US20030180382A1 - Hyaluronan as a cytotoxic agent, drug pre-sensitizer and chemo-sensitizer in the treatment of disease - Google Patents

Hyaluronan as a cytotoxic agent, drug pre-sensitizer and chemo-sensitizer in the treatment of disease Download PDF

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US20030180382A1
US20030180382A1 US10/088,774 US8877403A US2003180382A1 US 20030180382 A1 US20030180382 A1 US 20030180382A1 US 8877403 A US8877403 A US 8877403A US 2003180382 A1 US2003180382 A1 US 2003180382A1
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drug
hyaluronan
cells
chemotherapeutic agent
treatment
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Tracey Brown
Richard Fox
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Alchemia Oncology Pty Ltd
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Meditech Research Ltd
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Publication of US20030180382A1 publication Critical patent/US20030180382A1/en
Priority to US11/191,407 priority Critical patent/US8287894B2/en
Priority to US11/198,663 priority patent/US9066919B2/en
Priority to US11/415,612 priority patent/US8388993B2/en
Assigned to ALCHEMIA ONCOLOGY LIMITED reassignment ALCHEMIA ONCOLOGY LIMITED CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: MEDITECH RESEARCH LIMITED
Priority to US14/634,600 priority patent/US20150265648A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/525—Isoalloxazines, e.g. riboflavins, vitamin B2
    • 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
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • 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
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/728—Hyaluronic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • the present invention relates to the enhancement of bioavailability of chemotherapeutic agents for the treatment of disease.
  • the present invention relates to the use of hyaluronan either alone or in combination with a chemotherapeutic agent to enhancement the bioavailability of the chemotherapeutic agent for treatment of disease.
  • the present invention also relates to the treatment of a drug resistant disease whereby the drug resistance is overcome or alleviated with the use of hyaluronan either alone or in combination with a chemotherapeutic agent.
  • chemotherapeutic agents have proven valuable in the treatment of neoplastic disorders including connective or autoimmune diseases, metabolic disorders, and dermatological diseases, and many of these agents are highly effective and do not suffer from any bioavailability problems.
  • chemotherapeutic agents Proper use of chemotherapeutic agents requires a thorough familiarity with the natural history and pathophysiology of the disease before selecting the chemotherapeutic agent, determining a dose, and undertaking therapy.
  • Each subject must be carefully evaluated, with attention directed toward factors which may potentiate toxicity, such as overt or occult infections, bleeding dyscrasias, poor nutritional status, and severe metabolic disturbances.
  • factors which may potentiate toxicity such as overt or occult infections, bleeding dyscrasias, poor nutritional status, and severe metabolic disturbances.
  • the functional condition of certain major organs, such as liver, kidneys, and bone marrow is extremely important. Therefore, the selection of the appropriate chemotherapeutic agent and devising an effective therapeutic regimen is influenced by the presentation of the subject. Such considerations affect the dosage and type of drug administered.
  • chemotherapeutics are readily useable.
  • some chemotherapeutic agents are inherently refractory in that animal cells do not readily respond to these agents, while other chemotherapeutics suffer from acquired resistance.
  • it is well recognised that some subjects on prolonged chemotherapy are forced to change chemotherapeutics as these become less efficacious with time.
  • some chemotherapeutics while not affected by inherent or acquired resistance per se, are not effective in the treatment of certain diseases as they have innate problems with bioavailability.
  • One disease that is frequently affected by both cellular resistance and bioavailability problems is cancer.
  • Cancer is responsible for one in four deaths in Western society. While the rates of new cases of cancer and deaths with cancer decreased in the United States and Canada between 1990-1994, the data show that 2,604,650 people in the United States died from cancer between 1990-1994, with more men (53%) than women (47%) affected. The most common cancer deaths were due to cancer of the lung (728,641), colon and rectum (285,724), breast (218,786), and prostate (169,943).
  • breast and ovarian cancer representing approximately 35% of all cancers found in women.
  • the majority of women diagnosed with these forms of cancer receive a combination of surgical, radiation therapy or chemotherapy.
  • Chemotherapeutic agents used to treat cancer can be subdivided into several broad categories, including, (1) alkylating agents, such as mechlorethamine, cyclophosphamide, melphalan, uracil mustard, chlorambucil, busulfan, carmustine, lomustine, semustine, streptozoticin, and decrabazine; (2) antimetabolites, such as methotrexate, fluorouracil, fluorodeoxyuridine, cytarabine, azarabine, idoxuridine, mercaptopurine, azathioprine, thioguanine, and adenine arabinoside; (3) natural product derivatives, such as vinblastine, vincristine, dactinomycin, daunorubicin, doxorubicin, mithramycin, taxanes (e.
  • alkylating agents such as mechlorethamine, cyclophosphamide, melphalan, urac
  • paclitaxel bleomycin, etoposide, teniposide, and mitomycin C
  • miscellaneous agents such as hydroxyurea, procarbezine, mititane, and cisplatinum.
