EP1592432A2 - Polysaccharides modifies associes a des medicaments anticancereux pour accroitre l'efficacite d'un traitement contre le cancer - Google Patents

Polysaccharides modifies associes a des medicaments anticancereux pour accroitre l'efficacite d'un traitement contre le cancer

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Publication number
EP1592432A2
EP1592432A2 EP04702115A EP04702115A EP1592432A2 EP 1592432 A2 EP1592432 A2 EP 1592432A2 EP 04702115 A EP04702115 A EP 04702115A EP 04702115 A EP04702115 A EP 04702115A EP 1592432 A2 EP1592432 A2 EP 1592432A2
Authority
EP
European Patent Office
Prior art keywords
cancer
modified polysaccharide
side chain
backbone
saccharides
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04702115A
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German (de)
English (en)
Inventor
David Platt
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Pro Pharmaceuticals Inc
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Pro Pharmaceuticals Inc
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Filing date
Publication date
Application filed by Pro Pharmaceuticals Inc filed Critical Pro Pharmaceuticals Inc
Publication of EP1592432A2 publication Critical patent/EP1592432A2/fr
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Classifications

    • 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
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof

Definitions

  • the present invention relates to chemically modified polysaccharides having a molecular weight in the range of 5 kD to 60 kD and a method of using the same in the delivery anticancer drugs for treating and preventing malignant cancer.
  • prostate cancer is the most commonly diagnosed cancer in American men as well as the second leading cause of male cancer deaths.
  • Prostate cancer metastasizes to the skeletal system and patients typically die with overwhelming osseous metastatic disease.
  • effective curative therapy is limited and very little palliative therapy for patients with metastatic disease.
  • Most common proven anticancer drugs are cytotoxic due to non-specific delivery to the tumor site and side effects from toxicity to normal tissues.
  • a desirable therapeutic combination would be where the polysaccharides reversibly trap the cytotoxic drugs, deliver them to the tumor site where the polysaccharides bind to the tumor and release the drug. This target delivery enhances therapeutic efficiency of these anticancer drugs, while substantially reduces their undesirable toxicity.
  • the present invention relates to polysaccharide obtained by a chemical modification, which may reversibly interact with anti-cancer chemotherapeutic agent and effectively deliver it along with the polysaccharide itself to metastatic cancer, improving the pharmacological index as compared to that of the chemotherapeutic agent alone.
  • the polysaccharide includes a saccharide backbone being less than about 5% esterified and containing repeating units wherein each repeating unit has a plurality of uronic acid or other glycosidic acid residues, with each repeating sequence unit having at least one neutral monosaccharide residue attached thereto; at least one side chain of oligosaccharide attached to the backbone via glucosidic bond to the neutral monosaccharide, further comprising a plurality of neutral saccharides or saccharide derivatives; with majority terminal galactose unit and an average molecular weight in the range of 5 to 60 kD.
  • the polysaccharides 3 dimensional structure has a combination of hydrophobic, hydrophilic and slightly negative charged moieties which may interact with anti-cancer agents and effectively deliver them to metastatic cancer via interaction with galectin receptors.
  • anticancer agents are being targeted to cancer cells effectively and initiate less toxicity to normal tissue.
  • Another embodiment of the present invention includes a polysaccharide as described above where the uronic acid saccharide backbone further includes galacturonic acid and the neutral monosaccharide connected to the repeating unit is a rhamnose.
  • Another more specific embodiment provides a polysaccharide wherein at least one side chain comprises neutral saccharides and their derivatives connected to the backbone via rhamnose monosaccharides. This plurality in structure may enhance the polymer association with variety of anti-cancer drugs for more efficient delivery, while reducing side effects.
  • Yet other embodiments in accordance with the present invention include treating cancer in a subject diagnosed with cancer wherein a therapeutically effective amount of a known anti-cancer drug combined with a polysaccharide are co-administered to a subject. More specifically, the combination may be administered by any one of a plurality of routes including intravenous, subcutaneous, topical, intraperitoneal, and intramuscular routes.
  • Another embodiment of the present invention is a method of preventing cancer in a subject post surgical intervention or diagnosed as having a high risk of cancer, wherein a therapeutically effective amount of a polysaccharide in combination with an anti-cancer drug is co-administered to a subject.
