WO1995031981A2 - Procedes et compositions de reduction de la resistance a de multiples medicaments - Google Patents

Procedes et compositions de reduction de la resistance a de multiples medicaments Download PDF

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Publication number
WO1995031981A2
WO1995031981A2 PCT/US1995/006167 US9506167W WO9531981A2 WO 1995031981 A2 WO1995031981 A2 WO 1995031981A2 US 9506167 W US9506167 W US 9506167W WO 9531981 A2 WO9531981 A2 WO 9531981A2
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Prior art keywords
approximately
acid
human
fatty acid
fatty acids
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PCT/US1995/006167
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English (en)
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WO1995031981A3 (fr
Inventor
John S. Coon
Mannarsamy Balasubramanian
R. Martin Emanuele
Himashu Shah
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Rush-Presbyterian-St. Luke's Medical Center
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Priority to AU26894/95A priority Critical patent/AU2689495A/en
Priority to EP95922084A priority patent/EP0759753A1/fr
Publication of WO1995031981A2 publication Critical patent/WO1995031981A2/fr
Publication of WO1995031981A3 publication Critical patent/WO1995031981A3/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
    • A61K31/74—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
    • A61K38/08—Peptides having 5 to 11 amino acids

Definitions

  • the present mvention relates to the use of resistance modification agents in vivo to reverse multidrug resistance in human or . animal cells and in drug resistant microorganisms.
  • the present invention comprises polyethylene glycol polymers with either fatty acids or block polypropylene glycol on both ends of the polyethylene glycol polymer. These compositions are capable of reducing multidrug resistance in vivo.
  • Mdrl protein a cell membrane drug efflux transporter
  • P- glycoprotein a cell membrane drug efflux transporter
  • This membrane "pump” has broad specificity and acts to remove from the cell a wide variety of chemically unrelated toxins.
  • Recently, a similar mechanism of a broad spectrum drug resistance has been reported for certain microorganisms. These results indicate the existence of bacterial efflux systems of extremely broad substrate specificity that is similar to the multidrug resistance pump of mammalian cells.
  • RMAs resistance modification agents
  • 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 determination of factors contributing to doxorubicin resistance in multidrug resistant cells," J. Natl. Cancer Inst., 81:1887-1892,
  • non-ionic amphipathic surfactants such as Tween 80 and CREMOPHOR® EL, have evidenced RMA activity.
  • CREMOPHOR® EL is a complicated mixture of polyoxyethylated esters of triglycerides of mainly ricinoleic acid (castor oil), the composition and RMA active component of which have not been identified.
  • Use of CREMOPHOR® EL in vivo is complicated by adverse histamine release in some patients. There have also been reports of neurotoxicity associated with the administration of CREMOPHOR® EL.
  • Cancer chemotherapy with cytotoxic agents can be successful only if the tumor cells are more sensitive than normal cells whose destruction is incompatible with survival of the host.
  • tumor cells with constitutive c-myc expression may undergo apoptosis in response to DNA damage by anticancer agents, whereas normal cells are able to pause at checkpoints in the cell cycle to repair the damage, or may not be cycling at all, rendering them highly resistant to apoptosis in this setting.
  • some tumors are composed of cells which are highly sensitive to apoptotic stimuli, and others have a genetic changes which, in isolation, predispose to apoptosis, most tumors tend to acquire other genetic lesions which abrogate this increased sensitivity. Either at presentation or after therapeutic attempts, the tumor cells actually become less sensitive to apoptosis than vital normal dividing cells. Such tumors are generally not curable by available chemotherapeutic approaches.
  • apoptotic response has been associated with increased malignant potential and has been shown to confer pleiotropic drug resistance by oncogene transfer techniques. Therefore, although previously recognized mechanisms of drug resistance, such as decreased drug uptake, altered intracellular drug localization, accelerated detoxification and alteration of drug target continue to be regarded as important factors, pleiotropic resistance due to defective apoptotic response has recently emerged as a distinct and significant category of drug resistance in cancer. Resistance due to failure to trigger apoptosis is sometimes called "downstream" drug resistance to distinguish it from the "classical” mechanisms mentioned above. Thus, what is needed is a clearly identified class of compositions that reverse multidrug resistance in vivo. The composition should have a low occurrence of adverse side-effects. In addition, what is further needed is a composition and method for stimulating apoptosis in cancer cells.
  • 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 or super critical extraction. It has been found that the RMA activity in the SOLUTOL® HS 15 resides in a narrow fraction from the reverse phase liquid chromatography. It has been further determined that the toxicity to cells which is inherent in SOLUTOL® resides in a fraction different from the fraction containing the RMA activity.