  • Important cancer chemotherapeutic agents include vinblastine (0.1 mg per kilogram per week), vincristine (0.01 mg per kilogram per week), etoposide (35 to 50 mg per square meter per day), dactinomycin (0.15 mg per kilogram per day), doxorubicin (500 to 600 mg per square meter per week), daunorubicin (65 to 75 mg per square meter per week), and mithramycin (0.025 mg per kilogram per day).
  • HA hyaluronan
  • PCT/AU00/00004 International patent application no. PCT/AU00/00004 was filed covering this invention, and is incorporated in its entirety herein by reference.
  • HA also known as hyaluronic acid, is a naturally occurring polysaccharide comprising linear-chain polymers, which is found ubiquitously throughout the animal kingdom. HA is highly water-soluble, making it an ideal drug delivery vehicle for biological systems.
  • HA could act as a sole agent. It was found that HA could exert a cytotoxic effect on human breast cancer cells, as well as pre-sensitizing cells so that they became more susceptible to chemotherapeutic agents.
  • the present invention therefore provides methods whereby cells that were, or had become resistant to chemotherapeutic agents could be effectively treated. More importantly, by using the disclosed methods it is possible to decrease the dosages of chemotherapeutic agents without decreasing the efficacy to the subject.
  • the methods of the invention include administering hyaluronan either alone in conjunction with a chemotherapeutic agent.
  • the present invention is based upon the discovery that hyaluronan, derivatives, analogues, and salts thereof, not only inhibit cells per se, but also allows the safe administration of selected chemotherapeutic agents at standard or lower doses thought to be less effective, to treat subjects including human subjects.
  • hyaluronan in combination with chemotherapeutic agents also enhances the therapeutic effect of these agents against cells that are refractory, thus preventing the subsequent emergence of multidrug resistance.
  • HA internalisation could elevate the mitochondrial membrane potential which could result in cell death or increased drug retention.
  • the present invention provides a method of treating a subject in need thereof comprising the step of administering to said subject a therapeutically effective amount of hyaluronan in conjunction with a chemotherapeutic agent such that said chemotherapeutic agent is more effective than when administered alone.
  • the present invention also provides a method of enhancing the bioavailability of a chemotherapeutic agent comprising the step of administering to a subject in need thereof a therapeutically effective amount of hyaluronan.
  • Hyaluronan can be used to significantly enhance the bioavailability of any administered chemotherapeutic agent.
  • the chemotherapeutic agent that is administered is selected from the group consisting of carmustine (BCNU), chlorambucil (Leukeran), cisplatin (Platinol), Cytarabine, doxorubicin (Adriamycin), fluorouracil (5-FU), methoxetrate (Mexate), CPT111, etoposide, plicamycin (Mithracin) and taxanes such as, for example, paclitaxel.
  • the invention provides a method of treating or preventing multidrug resistance or drug-resistant cells comprising the step of administering a therapeutically effective amount of hyaluronan, prior to, together with, or subsequent to the administration of a chemotherapeutic agent.
  • administering results in the suppression of tumor growth by at least 50%; preferably 60%; and, more preferably, greater than 70%. Accordingly, the elimination of tumor growth and proliferation eliminates the production of multidrug resistant cells reducing the recurrence of cancer and increasing the efficacy of chemotherapeutic treatments.
  • the present invention further provides a pharmaceutical composition for increasing the sensitivity of cells to chemotherapeutic agents comprising hyaluronan.
  • chemotherapeutic agents comprising hyaluronan.
  • the hyaluronan and/or chemotherapeutic agent may also be administered together with a further pharmaceutical carrier.
  • the present invention also provides a method of treating cancer cells comprising the step of administering to a patient in thereof a therapeutically effective amount of hyaluronan.
  • cancer cells are resistant to chemotherapeutic drugs.
  • a method of overcoming cellular resistance comprising the step of administering a therapeutically effective amount of HA.
  • FIG. 1 shows exponentially growing breast cancer cells exposed to 750,000 dalton HA for 24 h at which stage the cells were photographed. At 10 ng/ml there was a reduction in cell number, but no difference in morphology was noted. At 100 ng/ml and 1 ⁇ g/ml the cells appeared top be undergoing a osmotic response where the cells appeared to swell. At 2 mg/ml and 5 mg/ml the cells became granular and the plasma membrane was “pitted” possibly indicating an osmotic response and/or the commencement of cell death.
  • FIGS. 2 a - 2 f shows exponentially growing breast cancer cells that were exposed to 750,000 dalton HA for 30 min, 1 h, or 24 h at which stage the cells were varying concentrations of adriamycin. These figures also illustrate the effect of HA/drug co-incubation for the period of 1 or 3 days. These diagrams illustrate that HA can “pre-sensitise” and/or chemosensitise cells to therapeutic drugs.