  • the polysaccharide and anti-cancer drug may be administered by any one of a plurality of routes including intravenous, subcutaneous, topical, intraperitoneal, and intramuscular routes.
  • Still another embodiment of the present invention is a method for inhibiting metastasis in a subject wherein a therapeutically effective amount of a polysaccharide in combination with an anti-cancer drug is co-administered to the subject.
  • the polysaccharide and anticancer drug may be administered by any one of a plurality of routes including oral, intravenous, subcutaneous, topical, intraperitoneal, and intramuscular routes.
  • Yet other embodiments of the present invention include a pharmaceutical formulation for treating cancer wherein the formulation comprises an effective dose of a polysaccharide and a known anti-cancer drug, the polysaccharide having a backbone formed from a plurality of uronic acid saccharides and about one-in-seven to twenty-five neutral monosaccharides connected to the backbone, at least one side chain of neutral saccharides or saccharide derivatives connected via the neutral monosaccharide(s), and an average molecular weight in the range of 5 kD to 60 kD.
  • PS polysaccharide
  • EHS Eaglebreth-Holm
  • DMEM Dulbecco's Modified Eagle's Minimal Essential Medium
  • CMF-PBS Ca 2+ - and Mg 2+ -Free Phosphate-Buffered Saline, pH 7.2
  • BSA Bovine Serum Albumin
  • galUA galactopyranosyl uronic acid, also called galacturonic acid
  • gal galactose
  • man mannose
  • glc glucose
  • ara arabinose, rib, ribose
  • lyx lyxose
  • xyl xylose
  • fru fructose
  • psi psicose
  • fuc fucose
  • quin quinovose
  • administering refers to oral, or parentereal including intravenous, subcutaneous, topical, transdermal, transmucosal, intraperitoneal, and intramuscular.
  • Subject refers to an animal such as a mammal for example a human.
  • Treatment of cancer refers to prognostic treatment of subjects at high risk of developing a cancer as well as subjects who have already developed a tumor.
  • treatment may be applied to the reduction or prevention of abnormal cell proliferation, cell aggregation and cell dispersal (metastasis) to secondary sites.
  • Cancer refers to any neoplastic disorder, including such cellular disorders as, for example, renal cell cancer, Kaposi's sarcoma, chronic leukemia, breast cancer, sarcoma, ovarian carcinoma, rectal cancer, throat cancer, melanoma, colon cancer, bladder cancer, mastocytoma, lung cancer, mammary adenocarcinoma, pharyngeal squamous cell carcinoma, and gastrointestinal or stomach cancer.
  • Depolymerization refers to partial or complete hydrolysis of the polysaccharide backbone occurring for example when the polysaccharide is treated chemically resulting in fragments of reduced size when compared with the original polysaccharide.
  • Effective dose refers to a dose of an agent that improves the symptoms of the subject or the longevity of the subject suffering from or at high risk of suffering from cancer.
  • saccharide refers to any simple carbohydrate including monosaccharides, monosaccharide derivatives, monosaccharide analogs, sugars, including those which form the individual units in an oligosaccharide or a polysaccharide.
  • Methyde refers to polyhydroxyaldehyde (aldose) or polyhydroxyketone (ketose) and derivatives and analogs thereof.
  • Oletaccharide refers to a linear or branched chain of monosaccharides that includes up to about 20 saccharide units linked via glycosidic bonds.
  • Polysaccharide refers to polymers formed from about 20 to about 10,000 and more saccharide units linked to each other by hemiacetal or glycosidic bonds.
  • the polysaccharide may be either a straight chain, singly branched, or multiply branched wherein each branch may have additional secondary branches, and the monosaccharides may be standard D- or L- cyclic sugars in the pyranose (6-membered ring) or furanose (5- membered ring) forms such as D-fructose and D-galactose, respectively, or they may be cyclic sugar derivatives, for example amino sugars such as D-glucosamine, deoxy sugars such as D-fucose or L-rhamnose, sugar phosphates such as D-ribose-5 -phosphate, sugar acids such as D-galacturonic acid, or multi-derivatized sugars such as N-acetyl-D- glucosamine, N-acetylneur
  • Backbone means the major chain of a polysaccharide, or the chain originating from the major chain of a starting polysaccharide, having saccharide moieties sequentially linked by either ⁇ or ⁇ glycosidic bonds.
  • a backbone may comprise additional monosaccharide moieties connected thereto at various positions along the sequential chain.
  • Esterification refers to the presence of methylesters or other ester groups at the carboxylic acid position of the uronic acid moieties of a saccharide.
  • Substantially de-esterified means, for the purposes of this application, that the degree of esterification on the backbone of the polysaccharide is less than about 1% to 5%.
