barrier. It is contemplated as part of the present invention that the methods and compounds described herein can be used to reduce the blood-brain barrier thereby allowing beneficial therapeutic agents to cross the barrier.
  • Another embodiment of the present invention are compounds that are effective in reducing multidrug resistance in cancer cells that are polyoxyethylene/polyoxypropylene copolymers with the following general formula:
  • the block copolymer comprises a polymer of hydrophilic polyoxyethylene (POE) built on an ethylene diamine initiator. Polymers of hydrophobic polyoxypropylene (POP) are then built on the block of hydrophilic polyethylene (POE). This results in an octablock copolymer with the following general formula: (C 3 H 6 0) b (c 2 H 4 ⁇ ) a (C 2 H 4 0) a (C 3 H 6 ⁇ ) b
  • the mean aggregate molecular weight of the portion of the octablock copolymer represented by the polyoxypropylene is between approximately 4500 and 7000 daltons; a is a number such that the portion represented by polyoxyethylene constitutes between approximately 10% to 20% of the compound by weight, and; b is a number such that the polyoxypropylene portion of the total molecular weight of the octablock copolymer constitutes between approximately 80% and 90% of the compound by weight.
  • the block copolymer comprises a polymer of hydrophobic polyoxypropylene (POP) built on an ethylenediamine initiator. Polymers of hydrophihc polyoxyethylene (POE) are then built on the block of hydrophobic polyoxypropylene (POP). This results in an octablock copolymer with the following general formula:
  • the mean aggregate molecular weight of the portion of the octablock copolymer represented by the polyoxypropylene is between approximately 4500 and 7000 daltons; a is a number such that the portion represented by polyoxyethylene constitutes between approximately 10% to 40% of the compound by weight, and; b is a number such that the polyoxypropylene portion of the total molecular weight of the octablock copolymer constitutes between approximately 60% and 90% of the compound by weight.
  • the octablock copolymers comprising the biologically active copolymers of the present invention include, but are not limited to, the block copolymers Tetronic® and reverse Tetronic® manufactured by the BASF Corporation (BASF Corporation, Parsippany, NJ).
  • the triblock copolymers are sold under the trademark PLURONIC® and are available from BASF Corporation.
  • cells from the three lines were plated as is well known in the art in 96-well plates, with increasing concentrations of cytotoxic drag along one axis of the plate and increasing concentrations of the RMA along the other axis of the plate. After incubation for five days, the plates were washed and dyed according to methods known in the art, and a cell count was determined. The mean concentration of the cytotoxic drug that caused 50% inhibition of cell growth compared to controls (IC50) was plotted at various concentrations of the RMA.
  • SOLUTOL® HS 15 Complete reversal of the MDR phenotype in KB 8-5 and KB 8-5-11 cells was achieved by SOLUTOL® HS 15, while the RMA did not potentiate drug toxicity in drug-sensitive KB 3-1 cells, indicating the potentiating effect was not due to any toxicity of SOLUTOL® HS 15 itself.
  • SOLUTOL® HS 15 produced a 35-, 28-, and 42-fold reduction in the resistance of KB 8-5-11 cells to colchicine, vinblastine, and doxorubicin, respectively.
  • Example II Efflux of rhodamine 123 from MDR cells was also examined to provide direct information about the action of the transport protein Mdr 1. Briefly, prepared cells from the KB 8- 5-11 line were washed and incubated in 0.5 ⁇ g ml rhodamine 123 and 24 ⁇ M verapamil for 3 hours at 37° C. The cells were washed in ice cold DMEM, split into 3 aliquots, and incubated in either complete medium alone or complete medium with 24 ⁇ M verapamil or 70 ⁇ M SOLUTOL® HS 15 at 37°C. The rhodamine 123 fluorescence of the cells was measured periodically by flow cytometric analysis as described in Coon et al. The rhodamine 123 studies showed that SOLUTOL® HS 15 promotes drug accumulation in MDR cells, and furthermore that such accumulation is at least partly due to a pronounced decrease in the rate of drag efflux.
  • SOLUTOL® HS 15 was fractionated using reverse phase liquid chromatography to determine where the activity resides in the preparation.
  • An approximately 50% solution of SOLUTOL® HS 15 was prepared in 100% acetonitrile (ACN) and water.
  • ACN acetonitrile
  • One ml of the SOLUTOL® HS 15 solution was injected onto a Phenomenex IB-Sil reversed phase column. The column has 5 ⁇ m particles, and is 4.6 mm internal diameter by 150 mm.
  • the flow rate was 2.0 mVrnin.
  • the gradient was linear with 100% A to 100% B in 15 minutes, then was maintained at 100%
  • the RMA activity is confined in a single peak which elutes at approximately 20 minutes into the chromatographic run.
  • the toxicity is confined to another peak that elutes before the activity peak and slightly overlaps the RMA peak.
  • most of the material that is responsible for the RMA activity is non-toxic.
  • SOLUTOL® HS 15 is extremely well tolerated in vivo. Pure-bred beagle dogs received intravenous doses of 5, 25, 50 or 100 milligrams of SOLUTOL® HS 15 per kilogram body weight, daily over a period of 4 weeks. No signs of toxicity were found in doses up to 25 mg/kg. At 50 mg/kg, sporadic and transient pruritus, erythema, and/or urticaria were observed. After doses of 100 mg/kg, the dogs showed different degrees of pruritus, erythema, or urticaria, most pronounced 5 to 10 minutes after injection, and no longer detectable after 60 minutes. These studies indicate SOLUTOL® HS 15 is better tolerated in vivo than Cremophor EL. Example VI