  • FIGS. 3 a - 3 d shows exponentially growing breast cancer cells exposed to varying concentrations of 750,000 dalton hyaluronan for 1 h, 24 h or 3 days followed by treatment with 40 nM Adriamycin for varying time periods of 1 h, 24 h or 3 days. These figures show that a wide concentration range of hyaluronan can act as a chemosenitiser or exert a cytotoxic effect.
  • FIG. 4 shows that there was no treatment toxicity noted throughout the 6-week study.
  • the mice receiving HA therapy that is as a sole agent or as a chemosensitizer, demonstrated enhanced well being where the animal did not loose weight, but maintained its body mass.
  • HA as a sole agent also demonstrated its effect by reducing the primary tumour mass in comparison to the saline control. No significant differences in tumour response were noted in the initial 2 weeks of treatment, but thereafter the HA followed by 5-FU tumour growth was retarded in comparison to the other treatment groups. During the 6 weeks of treatment interesting differences were noted in the number of tumour doubling cycles.
  • mice receiving the saline treatment underwent an average of 4 tumour doublings, while the incorporation of HA into the treatment regimen significantly increased the tumour doubling time where HA/5-FU animals underwent an average of one tumour doubling cycle, once again highlighting the effect of HA on 5-FU cytotoxicity.
  • FIG. 6 shows that the co-administration of HA resulted in a significant reduction in non-lymphoid metastasis. With the exception of the mice receiving the HA therapy, new tumours were observed around the neck or underarm region of the area adjacent to the primary tumour.
  • the methods and compositions of the invention are useful for increasing the sensitivity of cells to chemotherapeutic agents such as, for example, anti-cancer agents like paclitaxel, analgesics, opiates, hormones or antibiotics and the like.
  • chemotherapeutic agents such as, for example, anti-cancer agents like paclitaxel, analgesics, opiates, hormones or antibiotics and the like.
  • the methods and compositions of the invention are useful for increasing the sensitivity of cells associated with cellular proliferative disorders (eg., a neoplasm).
  • a neoplasm e.g., a neoplasm
  • the invention eliminates or reduces the number of multidrug resistant cells by eliminating cancer cells prior to any mutation inducing a multidrug resistant phenotype. Accordingly, by reducing multi-drug resistant tumor cells from arising, the invention satisfies the shortcomings of current therapeutic modalities.
  • subject refers to any animal having a disease or condition which requires treatment with a chemotherapeutic agent wherein the chemotherapeutic agent has reduced efficacy relative to that desired.
  • the subject is suffering from a cellular proliferative disorder (eg., a neoplastic disorder).
  • a cellular proliferative disorder eg., a neoplastic disorder.
  • Subjects for the purposes of the invention include, but are not limited to, mammals (eg., bovine, canine, equine, feline, porcine) and preferably humans.
  • cell proliferative disorder is meant that a cell or cells demonstrate abnormal growth, typically aberrant growth, leading to a neoplasm, tumor or a cancer.
  • Cell proliferative disorders include, for example, cancers of the breast, lung, prostate, kidney, skin, neural, ovary, uterus, liver, pancreas, epithelial, gastric, intestinal, exocrine, endocrine, lymphatic, haematopoietic system or head and neck tissue.
  • neoplastic diseases are conditions in which abnormal proliferation of cells results in a mass of tissue called a neoplasm or tumor.
  • Neoplasms have varying degrees of abnormalities in structure and behaviour. Some neoplasms are benign while others are malignant or cancerous. An effective treatment of neoplastic disease would be considered a valuable contribution to the search for cancer preventive or curative procedures.
  • the methods of this invention involve in one embodiment, (1) the administration of hyaluronan, prior to, together with, or subsequent to the administration of a chemotherapeutic agent; or (2) the administration of a combination of hyaluronan and a chemotherapeutic agent.
  • terapéuticaally effective amount is meant an amount of a compound of the present invention effective to yield a desired therapeutic response. For example to prevent cancer or treat the symptoms of cancer in a host or an amount effective to treat cancer.
  • the specific “therapeutically effective amount” will, obviously, vary with such factors as the particular condition being treated, the physical condition of the patient, the type of mammal being treated, the duration of the treatment, the nature of concurrent therapy (if any), and the specific formulations employed and the structure of the compounds or its derivatives.
  • a “pharmaceutical carrier” is a pharmaceutically acceptable solvent, suspending agent or vehicle for delivering the hyaluronan and/or chemotherapeutic agent to the animal or human.
  • the carrier may be liquid or solid and is selected with the planned manner of administration in mind.