  • the present invention also includes a class of compounds that are ethoxylated fatty acids that exhibit strong
  • RMA activity These compounds have been found to be a polyethylene glycol with between approximately 4 to 100 ethylene oxide units with two fatty acids of between approximately 8 and 60 carbon atoms attached to the ends of the polymer in preferably an ester linkage.
  • the fatty acid component of the present invention can be unsaturated or can have substitutions in the carbon chain.
  • the ethoxylated compound is preferrablyof the present invention has the following general structure:
  • compositions described herein to increase the effectiveness of tetracycline. According to the present invention, by administering tetracycline with the compositions described herein, the tissue concentration can be significantly increased. In addition, the duration of drug presence is also increased.
  • Anticancer drugs often kill tumor cells by inducing apoptosis, a form of cell death requiring active participation of the target cells. Impaired ability of cells to execute an apoptotic response results in pleiotropic drug resistance, and modulation of apoptosis resistance might improve the effectiveness of chemotherapy. Prominent involvement of the cell membrane in the pathways leading to apoptosis suggests the opportunity to modify the cellular sensitivity or threshold for apoptosis with membrane interactive agents. It is contemplated as part of the present invention compositions that are novel surfactants that reverse P-glycoprotein-mediated multidrug resistance with negligible toxicity of their own.
  • compositions and methods for inhibiting the expression of genes that code for P-glycoprotein or other proteins that mediate the transport of chemotherapeutic agents include the use of the disclosed compositions prophylactively in cancer therapy before the use of chemotherapy.
  • Another embodiment of the present invention are the polyoxyethylene/polyoxypropylene copolymers with the following general formula:
  • propylene copolymer can be substituted with a butylene copolymer or even mixtures of butylene and propylene units.
  • the preferred copolymer is a polyoxyethylene/polyoxypropylene copolymers with the following general formula:
  • Figure 1 shows fractionation of SOLUTOL® HS 15 using reverse phase liquid chromatography.
  • Figure 2 shows the effect of CRL- 1095 on Rhodamine 123 (P-gp substrate) accumulation in MDR KB 8-5-11 cells (In Vitro).
  • Figure 3 shows the effect of CRL- 1095 on modulation of colchicine resistance on MDR KB 8-5 cells in vitro.
  • Figure 4 shows the effect of CRL- 1095 on modulation of VP-16 resistance on MDR KB 8-5-11 cells in vitro.
  • Figure 5 shows the effect of CRL- 1095 on modulation of doxorubicin resistance on MDR KB 8-5-11 cells in vitro.
  • Figure 6 shows effect of CRL- 1095 on modulation of actinomycin resistance on MDR KB 8-5-11 cells in vitro.
  • Figure 7 shows the effect of CRL-1095 on modulation of colchicine resistance on MDR KB 8-5-11 cells in vitro.
  • Figure 8 shows the effect of CRL-1095 on modulation of Taxol resistance on MDR KB 8-5-11 cells in vitro.
  • Figure 9 shows the effect of CRL-1095 on modulation of daunorubicin resistance in MDR erythro-leukemic K562/ ⁇ i cells.
  • Figure 10 shows the cytotoxicity of CRL-1095 on KB 3-1, KB 8-5, KB 8-5-11, and K562/ ⁇ I cells.
  • Figure 11 shows the effect of CRL-1095 on vincristine accumulation in KB 8-5 human xenograf tumor tissue in mice.
  • Figure 12 shows the effect of CRL- 1605 on modulation of Taxol resistance on MDR KB 8-5 cells.
  • Figure 13 shows the effect of CRL- 1605 on modulation of daunorubicin resistance on MDR K562/IU cells.
  • Figure 14 shows the effect of CRL- 1605 on vincristine accumulation in KB 8-5 human xenograft tumor tissue in mice.
  • Figure 15 shows the modulation of tumor growth in KB 8-5 human xenograft model by CRL- 1605.
  • multidrug resistance means resistance or acquired or natural resistance of tumor or microorganisms to chemotherapeutic agents.
  • the multidrug resistance can be mediated by P-glycoprotein or can be mediated by other mechanisms.
  • patient means either a human or animal with multidrug resistant cancer or a human or animal infected with a multidrug-resistant microorganism or a combination of microorganisms.
  • the present invention comprises methods and compositions for reducing or eliminating multidrug resistance in cancers in patients.
  • a non-ionic amphipathic ester or diester of a fatty acid is administered to a patient in which a 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.
  • Another embodiment of the present invention is directed to compositions and methods for increasing the tissue concentration of certain antibiotics such as tetracycline.