Abstract

Procédés et compositions destinés à réduire ou à éliminer la multirésistance aux médicaments en cas de cancer humain ou animal, qui consistent à administrer un ester non ionique amphipathique d'un acide gras à un patient humain ou animal atteint d'un cancer présentant une multirésistance à l'agent chimiothérapeutique. Le procédé et la composition de la présente invention peuvent être employés avec une efficacité particulière en cas de cancer multirésistant à tout agent chimiothérapeutique.
PCT/US1992/010563 1991-12-10 1992-12-09 Procedes et compositions destines a reduire la multiresistance aux medicaments WO1993011668A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CA002125279A CA2125279A1 (fr) 1991-12-10 1992-12-09 Methodes et compositions pour reduire la resistance polymedicamenteuse
JP5511010A JPH07502274A (ja) 1991-12-10 1992-12-09 多薬剤耐性を低下させる方法および組成物
EP19930900961 EP0616493A4 (fr) 1991-12-10 1992-12-09 Procedes et compositions destines a reduire la multiresistance aux medicaments.

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US80518691A 1991-12-10 1991-12-10
US805,186 1991-12-10
US98276692A 1992-12-07 1992-12-07
US982,766 1992-12-07

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JP (1) JPH07502274A (fr)
CN (1) CN1076358A (fr)
AU (1) AU3243393A (fr)
CA (1) CA2125279A1 (fr)
IL (1) IL104063A0 (fr)
MX (1) MX9207150A (fr)
WO (1) WO1993011668A1 (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0643971A2 (fr) * 1993-08-25 1995-03-22 Eli Lilly And Company Compositions antifongiques contenant un agent antifongique, e.g. antibiotique R-106I, et un inhibiteur MDR fongique
WO1995031981A2 (fr) * 1994-05-19 1995-11-30 Rush-Presbyterian-St. Luke's Medical Center Procedes et compositions de reduction de la resistance a de multiples medicaments
US5591715A (en) * 1991-12-10 1997-01-07 Rush Presbyterian-St. Luke's Medical Center Methods and compositions for reducing multidrug resistance
WO2000020036A1 (fr) * 1998-10-02 2000-04-13 Abbott Laboratories Compositions pharmaceutiques a base de paclitaxel
WO2000053231A2 (fr) * 1999-03-09 2000-09-14 Protarga, Inc. Conjugues d'acides gras et d'agents anticancereux, et utilisations correspondantes
WO2000067802A1 (fr) * 1999-05-10 2000-11-16 Protarga, Inc. Compositions d'acides gras -n-substituted indol-3-glyoxyl-amide et leur utilisation
US7235583B1 (en) 1999-03-09 2007-06-26 Luitpold Pharmaceuticals, Inc., Fatty acid-anticancer conjugates and uses thereof
US9066990B2 (en) 2001-03-26 2015-06-30 Bayer Intellectual Property Gmbh Preparation for restenosis prevention