  • cancer refers to all types of cancers or neoplasm or malignant tumours found in mammals. Cancer includes sarcomas, lymphomas and other cancers. The following types are examples, but are, but is not intended to be limited to these particular types of cancers: prostate, colon, breast, both the MX-1 and the MCF lines, pancreatic, neuroblastoma, rhabdomysarcoma, home, lung, murine, melanoma, leukemia, pancreatic, melanoma, ovarian, brain, head & neck, kidney, mesothelioma, sarcoma, Kaposi's, sarcoma, stomach, and uterine.
  • cell include but is not limited to mammalian cells (eg., mouse cells rat cells or human cells).
  • the hyaluronan and/or chemotherapeutic agents may be administered orally, topically, or parenterally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and vehicles.
  • parenteral as used herein includes subcutaneous injections, aerosol, intravenous, intramuscular, intrathecal, intracranial, intrasternal injection or infusion techniques.
  • the present invention also provides suitable topical, oral, and parenteral pharmaceutical formulations for use in the novel methods of treatment of the present invention.
  • the compounds of the present invention may be administered orally as tablets, aqueous or oily suspensions, lozenges, troches, powders, granules, emulsions, capsules, syrups or elixirs.
  • the composition for oral use may contain one or more agents selected from the group of sweetening agents, flavouring agents, colouring agents and preserving agents in order to produce pharmaceutically elegant and palatable preparations.
  • the tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be, for example, (1) inert diluents, such as calcium carbonate, lactose, calcium phosphate or sodium phosphate; (2) granulating and disintegrating agents, such as corn starch or alginic acid; (3) binding agents, such as starch, gelatin or acacia; and (4) lubricating agents, such as magnesium stearate, stearic acid or talc.
  • inert diluents such as calcium carbonate, lactose, calcium phosphate or sodium phosphate
  • granulating and disintegrating agents such as corn starch or alginic acid
  • binding agents such as starch, gelatin or acacia
  • lubricating agents such as magnesium stearate, stearic acid or talc.
  • These tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as gly
  • the hyaluronan as well as the chemotherapeutic agents useful in the method of the invention can be administered, for in vivo application, parenterally by injection or by gradual perfusion over time independently or together. Administration may be intravenously, intraperitoneally, intramuscularly, subcutaneously, intracavity, or transdermally. For in vitro studies the agents may be added or dissolved in an appropriate biologically acceptable buffer and added to a cell or tissue.
  • Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and other additives may also be present such as, for example, anti-microbials, anti-oxidants, chelating agents, growth factors and inert gases and the like.
  • the invention can be used to treat pathologies associated cell proliferative disorders, including, for example, neoplasms, cancers (eg., cancers of the breast, lung, prostate, kidney, skin, neural, ovary, uterus, liver, pancreas, epithelial, gastric, intestinal, exocrine, endocrine, lymphatic, haematopoietic system or head and neck tissue), fibrotic disorders and the like.
  • cancers eg., cancers of the breast, lung, prostate, kidney, skin, neural, ovary, uterus, liver, pancreas, epithelial, gastric, intestinal, exocrine, endocrine, lymphatic, haematopoietic system or head and neck tissue
  • the methods and compounds of the invention may also be used to treat other diseases associated with chemotherapeutic treatment such as neurodegenerative disorders, hormonal imbalance and the like. Therefore, the present invention encompasses methods for ameliorating a disorder associated with cell proliferation, neoplasms, cancers and the like, including treating a subject having the disorder, at the site of the disorder, with hyaluronan and a chemotherapeutic agent in an amount sufficient to inhibit or ameliorate the cell's proliferation or the disorder.
  • the terms “treating”, “treatment” and the like are used herein to mean affecting a subject, tissue or cell to obtain a desired pharmacologic and/or physiologic effect.
  • the effect may be prophylactic in terms of completely or partially preventing a cell proliferative disorder or sign or symptom thereof, and/or may be therapeutic in terms of a partial or complete cure for a disorder and/or adverse effect attributable to, for example, aberrant cell proliferation.
  • “Treating” as used herein covers any treatment of, or prevention of a cell proliferative disorder in a vertebrate, a mammal, particularly a human, and includes: (a) preventing the disorder from occurring in a subject that may be predisposed to the disorder, but has not yet been diagnosed as having it; (b) inhibiting the disorder, i.e., arresting its development; or (c) relieving or ameliorating the disorder, i. e., cause regression of the disorder.
  • the invention includes various pharmaceutical compositions useful for ameliorating cell proliferative disorder, including neoplasms, cancers and the like.
  • the pharmaceutical compositions according to one embodiment of the invention are prepared by bringing hyaluronan, analogue, derivatives or salts thereof and one or more chemotherapeutic agents or combinations of hyaluronan and one or more chemotherapeutic agents into a form suitable for administration to a subject using carriers, excipients and additives or auxiliaries.
  • Frequently used carriers or auxiliaries include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, vitamins, cellulose and its derivatives, animal and vegetable oils, polyethylene glycols and solvents, such as sterile water, alcohols, glycerol and polyhydric alcohols.