  • tetracycline is believed to be excluded from tissues via the multidrug resistance pump.
  • the present invention includes a method of treating a patient with a cancer that exhibits multidrug resistance to reduce or eliminate the multidrug resistance which includes administering to the patient an effective amount of a non-ionic amphipathic diester of a fatty acid or a polyoxypropylene/polyoxyethylene copolymer.
  • a preparation that exhibits the desired biologic activity is SOLUTOL® HS 15. This preparation is a mixture of various compounds with surfactant activities.
  • fatty acids or polymers of fatty acids with between approximately 8 and 60 carbon atoms and between approximately 4 to 100 ethylene oxide units.
  • the fatty acid component of the present invention can be unsaturated and/or substituted and still exhibit activity.
  • the preferred fatty acids are straight chained.
  • the fatty acids without the ethylene oxide units have little or no RMA activity. It has been determined that the most active fraction of SOLUTOL® HS 15 and CREMOPHOR® EL are diesters of polyethylene glycol. For example, when native CREMOPHOR® EL was fractionated using supercritical extraction, as shown in Example VIII, 35 percent of the total preparation of CREMOPHOR® was extracted. The unextracted portion of the
  • CREMOPHOR® showed little or no activity. Approximately 14% of the total CREMOPHOR® EL mixture was found to have significantly higher (10X) RMA activity compared to native CREMOPHOR® EL. The active fractions of CREMOPHOR® EL are less toxic than the native CREMOPHOR® EL. Infrared analysis of the active fraction shows that the fractions are polyethylene glycol/fatty acid diesters.
  • the present invention includes ethoxylated fatty acids.
  • the fatty acids of the present invention have between 8 and 60 carbon atoms and between approximately 4 to 100 ethylene oxide units.
  • the polyethylene glycol polymers have fatty acids attached, preferably via an ester linkage to both ends of the polyethylene glycol polymer.
  • the fatty acids that are components of the RMA molecule of the present invention have between approximately 4 and 60 carbon atoms.
  • the preferred compounds have a fatty acids with between 12 and 40 carbons with the more preferred compounds with between 8 and 30 carbon atoms with the most preferred compounds having between approximately 15 and 20 carbon atoms. It is to be understood that the two fatty acids in the diester can be different fatty acids.
  • Preferred fatty acids include, but are not limited to, stearic acid, linoleic, oleic acid, palmitic acid and linolenic acid.
  • the preferred polyethylene glycol polymers in the RMA compounds have between approximately 4 and 100 ethylene oxide units, with the more preferred compounds having between
  • 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.
  • a hydrophilic head which comprises polyethylene glycol
  • a hydrophobic tail comprising a fatty acid.
  • Such a molecule is amphipathic.
  • the molecule is large enough that each end displays its own solubility behavior.
  • the polyethylene glycol has two hydrophobic fatty acid tails on either end of the polyethylene glycol polymer.
  • the fatty acid tails are attached to the polyethylene glycol polymer preferably via an ester hnkage, although the linkage can be via other bonds such as an ether hnkage or an amide or similar hnkage.
  • the molecule has the following general structure: Fatty acid Polyethylene glycol Fatty acid
  • 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:
  • propylene copolymer can be substituted with a butylene copolymer or even mixtures of butylene and propylene units.
  • the preferred copolymer is a polyoxyethylene/polyoxypropylene copolymers with the following general formula:
  • the molecule 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.
  • a chemotherapeutic agent typically includes, but is not limited to, doxorubicin, vincristine, vinblastine, Taxol, colchicine, VP-16 and actinomycin D.
  • doxorubicin 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 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 RMA, followed by administration of the chemotherapeutic agent throughout the period until the next session of chemotherapy, either by continuous infusion or oral time release capsules.
  • a typically preferred plasma concentration is between 0.1 to 5 mg/ml.
  • a more preferred plasma concentration of RMA of the present invention is between approximately 0.5 mg/ml and 2.5 mg/ml.
  • the preferred plasma concentration is between approximately 0.01 mg/ml and 2.5 mg/ml with the more preferred plasma concentration between approximately 0.1 mg/ml and 2 mg/ml.
  • 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.
  • the RMA of the present invention preferably should be administered at least one hour prior to and during administration of a cancer chemotherapeutic agent.
  • the RMA of the present invention should be given for at least 12 to 24 hours after administration of the cancer chemotherapy. However, the administration protocol will be dependent upon the pahrmacokinetics of the chemotherapy and RMA.
  • Preparation of an emulsion of the chemotherapeutic agent with the RMA will depend on the particular agents used. Typically, 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 formulations include those suitable for oral, rectal, nasal, topical (including buccal and subhngual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intratracheal, and epidural) administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by conventional pharmaceutical techniques. Such techniques include the step of bringing into association the RMA or the present invention and the pharmaceutical carrier(s) or excipient(s).