  • the polysaccharides may have a molecular weight range of between about 40,000-400,000 dalton with multiple branches of saccharides, for example, branches comprised of glucose, arabinose, galactose etc, and these branches may be connected to the backbone via neutral monosaccharides such as rhamnose. These molecules may further include a uronic acid saccharide backbone that may be esterified from as little as about 10% to as much as about 90% of uronic acid residues.
  • the multiple branches themselves may have multiple branches of saccharides, the multiple branches optionally including neutral saccharides and neutral saccharide derivatives.
  • Described herewith is a chemical modification procedure that involves a pH-dependent depolymerization into smaller, de-branched polysaccharide molecules, using sequentially controlled pH, temperature and time e.g. pH 10.0 at 37C for 30 minutes and than pH of about 3.5 at 25C for 12 hours (see Example 1).
  • An optional alternative modification procedure is hydrolysis of the polysaccharide in an alkaline solution in the presence of a reducing agent such as a potassium borohydride to form fragments of a size corresponding to a repeating subunit (U.S. Pat. No. 5,554,386).
  • the molecular weight range for the chemically modified polysaccharides is in the range of 5 to 60 kD, more specifically, in the range of about 15-40 kD, and more specifically, for example, 20 kD.
  • Example 1 vivo assays to demonstrate the biological efficacy of the compositions.
  • Inhibition of metastasis can be shown using cancer cell lines which normally aggregate in culture, in the presence of the polysaccharide combined with the chemotherapy agent remain dispersed and more susceptible to the anti cancer drug. (Example 3 using B16-F1 cell, UN 2237-10- 3 murine fibrosarcoma cells, HT 1080 human fibrosarcoma cells, and A375 human melanoma cells).
  • Inhibition of metastasis can also be demonstrated using a Metastasis Assay (Example 4) in which MLL cells which have enhanced levels of galectins-3 on their cell surface, which is associated with tumor endothelial cell adhesion.
  • Galectin-3 represents a wide range of molecules i.e., the murine 34 kD (mL- 34) and human 31 kD (hL-31) tumor-associated galactoside-binding lectins, the 35 kD fibroblast carbohydrate-binding protein (CBP35), the IgE-binding protein (cBP), the 32 kD macrophage non-integrin laminin-binding protein (Mac-2), and the rat, mouse, and human forms of the 29 kD galactoside-binding lectin (L-29). Molecular cloning studies have revealed that polypeptides of these lectins share identical aminoacid sequences.
  • Galectin-3 is highly expressed by activated macrophages and oncogenically transformed onto metastatic cells. Many cancer cells, including MLL cells, express galectin-3 on their cell surface and its expression has been implicated in metastatic processes in tumor cells. Elevated expression of the polypeptide is associated with an increased capacity for anchorage-independent growth, homotypic aggregation, and tumor cell lung colonization, which suggests that galectin-3 promotes tumor cell embolization in the circulation, and enhances metastasis. Tumor-endothelial cell adhesion is thought to be a key event in the metastatic process.
  • Galectins may bind with high affinity to oligosaccharides containing poly- ⁇ -acetyllactosamine sequences, and also bind to the carbohydrate side chains of laminin in a specific sugar-dependent manner.
  • Laminin the major non-collagenous component of basement membranes, is an ⁇ -linked glycoprotein carrying poly-N-acetyllactosamine sequences, and is implicated in cell adhesion, migration, growth, differentiation, invasion and metastasis.
  • Tumor cells may interact with carbohydrate residues of glycoproteins via cell surface galectin-3 and this may be correlated with their ability to interact with the galactose residues of agarose (a polymer of D-galactose and L-anhydro-galactose) and to provide the minimal support needed for cell proliferation in this semi-solid medium.
  • Anti- galectin-3 monoclonal antibodies can inhibit the growth of tumor cells in agarose.
  • transfection of normal mouse fibroblasts with the mouse galectin-3 cDNA results in the acquisition of anchorage-independent growth.
  • the in vivo results reported here with polysaccharides of example 1 are consistent with studies reported earlier and performed on human prostate cancer tissue using galectin-3 (U.S. Pat. No. 5,895,784).
  • We propose that the polysaccharides described herein when combined with anti-cancer drugs for co-administration provide delivery, targeting and overall enhancement of anti- metastatic drugs in humans.
  • the polysaccharides and anti-cancer drugs may be co-administered by any of several routes including oral, intravenous, subcutaneous, topical, intraperitoneal, and intramuscular routes, at equal intervals i.e., from about 10 to about 1000 mg/kg every 24 hours and/or from about 2.5 to 250 mg kg every 6 hours.