  • Intravenous vehicles include fluid and nutrient replenishers.
  • Preservatives include antimicrobial, anti-oxidants, chelating agents and inert gases.
  • Other pharmaceutically acceptable carriers include aqueous solutions, non-toxic excipients, including salts, preservatives, buffers and the like, as described, for instance, in Remington's Pharmaceutical Sciences, 15th ed.
  • the pharmaceutical compositions are preferably prepared and administered in dose units.
  • Solid dose units are tablets, capsules and suppositories.
  • different daily doses can be used for treatment of a subject. Under certain circumstances, however, higher or lower daily doses may be appropriate.
  • the administration of the daily dose can be carried out both by single administration in the form of an individual dose unit or else several smaller dose units and also by multiple administration of subdivided doses at specific intervals.
  • compositions according to the invention may be administered locally or systemically in a therapeutically effective dose. Amounts effective for this use will, of course, depend on the severity of the disease and the weight and general state of the subject. Typically, dosages used in vitro may provide useful guidance in the amounts useful for in situ administration of the pharmaceutical composition, and animal models may be used to determine effective dosages for treatment of particular disorders. Various considerations are described, eg., in Langer, Science, 249: 1527, (1990).
  • Formulations for oral use may be in the form of hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. They may also be in the form of soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions normally contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspension.
  • excipients may be (1) suspending agent such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; (2) dispersing or wetting agents which may be (a) naturally occurring phosphatide such as lecithin; (b) a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate; (c) a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadecaethylenoxycetanol; (d) a condensation product of ethylene oxide with a partial ester derived from a fatty acid and hexitol such as polyoxyethylene sorbitol monooleate, or (e) a condensation product of ethylene oxide with a
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension.
  • This suspension may be formulated according to known methods using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono-or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • Hyaluronan together with a chemotherapeutic agent of the present invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
  • Dosage levels of the compounds of the present invention are of the order of about 0.5 mg to about 10 mg per kilogram body weight, with a preferred dosage range between about 5 mg to about 20 mg per kilogram body weight per day (from about 0.3 gms to about 1.2 gms per patient per day).
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage will vary depending upon the host treated and the particular mode of administration.
  • a formulation intended for oral administration to humans may contain about 5 mg to 1 g of an active compound with an appropriate and convenient amount of carrier material which may vary from about 5 to 95 percent of the total composition.
  • Dosage unit forms will generally contain between from about 5 mg to 500 mg of active ingredient.
  • the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
  • the compounds of the present invention may additionally be combined with other compounds to provide an operative combination. It is intended to include any chemically compatible combination of chemotherapeutic agents, as long as the combination does not eliminate the activity of the hyaluronan of this invention.
  • HA used in all of the in vitro and in vivo studies were obtained from Kyowa Hakko Kogyo (Yamaguchi, Japan). 5-FU was obtained from Sigma, St. Louis, USA. And Adraimycin from Cytomix, Northcote, Melbourne, Australia. A standard profile of the HA used is shown in Table 1. TABLE 1 Specification Sheet For Hyaluronan Bulk Dried Powder TEST SPECIFICATION 1. Description White or cream coloured powder or granules, odourless 2. Identification (IR Spectrum) Conforms to Reference Standard 3. pH (1% solution) 5.0 to 7.0 4. Loss on Drying NMT 10.0% 5. Residue on Ignition 15.0 to 19.0% 6. Protein Content NMT 0.1% 7.
  • a 10 mg/ml stock of HA solution was prepared by dissolving desiccated HA (modal M r 7.5 ⁇ 10 5 kDa,) in pyrogen-free injection grade water. To ensure a homogenous solution the HA was dissolved overnight at 4° C. followed by thorough vortexing. To ensure that the HA had maintained its molecular weight during the preparation of the stock solution, the solution was analysed on a Sephacryl S-1000 size exclusion gel with column specifications of 1.6 cm ⁇ 70 cm, sample size 2 ml, flow rate 18 ml/h and 2 ml fraction size. Hyaluronan was detected in column fractions by the uronic acid assay.
  • the uronic acid assay was used to detect the presence of hyaluronan qualitatively from the fractions collected from the gel filtration chromatography procedure. A 25 ⁇ l aliquot of each fraction was then transferred into a 96 well plate. 250 ⁇ l of a carbazole reagent (3M carbazole/0.025M borate in H 2 SO 4 ) was then added to these fractions. The 96 well plate was incubated for 45-60 min at 80° C. A Dynatech MR7000 plate reader with a 550 nm filter was used to read the 96 well plate. The absorbance was considered to be significant when it was >3 standard deviations above the background absorbance. The background was calculated by taking an equal number of sample points before and after V o and V t where the average number taken was 16 (Fraser et al. 1998).