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredient with hquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as ' capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous hquid or a non-aqueous hquid; or as an oil-in-water hquid emulsion or a water-in-oil emulsion and as a bolus, etc.
  • Desired parenteral formulation of the polyoxypropylene/polyoxyethylene block copolymers or the ethoxylated fatty acids may optionally contain solubilizers such as CHREMAPHORE or SOLUTOL.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent.
  • Molded tablets may be made by molding, in a suitable machine, a mixture of the powdered compound moistened with an inert hquid diluent.
  • the tablets may be optionally coated or scored and may be formulated so as to provide a slow or controlled release of the active ingredient therein.
  • Formulations suitable for topical administration to the skin may be presented as ointments, creams, gels and pastes comprising the ingredient to be administered in a pharmaceutical acceptable carrier.
  • a preferred topical delivery system is a transdermal patch containing the ingredient to be administered.
  • Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.
  • Formulations suitable for nasal administration include a coarse powder having a particle size, for example, in the range of 20 to 500 microns which is administered in the manner in which snuff is administered, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Suitable formulations, wherein the carrier is a hquid, for administration, as for example, a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient.
  • Formulations suitable for vaginal administration may be presented as pessaries, tamports, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation approximately isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi- dose containers, for example, sealed ampules and vials, and may be stored in a freeze-dried (lyophilized) conditions requiring only the addition of the sterile hquid carrier, for example, water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Preferred unit dosage formulations are those containing a daily dose or unit, daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the administered ingredient.
  • the formulations of the present invention may include other agents conventional in the art having regard to the type of formulation in question, for example, those suitable for oral administration may include flavoring agents.
  • 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 than 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 or other RMAs comprised of ethoxylated fatty acids 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 drug 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 drug 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 drug 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 drugs.
  • microorganisms contain membrane proteins which are similar in structure and function to the P-glycoprotein that is expressed by the Mdrl 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 drugs. 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 Blood-Brain Barrier", /. Biol. Chem., Vol. 267, pgs. 20383-
  • the brain is a pharmacological sanctuary in that many drugs administered systemically have limited 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.
  • ADM adriamycin
  • the drug sensitive human carcinoma cell line, KB 3- 1, and the MDR variants, KB 8-5-11 and KB V-l used in this study were generously provided by Dr. M. Gottesman, NCI, Bethesda, MD.
  • the properties of these cells and their culture conditions have been previously described in detail (Akiyama, et al., Isolation and genetic characterization of human KB cell hnes resistant to multiple drugs. Somat. Cell. Molec. Genet., 11, 117-
  • the KB 8-5-11 cell line was maintained medium containing 100 ng/ml colchicine (Sigma, St. Louis, MO) and the KB V-l cell line was maintained in medium containing 1 mg/ml vinblastine (donated by Eh Lilly and Co., Indianapolis, IN).
  • KB 8-5-11 which exhibit multidrug resistance
  • parental cell line KB 3-1 which is drug sensitive
  • SOLUTOL® HS 15 in combination with various chemotherapeutic agents, namely colchicine, vinblastine, and doxorubicin.
  • chemotherapeutic agents namely colchicine, vinblastine, and doxorubicin.
  • the details of the treatment are described in Coon,
  • SOLUTOL® HS 15 produced a marked reduction in the resistance of KB 8-5-11 cells to colchicine, vinblastine, and doxorubicin.
  • Example II Human epidermoid carcinoma cell lines KB 8-5 and KB 8-5- 11 , which exhibit multidrug resistance, and their parental cell hne KB 3-1, which is drug sensitive, were treated in vitro with SOLUTOL® HS 15 in combination with various chemotherapeutic agents, namely colchicine, vinblastine, and doxorubicin.
  • various chemotherapeutic agents namely colchicine, vinblastine, and doxorubicin.
  • the details of the treatment are described in Coon, J.S., et al, "SOLUTOL® HS 15, nontoxic polyoxyethylene esters of 12-hydroxystearic acid, reverses multidrug resistance", Cancer Research, 51, 897-902, 1991, which is incorporated by reference.
  • cells from the three lines were plated as is well known in the art in 96-well plates, with increasing concentrations of cytotoxic drug 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 marked reduction in the resistance of KB 8-5-11 cells to colchicine, vinblastine, and doxorubicin.
  • Efflux of rhodamine 123 from MDR cells was also examined to provide direct information about the action of the transport protein Mdr 1.