US9649476B2 (en) 2002-09-20 2017-05-16 Bayer Intellectual Property Gmbh Medical device for dispersing medicaments

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5681812A (en) * 1991-12-10 1997-10-28 Rush Presbyterian-St. Luke's Medical Center Methods and compositions for reducing multidrug resistance
US5776891A (en) * 1991-12-10 1998-07-07 Rush Prebyterian-St. Luke Medical Center Compositions for reducing multidrug resistance
US5591715A (en) * 1991-12-10 1997-01-07 Rush Presbyterian-St. Luke's Medical Center Methods and compositions for reducing multidrug resistance
EP0643971A3 (fr) * 1993-08-25 1996-05-29 Lilly Co Eli Compositions antifongiques contenant un agent antifongique, e.g. antibiotique R-106I, et un inhibiteur MDR fongique.
EP0643971A2 (fr) * 1993-08-25 1995-03-22 Eli Lilly And Company Compositions antifongiques contenant un agent antifongique, e.g. antibiotique R-106I, et un inhibiteur MDR fongique
WO1995031981A3 (fr) * 1994-05-19 1996-07-18 Rush Presbyterian St Luke Procedes et compositions de reduction de la resistance a de multiples medicaments
WO1995031981A2 (fr) * 1994-05-19 1995-11-30 Rush-Presbyterian-St. Luke's Medical Center Procedes et compositions de reduction de la resistance a de multiples medicaments
WO2000020036A1 (fr) * 1998-10-02 2000-04-13 Abbott Laboratories Compositions pharmaceutiques a base de paclitaxel
AU759034B2 (en) * 1998-10-02 2003-04-03 Abbott Laboratories Pharmaceutical compositions containing paclitaxel
WO2000053231A2 (fr) * 1999-03-09 2000-09-14 Protarga, Inc. Conjugues d'acides gras et d'agents anticancereux, et utilisations correspondantes
WO2000053231A3 (fr) * 1999-03-09 2001-10-04 Protarga Inc Conjugues d'acides gras et d'agents anticancereux, et utilisations correspondantes
US7235583B1 (en) 1999-03-09 2007-06-26 Luitpold Pharmaceuticals, Inc., Fatty acid-anticancer conjugates and uses thereof
WO2000067802A1 (fr) * 1999-05-10 2000-11-16 Protarga, Inc. Compositions d'acides gras -n-substituted indol-3-glyoxyl-amide et leur utilisation
US9066990B2 (en) 2001-03-26 2015-06-30 Bayer Intellectual Property Gmbh Preparation for restenosis prevention
US9649476B2 (en) 2002-09-20 2017-05-16 Bayer Intellectual Property Gmbh Medical device for dispersing medicaments

Also Published As

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JPH07502274A (ja) 1995-03-09
EP0616493A4 (fr) 1994-11-09
MX9207150A (es) 1993-12-01
AU3243393A (en) 1993-07-19
CN1076358A (zh) 1993-09-22
EP0616493A1 (fr) 1994-09-28
IL104063A0 (en) 1993-05-13
CA2125279A1 (fr) 1993-06-24

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