  • a stock solution of 5-FU was prepared by dissolving powdered 5-FU in 0.1M NaOH (pH 8.9) and brought to a concentration of 1 mg/ml with pyrogen-free injection grade 0.9% w/v NaCl. The stock solution was filtered through a 0.22 ⁇ m filter to ensure sterility. The 5-FU was diluted by adding the required volume of stock solution to the cell-line specific growth medium as specified above.
  • Human breast adenocarcinoma cell lines MDA-MB-468, MDA-MB-435 and MDA-MB-231 were selected based on HA binding affinity (Culty et al, 1994), and the expression of the HA receptors of CD44 and RHAMM (Wang et al, 1996). The characteristics of these cell lines are shown in Table 2.
  • Cell lines MDA-MB-468, MDA-MB-435 and MDA-MB-231 were routinely grown and subcultured as a monolayer in 175 cm 2 culture flasks in Leibovitz L-15 Medium supplemented with 10% Foetal calf serum (FCS) and antibiotic/antimycotic reagents at 37° C. in humidity controlled incubator with 100% (v/v) air.
  • FCS Foetal calf serum
  • antibiotic/antimycotic reagents at 37° C. in humidity controlled incubator with 100% (v/v) air.
  • Leibovitz-L-15 with glutamine (10 ⁇ concentrate), RPMI (10 ⁇ concentrate), Eagles basal medium (EBM, 10 ⁇ concentrate), 20 mM HEPES, 0.09% w/v bicarbonate, Hanks' Balanced Salt Solution (HBSS, 10 ⁇ concentrate) and Dulbecco's Phosphate Buffered Saline without calcium and magnesium (PBS, 10 ⁇ concentrate) were purchased from Sigma (St Louis, Mo., USA). Powder concentrates were dissolved in the required volume of reverse osmosis deionised pyrogen-free distilled water to make a single strength solution, sterilised by 0.22 ⁇ m high pressure filtration (Millipore Corporation, MA.
  • MDA MB-468, MDA MB-231 and MDA MB-435 cell line were grown in 90% Leibovitz L-15 medium supplemented with 10% FCS. When confluent the cultures were washed 1 ⁇ in HBSS and trypsinised in 0.25% trypsin/0.05% EDTA. The cell suspensions were counted with an automated cell counter (ZM-2 Coulter Counter) by adding 15 mL saline+0.2 ml of cell suspension.
  • ZM-2 Coulter Counter automated cell counter
  • MDA MB-468 25,000 cell/ml of media
  • MDA MB-231 12,000 cell/ml of media
  • MDA MB-435 12,000 cell/ml of media
  • the cells were plated into 48-well plates (1 cm 2 surface area) by adding 1 ml of cell suspension per well. Cells were allowed to attach for 24 h, before the media was removed, monolayers washed. The test media was; growth media containing 0-1 ⁇ m adriamycin or 5-fluorouracil with or without the addition of 0-1 ⁇ M of HA (modal Mw 750,000). The cells were exposed to the several combinations of HA and drugs for different times and at different concentrations (Table 3).
  • Example 2 From the results in Example 2 the carcinoma cell line MDA-MB-468 was selected as the cancer cell inoculant for the generation of any nude mouse human tumour xenografts.
  • Cells were routinely grown and subcultured as a previously described in Example 2.
  • For injection into mice cells were grown to 100% confluency, trypsinised in 0.025% trypsin/0.01% EDTA solution, washed twice by centrifugation in a Beckman TJ-6 bench centrifuge at 400 g av for 10 min, counted using a Model-ZM Coulter counter and resuspended in serum-free Leibovitz L-15 medium at 1 ⁇ 10 8 cells/ml.
  • mice Six to eight weeks old athymic CBA/WEHI nude female mice, purchased from the Walter and Eliza Hall Research Institute, Melbourne Australia, were maintained under specific pathogen-free conditions, with sterilised food and water available ad libitum. Each mouse received one injection containing 5 ⁇ 10 6 cells in 50 ⁇ l. The cells were injected with a 26 gauge needle into the mammary fat pad directly under the first nipple (Lamszus et al, 1997). Tumour measurements were made weekly by measuring three perpendicular diameters (d 1 d 2 d 3 ). Tumour volume was estimated using the formula:
  • tumours were surgically removed and immediately fixed in 10% buffered formalin for 12 h.
  • the fixed tumour was dehydrated overnight in a series of 70-100% ethanol, followed by paraffin embedding from which 2-4 ⁇ m sections were cut.
  • the sections were placed on slides, de-waxed, and brought to water. Slides were washed 3 ⁇ 5 min in PBS. Heterophile proteins were blocked by incubation with 10% foetal calf serum for 10 min, followed by a PBS rinse.
  • the detection antibodies were applied for 60 min at RT.
  • the detection antisera or antibodies were against RHAMM , CD44H and CAE.