  • Enhanced accumulation of the P-gp substrate, rhodamine 123, in multidrug resistant KB 8-5-11 cells was used to measure RMA activity.
  • Row cytometric analysis was performed as described (Coon et al.* 1991; Buckingham et al. 1995). Briefly, multidrug resistant KB 8-5-11 cells (0.5 x 10 6 cells/ml) were incubated with 0.5 mg/ml rhodamine 123 at 37°C in the presence or absence of the putative RMA.
  • IC50 the drug concentration that reduces cell proliferation to 50% of untreated controls
  • RMI was calculated as the IC50 of drug alone/IC50 of drug + RMA. The average RMI was calculated from at least three independent assays.
  • SOLUTOL® HS 15 was fractionated using reverse phase hquid 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 ml/min.
  • the various fractions were assayed for RMA activity as described in Example IE. The results of the fractionation are shown in Figure 1. In addition the same fractions were assayed for toxicity by measuring 50% inhibitory concentrations (
  • 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 shghtly overlaps the RMA peak.
  • most of d e material that is responsible for the RMA activity is non-toxic.
  • Fatty acid diesters were synthesized by transesterification of PEG and fatty acid mediyl esters (Malkemus, 1956).
  • Stearic acid diester (CRL 1095) was synthesized from 2 moles of methyl stearate (Sigma) and 1 mole of PEG 900 in a reaction catalyzed by zinc acetate. The reaction temperature was kept at 160°C for 5 hrs. under high vacuum (5 microns) with shght stirring. After 8 hrs. of reaction, die product was heated with magnesium sihcate adsorbent at 120°C for 6 hrs. and filtered. The product was washed twice with deionized water to remove the residual zinc acetate, discarding the aqueous phase.
  • the final diester product was analyzed as 99% diester by HPLC.
  • Other diesters were synthesized in a similar manner by substituting appropriate PEG and fatty acid starting materials. The resulting diesters were hydrophobic and were therefore dissolved in 95% alcohol to make stock solutions.
  • Distearyl ether was synthesized by reacting stearyl bromide (Sigma) with PEG-900 in the presence of potassium hydroxide. Stearyl bromide (4.168 g in 10 ml toluene) was slowly added with stirring to 4.64 g of PEG-900 in 10 ml of toluene at 45°C. The mixture was then stirred at 60°C for 30 min. and refluxed for 6 hrs. The final product was treated with charcoal, filtered and isolated from toluene.
  • Distearyl amide was synthesized by reacting amine- modified PEG (Huntsman, Austin TX) with fatty acid chloride (Sigma). Stearyl chloride (0.61 g; Aldrich) was slowly added with stirring to 0.9 g of amine-modified PEG-900 and 2 moles of potassium hydroxide in a carbon tetrachloride/water mixture at room temperature. The carbon tetrachloride layer was separated and evaporated to produce the white powder of the diamide product (yield 68%).
  • Example VII a procedure different from that for making ethoxylated oleic acid (Example VII) was used. Approximately 1 mole of stearic, oleic or capric acid (Sigma) was mixed with 1 mole of PEG 600, PEG 900 or PEG 1500 (Aldrich, Milwaukee, WI) at a ratio of 1:1.1 fatty acid:PEG. The reactions were carried out as described (Wrigley et al.. Syn ⁇ ietic detergents from animal fats. Ethenoxylation of fatty acids and alcohols. J.
  • HLB hydrophile-lipophile balance
  • KB 8-5-11 cells were exposed to each agent for 60 min. at 37°C in the presence of 0.5 mg/ml rhodamine 123. Accumulation of rhodamine 123 was determined as described in Materials and Methods. ⁇ Mean fluorescence intensity resulting from intracellular rhodaminel23; average of three experiments.
  • Ethoxylated oleic acid was synthesized as described using established methods (Wrigley et al, Synthetic detergents from animal fats. Ethenoxylation of fatty acids and alcohols. J. Amer. Oil Chem. Soc. 34, 39-43 (1957); Malkemus, Production of alkylene oxide derivatives. J. Amer. Oil Chem. Soc 33, 571- 574 (1956)). Ethoxylated oleic acid was syndiesized by reacting ediylene oxide widi high purity oleic acid. About 1.38 grams of oleic acid (Sigman Chemical Co., St. Louis, MO) was allowed to react widi 4.45 grams of ethylene oxide (Proxair, Inc.
  • Ethoxylated oleic acid was fractionated by gradient reverse phase hquid chromatography on a Waters LC Module I wid gradient controller (Model 600), auto-sampler (Model 717), a UV detector (Model 486), and Millenium Software (Waters, Milford, MA).