  • Osmotic mini-pumps may also be used to provide controlled delivery of high concentrations of modified polysaccharide through cannulae to the site of interest, such as directly into a metastatic growth or into the vascular supply to that tumor.
  • modified polysaccharide through cannulae to the site of interest, such as directly into a metastatic growth or into the vascular supply to that tumor.
  • biodegradable polymers and their use are described, for example, in detail in Brem et al., J. Neurosurg., (1991), vol. 74, pp. 441-446.
  • the effective dose and dosage regimen of the polysaccharide and anti-cancer drug is a function of variables such as the subject's age, weight, medical history and other variables deemed to be relevant.
  • the preferred dose and dosage regimen based on the molecular weight of the modified polysaccharide component (i.e., disregarding the digestible carrier), and similarly the anti-cancer drug, may include a daily dose of about 10 to about 1000 mg per kg of body weight of the subject.
  • the dosages of the modified polysaccharide and anti-cancer drugs will depend on the disease state or condition being treated and other clinical factors such as weight and condition of the human or animal and the route of administration of the compound.
  • Modified polysaccharide and anti-cancer drug formulations include those suitable for oral, rectal, ophthalmic (including intravitreal or intracameral), nasal, topical (including buccal and sublingual), intrauterine, vaginal or parenteral (including subcutaneous, intraperitoneal, intramuscular, intravenous, intradermal, intracranial, intratracheal, and epidural) administration.
  • These 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 active ingredient and the pharmaceutical carrier(s) or excipient(s).
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • 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 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) condition requiring only the addition of the sterile liquid 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, or an appropriate fraction thereof, of the administered ingredient. It should be understood that in addition to the ingredients, particularly mentioned above, the formulations of the present invention may include more than one agent as it is common in the field and have synergistic effect. Optionally, cytotoxic agents may be incorporated or otherwise combined with modified polysaccharides to provide dual therapy to the patient.
  • Suitable digestible pharmaceutical carriers include gelatin capsules in which the polysaccharide is encapsulated in dry form, or tablets in which polysaccharide is admixed with hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, propylene glycol, zinc stearate and titanium dioxide and other appropriate binding and additive agents.
  • the composition may also be formulated as a liquid using distilled water, flavoring agents and some sort of sugar or sweetener as a digestible carrier to make a pleasant tasting composition when consumed by the subject.
  • a sustained-release matrix is a matrix made of materials, usually polymers, which are degradable by enzymatic or acid/base hydrolysis or by dissolution. Once inserted into the body, the matrix is acted upon by enzymes and body fluids.
  • the sustained-release matrix desirably is chosen from biocompatible materials such as liposomes, polylactides (polylactic acid), polyglycolide (polymer of glycolic acid), polylactide co-glycolide (co-polymers of lactic acid and glycolic acid) polyanhydrides, poly(ortho)esters, polypeptides, hyaluronic acid, collagen, chondroitin sulfate, carboxylic acids, fatty acids, phospholipids, polysaccharides, nucleic acids, polyamino acids, amino acids such as phenylalanine, tyrosine, isoleucine, polynucleotides, polyvinyl propylene, polyvinylpyrrolidone and silicone.
  • a preferred biodegradable matrix is a matrix of one of either polylactide, polyglycolide, or polylactide co-glycolide (co-polymers of lactic acid and glycolic acid).
  • the metastasis-modulating therapeutic composition of the present invention may be a solid, liquid or aerosol and may be administered by any known route of administration.
  • solid therapeutic compositions include pills, creams, and implantable dosage units.
  • the pills may be administered orally; the therapeutic creams may be administered topically.
  • the implantable dosage units may be administered locally, for example at a tumor site, or which may be implanted for systemic release of the therapeutic angiogenesis-modulating composition, for example subcutaneously.
  • liquid composition include formulations adapted for injection subcutaneously, intravenously, intra-arterially, and formulations for topical and intraocular administration.
  • aerosol formulation include inhaler formulation for administration to the lungs.