  • the slides were washed 3 ⁇ 5 min in PBS and endogenous peroxidase activity blocked by immersion in 0.3% H 2 O 2 in methanol for 20 min. Following a further PBS wash, the peroxidase-conjugated swine anti-rabbit secondary antiserum was applied for 60 min at RT, followed by 3 ⁇ 5 min washes in PBS.
  • Sigma Fast 3,3′-Diaminobenzidine tablets (DAB) were prepared according to the manufacturer's instructions and the DAB solution was applied for 5-10 min at RT.
  • the slides were washed in tap water for 10 min, counterstained with haematoxylin, dehydrated and mounted.
  • One of the most commonly used treatment regimens for human breast cancer is cyclophosphamide, methotrexate and 5-fluorouacil, which is administered on day 1 and 8 of a 28 day cycle.
  • the initial treatment regimen is for 6 cycles at which time the patient condition is re-assessed, therefore we tried to simulate the human treatment regimen as closely as possible by exposing the mice to 6 cycles (6 months) of treatment in a long term efficacy study and a 6 cycles (6 week) short term efficacy study.
  • Considering the life cycle of a mouse is approximately 2 years we commenced both short-term and long-term treatment protocols (see Table 7). TABLE 7 Treatment Administration Protocols. 6-Week Study Treatment Regimen Bolus Treatment Group Dosage injection on Days 1.
  • mice were randomly divided into 7 groups of 8 animals per group for the short term study and 5 groups of 8 animals for the long term study (refer to Table 7 for dosage and treatment administration schedule).
  • mice were weighed and tumour volumes measured on the day of treatment application for long term study. In the 6-week study animals were weighed and tumour volumes measured on a daily basis. Animals were individually placed in an injection box, and the injections were administered via the tail vein. It has been experimentally proven that stress can be a major factor in a patients response to chemotherapy (Shackney et al, 1978), therefore we ensured that equal numbers of mice were allocated to each cage, the animal number per cage varied from 5-8 depending on the stage of experimentation.
  • the experimental end-point occurred when the animal had to be euthanised due to degree of disease progression or when the 6 month (long term) or 6 week (short term) treatment regimen was completed. Due to the animal ethics guidelines the animals were monitored fortnightly by an independent animal ethics officer who assessed the degree of disease progression. The following criteria were used to determine if an animal had reached the stage of experimental end-point of necessary death:
  • Tumour size was greater than 10% of body mass.
  • liver, heart, spleen, bladder, left and right kidneys, uterus, lungs, stomach, intestines, brain and lymph nodes were excised and placed in 4% formalin buffered with 0.06M phosphate pH 7.5, and cetylpyridinium chloride, 1.0% w/v.
  • the tissue was fixed for 16-24 h before histological processing. Fixed tissue was dehydrated stepwise to 100% ethanol and embedded in paraffin blocks from which 2-4 ⁇ m sections were placed on glass microscope slides. Staining the tissue sections with a haematoxylin nuclear stain and eosin cytoplasmic stain highlighted any pathological features that could indicate treatment toxicity.
  • lymph nodes Nine to 11 lymph nodes were collected per animal, ensuring that all nodes which drained the tumour area were collected. There are currently two methods used for the detection of lymph node metastasis
  • the haematoxylin and eosin stained lymph nodes were examined by Dr P. Allen (certified pathologist) where each node was microscopically examined for the presence of tumour cells.
  • the CEA immunostained lymph nodes were microscopically examined, where any positively stained nodes were counted and considered positive for lymph node metastasis.
  • tumour volume was monitored on a daily or weekly basis by calliper measurements and tumour volume calculated as previously described.
  • No significant differences in tumour response were noted in the initial 2 weeks of treatment, but thereafter the HA followed by 5-FU tumour growth was retarded in comparison to the other treatment groups.
  • interesting differences were noted in the number of tumour doubling cycles.
  • mice receiving the saline treatment underwent an average of 4 tumour doublings, while the incorporation of HA into the treatment regimen significantly increased the tumour doubling time where HA/5-FU animals underwent an average of one tumour doubling cycle, once again highlighting the effect of HA on 5-FU cytotoxicity.
  • mice receiving HA therapy that is as a sole agent or as a chemosensitizer, demonstrated enhanced well being where the animal did not loose weight, but maintained its body mass (FIG. 4).
  • the overall patient survival time was calculated as the time (days or weeks) that the animal lived after the commencement of treatment. All animals in each treatment group completed the 6-week treatment program
  • MDA-MB 468, MDA-MB 435 and MDA-MB 231 cells were cultured as described in Example 2. When the cultures had reached 70-80% confluency they were washed in 1 ⁇ HBSS at 37° C. and trypsinised in 10 ml of 0.25% trypsin/0.05% EDTA until cells have fully detached. After add 1 ml of FCS to neutralise trypsin the cells were counted, centrifuged at 1,200 rpm for 5 min and resuspended as follows:
  • MDA-MB 231 12,000 cells/ml of media
  • MDA-MB 468 25,000 cells/ml of media
  • MDA-MB 435 12,000 cells/ml of media.