  • the sample solution was 2% ed oxylated oleic acid produced above in dichloroediane.
  • the sample was apphed to a Lichrosorb 5 ⁇ Diol, 250 mm x 4.0 mm column.
  • the injection volume was 200 ⁇ l wid a flow rate of 2.5 mL/min.
  • the mobile phases were A: 100% dichloroediane and B: 100% reagent alcohol.
  • the gradient was as follows:
  • mobile phase is 100% A and 0% B.
  • the various fractions obtained from die reverse phase hquid chromatography were analyzed to determine die RMA activity in each fraction.
  • the fractions were tiien analyzed by infrared spectrophotometry.
  • CREMOPHOR® EL was fractionated by super critical extraction. Approximately 25 grams of CREMOPHOR® EL was thoroughly mixed with 20 grams of hydromatrix (sihcon dioxide) manufactured by Varian - Harbor City, CA 40710 and loaded into a stainless steel high pressure extraction cell. The extraction cell was maintained at 40°C. Supercritical carbon dioxide was pumped into die extraction cell at a rate of approximately 3 liters of gaseous carbon dioxide per minute (4 ml of supercritical carbon dioxide per minute). The extractable material was dissolved under the extraction conditions, and separated from die matrix. The supercritical carbon dioxide solution widi dissolved component was tiien depressurized to evaporate die carbon dioxide gas, and to precipitate the solute. Extraction was done at various pressures of carbon dioxide and fractions were collected at each pressure from 2000 psi to 7000 psi with 400 psi intervals.
  • PEG 600 stearic acid diester is more active (31%) than PEG 400 stearic acid diester (13%).
  • the PEG 900 diesters containing two linolenic acids or two stearates had greater activity tiien die corresponding PEG 900 monoesters.
  • the free fatty acids and die monoesters only show minimal RMA activity.
  • tiiat the PEG 900 dicapric acid (8 carbons) showed minimal activity.
  • the ratio of hydrophil (EO) to hydrophobe (fatty acid) in die G 900 dicapric acid is not optimal.
  • This example shows the effect of CRL-1095 on Rhodamine 123 (P-gp substrate) accumulation in MDR KB 8-5-11 cells in vitro.
  • the cell suspension in DMEM (5xl0 5 /ml) is incubated widi 0.5 ⁇ g/ml of Rhodamine 123 and indicated concentrations of CRL-1095. After incubation for 60 min. at 37°C, the cell suspension was pelleted and washed in cold DMEM for immediate flow cytometric analysis (See Example III).
  • MFI means "mean fluorescence intensity" resulting from intracellular Rhodamine- 123.
  • Figure 2 shows that CRL-1095 enhances the uptake and accumulation of Rhodamine 123 witiiin KB 8-5-11 (resistant) epidermal carcinoma cells in a dose dependent manner.
  • This example shows the effect of CRL-1095 on modulation of VP-16 resistance on MDR KB 8-5-11 cells in vitro. 5xl0 3 cells/well were plated in the presence or absence of CRL- 1095 in combination with VP-16 and incubated for 96 hours. IC JO is equal to the drug concentration tiiat reduces cell proliferation to 50% of untreated controls using standard MTT cell proliferation assay.
  • Figure 4 shows that in KB 8-5-11 cells (resistant), CRL-1095 (1 ⁇ g/ml) completely reverses VP-16 resistance to levels similar in KB 3-1 (sensitive) cells.
  • Example XIII This example shows the effect of CRL-1095 on modulation of doxorubicin resistance on MDR KB 8-5-11 cells in vitro. 5xl0 3 cells/well were plated in the presence or absence of CRL-1095 in combination with Doxorubicin and incubated for 96 hours. IC 50 is equal to the drug concentration tiiat reduces cell proliferation to 50% of untreated controls using standard MTT cell proliferation assay. Figure 5 shows the IC 50 of doxorubicin (dox.) in KB 8-5-11 (resistant) cells in the presence of CRL-1095 (1 ⁇ g/ml) is similar to that in KB 3-1 (sensitive) cells.
  • This example shows the effect of CRL-1095 on modulation of actinomycin resistance on MDR KB 8-5-11 cells in vitro. 5xl0 3 cells/well were plated in die presence or absence of
  • IC JO is equal to the drug concentration diat reduces cell proliferation to 50% of untreated controls using standard MTT cell proliferation assay.
  • Figure 6 shows the IC 50 of actinomycin D (Act.D) in KB 8-5-11 (resistant) cells in the presence of CRL- 1095 (1 ⁇ g/ml) is similar to tiiat in KB 3-1 (sensitive) cells.