  • 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 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) condition requiring only the addition of the sterile liquid 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, or an appropriate fraction thereof, of the administered ingredient. It should be understood that in addition to the ingredients, particularly mentioned above, the formulations of the present invention may include other agents conventional in the art having regard to the type of formulation in question. Optionally, cytotoxic agents may be incorporated or otherwise combined with angiostatin proteins, or biologically functional peptide fragments thereof, to provide dual therapy to the patient.
  • a polysaccharide preparation is co-administered with a known cancer drug at a therapeutic dose of the known anti-cancer drug known in the art to be effective against cancer.
  • 5-FU is administered at 2 to 20 mg/mL at doses of 60 - 600 mg/m 2 /day.
  • paclitaxel is administered at 1- 10 mg/mL at doses of 30 to 300 mg/m 2 /day.
  • anticancer drugs for example 5-FU and paclitaxel as described above, are combined with 2 to 20 mg/mL of a polysaccharide at doses of 60 to 600 mg/m 2 .
  • up to 80% improvement was seen in the combination therapy versus the control with no treatment, and up to 40% improvement versus the 5-FU administered alone.
  • Laminin and Asialoglycoprotein adhesion assays A good correlation has been established between the propensity of tumor cells to undergo homotypic aggregation in vitro and their metastatic potential in vivo. B16 melanoma cell clumps produce more lung colonies after i.v. injection than do single cells. Moreover, anti-galectin-3 antibody has been shown to inhibit asialofetuin-induced homotypic aggregation (Fidler, I. J., (1970) J. Natl. Cancer Inst., 45:77.), suggesting that the cell surface galectin-3 polypeptides bring about the formation of homotypic aggregates following their interaction with the side chains of glycoproteins.
  • a total of 5xl0 4 cells are added to each well in DMEM with or without: 1) modified polysaccharide and anti-cancer drug; 2) modified polysaccharides of varying concentrations with non- varying doses of anti-cancer drug; or 3) modified polysaccharide in a non-varying concentration with varying doses of anti-cancer drug.
  • non-adherent cells are washed off with CMF-PBS, and adherent cells are fixed with methanol and photographed.
  • the relative number of adherent cells is determined in accordance with the procedure of Zollner, T. et al., Anti-cancer Research, (1993), vol. 13, pp. 923-930. Briefly, cells are stained with methylene blue followed by the addition of HCl-ethanol to release the dye. The optical density (650 ⁇ m) is then measured by a plate reader.
  • Recombinant galectin-3 can be extracted from bacteria cells by single-step purification through an asialofetuin affinity column as described elsewhere. Recombinant galectin-3 eluted by lactose is extensively dialyzed against CMF-PBS before use.
  • Horseradish peroxidase (HRP) - conjugated rabbit anti-rat IgG+IgM and the 2, 2'-azino-di(3-ethylbenzthiazoline sulfonic acid) (ABTS) substrate kit can be purchased from Zymed, South San Francisco, CA.
  • B16-F1 murine melanoma cells are grown as cultures in Dulbecco's modified Eagles' minimal essential medium (DMEM), as described above.
  • DMEM Dulbecco's modified Eagles' minimal essential medium
  • the time course for the attachment of MLL cells to a confluent monolayer of RAE cells in the absence or presence of independently varied concentrations of modified polysaccharide in combination with an anti-cancer drug is monitored.
  • the level of modified polysaccharide/anti-cancer drug inhibition on attachment of MLL cells to RAE cells is thereby determined.
  • Example 5 In Vivo Assays for Determining Efficacy of Modified Polysaccharides in Combination With Anti-cancer Drugs.
  • the Dunning (R3327) rat prostate adenocarcinoma model of prostate cancer was developed by Dunning from a spontaneously occurring adenocarcinoma found in a male rat as described by Dunning, W., Natl. Cancer Inst. Mono., (1963), vol. 12, pp. 351-369.
  • Several sub-lines have been developed from the primary tumor which have varying differentiation and metastatic properties as described by Isaacs, J. et al., Cancer Res., (1978), vol. 38, pp. 4353-4359. Injection of lxlO 6 MLL cells into the thigh of the rat leads to animal death within approximately 25 days secondary to overwhelming primary tumor burden as described by Isaacs, J.
  • Soluble modified polysaccharide in combination with a known anti-cancer drug, is given orally to rats in the drinking water on a chronic basis, to investigate the affect on spontaneous metastases is these tumors.
  • the rats are first injected with lxlO 6 MLL cells in the hind limb on day 0.
  • On day 4 when the primary tumors reach approximately 1 cm 3 in size, 0.01%, 0.1%, or 1.0% (w:v) modified polysaccharide and anti-cancer drug is added to the drinking water of the rats on a continuous basis.
  • the rats are anesthetized and the primary tumors removed by amputating the hind limb.
  • the rats are then followed to day 30 when all groups are sacrificed and autopsied. Animals continuously ingest modified polysaccharide/anti-cancer drug in their drinking water during this period. Control and treated animals are monitored for observable toxicity.