  • MDA-MB 468 40 nM adriamycin
  • MDA-MB 231 50 nM adriamycin
  • MDA-MB 435 10 nM adriamycin
  • the IC 50 of adriamycin has been determined as 90 nM.
  • the HA (700 kD) concentration will be varied to 1, 3, 10, 30, 100, 300 nM, 1 ⁇ M, 3 ⁇ M, 10 ⁇ M, 30 ⁇ M and 100 ⁇ M.
  • the incubation variables to be tested are:
  • HA receptor status will be determined using FACS surface epitope identification. Similar experiments will be performed with short HA oligiosaccharides, ie: 4 sacc, 6 sacc, 12 sacc, 5600 Da, 50,000 Da, 100,000 Da, 250,000 Da.
  • the IC 50 of adriamycin will be used in a series of time course experiments to observe any effect of HA on adriamycin metabolism.
  • Cells will be removed, hypotonically lysed and centrifuged at 113,000 gav for 1 hr. The membrane pellet and supernatant will be counted and analysed for metabolites using HPLC.
  • Cells will also be grown on coverslips, where they will be exposed to adriamycin ⁇ HA (exposures regimen as above) and a confocal photography time course will be used to track the cytosolic uptake and movement of the drug.
  • HA of molecular weight 4 sacc, 6 sacc, 12 sacc, 5600 Da, 50,000 Da, 100,000 Da, 250,000 Da, 750,000 Da and 1,500,000 Da will be incubated with breast cancer cell lines at pre-determined “observed-effect” concentrations and the following will be parameters investigated: Extracellular and intracellular calcium flux (cellular probe assays). Regulation of cytoskeletal components (micro-array of cytoskeletal genes), effect on volume of cells (Coulter size Analysis) and mobility of cancer cells (Boyden Chamber matrigel assays) will also be conducted.
  • HA effect of HA on the cell cycle will be undertaken by incubating HA of molecular weight, 4 sacc, 6 sacc, 12 sacc, 5600 Da, 50,000 Da, 100,000 Da, 250,000 Da, 750,000Da and 1,500,000 Da with breast cancer cell lines at pre-determined “observed-effect” concentrations.
  • Cells will be labelled with potassium iodide and subjected to FACS analysis. The number of cells in each stage of the cell cycle will be determined.
  • adriamycin in nude mice was 4 mg/kg which is a human equivalent dose of 60 mg/m 2 .
  • Nude mice bearing human tumours will be injected with adriamycin ⁇ HA.
  • adraimycin concentrations 4 mg/kg ⁇ 12.5 mg/kg HA.
  • the experimental protocol will include the following treatment groups:
  • mice At the time intervals of 2, 15, 30, 60 min and 1.5, 2, 4, 8, 24 and 48 h (4 animals/time point) the mice will be killed by a 0.1 ml IP injection of Nembutal. All body organs, skeletal muscle, lymph nodes, bone marrow, urine and blood will be removed and the adriamycin content determined using HPLC and fluorescence.
  • Mouse LD 50 is 10 mg/kg
  • mice Tumour volume, body mass, food intake and functionality of the mice will be monitored on a daily basis.
  • mice will be killed by a 0.1 ml IP injection of Nembutal. All body organs, tumour, skeletal muscle, lymph nodes, bone marrow, urine and blood will be removed processed for pathological assessment.
  • HA (700 kD) concentration will be varied to 1, 3, 10, 30, 100, 300 nM, 1 ⁇ M, 3 ⁇ M, 10 ⁇ M, 30 ⁇ M and 100 ⁇ M.
  • the IC 50 of 5-FU will be used in a series of time course experiments to observe any effect of HA on adriamycin metabolism.
  • the [ 3 H] 5-FU will be exposed to the cells for 30 min, 1 h, 2 h, 4 h, 8 h, 16 h and 24 h.
  • the experimental conditions will be:
  • Cells will be removed, hypotonically lysed and centrifuged at 113,000 gav for 1 hr. The membrane pellet and supernatant will be counted and analysed for metabolites using HPLC.
  • Cells will also be grown on coverslips, where they will be exposed to 5-FU ⁇ HA (exposures regimen as above) and a confocal photography time course will be used to track the cytosolic uptake and movement of the drug.
  • mice receiving the HA therapy have demonstrated that:
  • the BAG vector consists of a neomycin-resistant LacZ gene that can be stably transfected into human breast cancer cells. After intracardiac injections into the nude mice, followed by a 6-week treatment program it is possible to PCR detect the LacZ gene in any metastasizing cells/organs. Faxitron scanning with detection of bone lesions would detect any bone metastasis.
  • the below treatments will be administered on Day1 , Day 2 of a weekly cycle, for 6 weeks.
  • the treatment groups (5 animals per group) will consist of:

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