  • Example XV This example shows the effect of CRL-1095 on modulation of colchicine resistance on MDR KB 8-5-11 cells in vitro. 5xl0 3 cells/well were plated in die presence or absence of CRL-1095 in combination widi colchicine and incubated for 96 hours. IC JO 1S equal to the drug concentration tiiat reduces cell prohferation to 50% of untreated controls using the standard
  • Figure 7 whows that the IC 5 0 of Colchicine in KB 8-5-11 (resistant) cells in the presence of CRL- 1095 (1 ⁇ g/ml) is similar to tiiat in KB 3-1 (sensitive) cells.
  • This example shows the effect of CRL-1095 on modulation of Taxol resistance on MDR KB 8-5-11 Cells in vitro. 5xl0 3 cells/well were plated in the presence or absence of CRL- 1095 in combination with Taxol and incubated for 72h. IC 50 is equal to the drug concentration that reduces cell prohferation to
  • Figure 8 shows the IC 50 of Taxol in KB 8-5-11 (resistant) cells in the presence of CRL-1095 (1 ⁇ g/ml) is 5-6-fold reduced.
  • This example shows die effect of CRL-1095 on modulation of daunorubicin resistance in MDR erythro-leukemic K562/III cells.
  • 5xl0 3 K562/III erythro-leukemic cells /well were plated in die presence or absence of CRL-1095 plus increasing amounts of daunorubicin, and incubated for 72h.
  • "Fold modulation” is equal to IC 50 of drug alone/IC 30 of drug widi modulator.
  • IC 50 is equal to the drug concentration tiiat reduces cell proliferation to 50% of untreated controls using standard MTT cell prohferation assay. Cyclosporine was cytotoxic at 10 ⁇ g/ml, and fold modulation was not determined (ND).
  • FIG. 9 shows the CRL-1095 effectively modulates Daunorubicin resistance in a dose-dependent manner.
  • CRL-1095 exhibits a 4-fold higher modulatory effect than verapamil at 10 ⁇ g/ml.
  • At similar doses (1 ⁇ g/ml) modulation by CRL-1095 is more effective than verapamil and cyclosporine.
  • This example shows die cytotoxicity of CRL-1095 on KB 3-1, KB 8-5, KB 8-5-11, and K562/III cells.
  • cells are treated wid increasing concentrations of CRL- 1095 for 72 h.
  • IC JO is equal to the drug concentration tiiat reduces cell proliferation to 50% of untreated controls using standard MTT cell proliferation assay. Growth is related as % relative to untreated cells.
  • CRL-1095 is tolerated at relatively high doses in vitro.
  • a comparison of CC 30 levels for parental and drug resistant tumor cell hnes is shown in Table VI.
  • CRL-1095 is 4-19 times less cytotoxic than verapamil or cyclosporine.
  • This example shows the acute toxicity of CRL-1095 in C57B1/6 mice.
  • C57B1/6 mice were administered via intravenous route a bolus injection at concentrations indicated in Table VII, or with vehicle control. Survival was monitored dirough 14 days post injection.
  • Maximum tolerated dose (MTD) of CRL-1095 in which all mice survived is 500 mg/kg.
  • MTD of Verapamil is 75 mg kg (Horton, et al. 1989) and Cyclosporine is 30 mg/Kg (personnel communication widi Dr. plowman at NCI).
  • This example shows the effect of CRL-1095 on vincristine accumulation in KB 8-5 human xenograft tumor tissue in mice.
  • Nude mice carrying the human xenograft tumor, KB 8-5 were given 3 H- Vincristine (VCR) (2 mg/kg, i.p.) as a single injection with or without CRL-1095 (50 mg/kg, i.v.).
  • VCR H- Vincristine
  • FIG. 12 shows tiiat intravenous (IV) administration of CRL-1095 increases accumulation of H- Vincristine 4 - 6 fold in human xenograft tumor tissue in mice.
  • Examples XXI through XXV are directed to CRL- 1605. This molecule has the following structure:
  • This example shows the effect of the CRL- 1605 on modulation of Taxol resistance on MDR KB 8-5 cells.
  • 5X10 3 cells/ml were plated in the presence or absence of CRL- 1605 in combination with Taxol and incubated for 72h.
  • Figure 12 shows the IC JO of Taxol in KB 8-5 (R) cells is 2-fold reduced in the presence of CRL- 1605 (1 ⁇ g/ml).
  • This example shows the effect of CRL- 1605 on modulation of daunorubicin resistance on MDR K562/IH cells.
  • 5X10 3 cells/ml were plated in the presence or absence of CRL- 1605 in combination with Daunorubicin and incubated for 72h.