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Abstract

L'invention concerne des compositions de polysaccharides modifiés, ainsi que leur utilisation en association avec au moins un médicament anticancéreux pour traiter des sujets atteints d'un cancer, réduire la toxicité et inhiber les métastases. Le polysaccharide modifié comprend un squelette saccharide estérifié à moins de 5 % et comprenant des motifs récurrents. Chaque motif récurrent comporte une pluralité de molécules d'acide uronique, au moins un monosaccharide neutre étant fixé à chacun de ces motifs récurrents. Au moins une chaîne latérale de saccharides fixée au squelette comprend en outre une pluralité de saccharides neutres ou de dérivés de saccharides. Le polysaccharide modifié possède un poids moléculaire moyen compris entre 15 et 60 kD. Lorsqu'il est associé au médicament chimiothérapeutique, le polysaccharide selon l'invention se comporte comme un véhicule de distribution qui accroît de façon positive l'effet chimiothérapeutique tout en réduisant les effets secondaires.
EP04702115A 2003-01-16 2004-01-14 Polysaccharides modifies associes a des medicaments anticancereux pour accroitre l'efficacite d'un traitement contre le cancer Withdrawn EP1592432A2 (fr)

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US440496P 2003-01-16
PCT/US2004/000747 WO2004064777A2 (fr) 2003-01-16 2004-01-14 Polysaccharides modifies associes a des medicaments anticancereux pour accroitre l'efficacite d'un traitement contre le cancer

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KR102162351B1 (ko) * 2018-11-08 2020-10-06 순천향대학교 산학협력단 약물-결합 화합물 및 이의 용도

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US5569483A (en) * 1989-02-10 1996-10-29 Alko Group Ltd. Degraded polysaccharide derivatives
US5834442A (en) * 1994-07-07 1998-11-10 Barbara Ann Karmanos Cancer Institute Method for inhibiting cancer metastasis by oral administration of soluble modified citrus pectin
US6500807B1 (en) * 1999-02-02 2002-12-31 Safescience, Inc. Modified pectin and nucleic acid composition

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