  • Figure 13 shows die IC 50 of Daunorubicin in K562/m (R) is 40- fold reduced in die presence of CRL- 1605 (10 ⁇ g/ml).
  • This example shows the effect of CRL-1605 on vincristine accumulation in KB 8-5 human xenograft tumor tissue in mice.
  • Nude mice carrying the human xenograft tumor, KB 8-5 were given 3 H- Vincristine (VCR) (2 mg/kg, i.p.) as a single injection with or without CRL-1605 (50 mg/kg, i.v.).
  • VCR H- Vincristine
  • FIG. 14 shows that die intravenous (IV) administration of CRL-1605 increases accumulation of H- Vincristine 4 - 6 fold in human xenograft tumor tissue in mice.
  • This example shows the acute toxicity of CRL-1605 in C57B1/6 mice.
  • C57B1/6 mice In vivo studies in C57B1/6 mice indicate tiiat CRL-1605 is tolerated at relatively high doses.
  • MTD maximum tolerated dose
  • the maximum tolerated dose (MTD) of CRL-1605 is 350 mg/kg.
  • MTD of Verapamil is 75 mg/kg (Horton, et al, 1989) and die MTD of cyclosporine is 30 mg/Kg (personnel communication widi Dr. Plowman at National Cancer Institute).
  • This example shows the modulation of tumor growth in KB 8-5 human xenograft model by CRL-1605.
  • Human KB 8-5 tumors (2 mm 3 ) were implanted on bodi sides of d e hind flank in nude mice (strain NCR/Nu/NCI). Two weeks following implantation, treatment was administered on days 1, 5, and 23 as follows: Doxorubicin only animals received doxorubicin 8 mg/kg. Doxorubicin + vehicle animals received die same dose of doxorubicin plus die equivalent volume of CRL-1605 vehicle.

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Abstract

L'invention concerne des procédés et des compositions permettant de réduire ou d'éliminer la résistance à de multiples médicaments dans des cancers ou certaines infections par des microorganismes résistants aux médicaments chez des patients. Selon le procédé et la composition de la présente invention, un diester amphipathique non ionique d'acides gras ou un poloxmère inverse est administré à un patient dans lequel un cancer ou un microorganisme présente une résistance multimédicament à l'agent chimiothérapeutique. Le procédé et la composition de la présente invention peuvent être utilisés avec une efficacité particulière où une résistance multimédicament à un agent chimiothérapeutique s'est révélée lors d'un traitement d'un cancer.
PCT/US1995/006167 1994-05-19 1995-05-19 Procedes et compositions de reduction de la resistance a de multiples medicaments WO1995031981A2 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993011668A1 (fr) * 1991-12-10 1993-06-24 Rush-Presbyterian-St. Luke's Medical Center Procedes et compositions destines a reduire la multiresistance aux medicaments

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993011668A1 (fr) * 1991-12-10 1993-06-24 Rush-Presbyterian-St. Luke's Medical Center Procedes et compositions destines a reduire la multiresistance aux medicaments

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
CANCER IMMUNOL. IMMUNOTHER., vol. 36, no. 2, 1993, pages 133-139, XP002000100 A.S.-F- CHONG ET AL.: "Diverse multidrug-resistance-modification agents inhibit cytolytic activity of natural killer cells" *
CANCER RESEARCH, vol. 51, February 1991, pages 897-902, XP002000098 J.S. COON ET AL.: "Solutol HS 15, nontoxic polyoxyethylene esters of 12-hydroxystearic acid reverses multidrug resistance" cited in the application *
DATABASE BIOSIS BIOSCIENCES INFORMATION SERVICE, PHILADELPHIA, PA, US HOST STN: Accession No. 92:404446 BIOSIS, 1992 M. PAGE ET AL.: "Elimination of P-170 mediated multidrug resistance by solubilization in pluronic micelles" XP002000101 & PROC. AM. ASSOC. CANCER RES. ANNU MEET , vol. 33, no. 0, 1992, page 552 *
INT. J. CANCER, vol. 62, no. 4, August 1995, pages 436-442, XP002000097 L.E. BUCKINGHAM ET AL.: "Comparison of Solutol HS 15, Cremophor EL and novel ethoxylated fatty acid surfactants as multidrug resistance modification agents" *
INT. J. ONCOL., vol. 5, no. 6, 1994, pages 1305-1308, XP002000096 R. PARADIS ET AL.: "Use of pluronic micelles to overcome multidrug resistance " *
PROC. AM. ASSOC. CANCER. RES. ANN. MEET., vol. 33, no. 0, 1992, page 484 XP002000099 J.S. COON : "Survey of surfactants for reversing multidrug resistance" *

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