WO2007123468A1 - Polymer-based anti-cancer agents - Google Patents
Polymer-based anti-cancer agents Download PDFInfo
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- WO2007123468A1 WO2007123468A1 PCT/SE2007/000392 SE2007000392W WO2007123468A1 WO 2007123468 A1 WO2007123468 A1 WO 2007123468A1 SE 2007000392 W SE2007000392 W SE 2007000392W WO 2007123468 A1 WO2007123468 A1 WO 2007123468A1
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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
- A61K31/765—Polymers containing oxygen
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention generally relates to cancer treatment, and in particular to the use of polymer-based anti-cancer agents in such cancer treatment.
- Cancer is a class of diseases characterized by uncontrolled division of cells and the ability of these cells to spread, either by direct growth into adjacent tissue through invasion, or by implantation into distant sites within the body by metastasis.
- cancer is a leading cause of death in humans and the number of affected individuals increases for each year.
- different methods of treatment for cancer e.g. chemotherapy, endocrine therapy, radiotherapy and surgery, have improved tremendously the last decades, they are far from perfect in terms of outcome for different cancer types.
- several of the known cancer treatments are marred by disadvantages in high treatment costs, side effects and patient suffering and relative inefficiency. For these reasons, extensive research is conducted to find alternative or complementary forms of cancer treatment.
- Document [1] discloses the use of non-fermented osmotic laxative as active agents for the preparation of a medicinal product for treating colon and/ or rectum cancers.
- An example of such a laxative is PLURONIC ® F68 available from BASF Corporation. These compounds have laxative and gelling properties. The compounds attract and retain water inside the colon due to their physical-chemical properties, and are able to increase fecal excretion without fibers. It is believed that the laxative, non-fermented, osmotic and water-retaining properties of the compounds have a protective effect in relation to the two specific cancer types, colon and rectum cancer.
- Document [2] discusses the ability of circulating tumor cells to develop into metastasis, where this ability is based on an inherent physiochemical adherence to the endothelium and the formation of a microdot. It is described that substances interfering with the coagulation process could be used in the prevention of tumor metastasis. Suggested substances include heparin, sodium warfarin and PLURO NIC® F68. These substances can be used in connection with surgery to prevent metastasis secondary to operative tumor manipulation.
- the present invention overcomes these and other drawbacks of the prior art arrangements.
- the present invention involves usage of the unexpected anti-cancer effect of amphiphilic block copolymers.
- These copolymers are effective chemotherapeutic agents against a diversity of cancer types and have a proliferation rate reducing effect in the cancer cells.
- amphiphilic block copolymers of the present invention preferably comprise one hydrophobic polymer chain connected to at least two hydrophilic side chains.
- the hydrophobic polymer chain is preferably a central chain having a first end connected to at least one, preferably one or two, hydrophilic side chain and having a second end connected to at least one, preferably one or two, hydrophilic side chain.
- Preferred amphiphilic block copolymers are those having the structure (I):
- copolymers with a central polymer chain of propylene oxide flanked by side chains of ethylene oxide are preferred.
- n is preferably equal to p.
- Such copolymers are available under the trade name PLURO NIC ® by BASF Corporation.
- Preferred such PLURONIC ® copolymers of the invention are those that have an average ethylene oxide content of at least 40 % w/w and preferably an average ethylene oxide content lower below 80 % w/w.
- the average propylene oxide content of the amphiphilic block copolymer is preferably at least 2 000 g/mol, more preferably at least 3 000 g/mol, such as about 4 000+500 g/mol.
- An example of a preferred copolymer is PLURONIC ® F 127 having an average molecule weight of 12 600 g/mol, an average ethylene oxide content of 73.2 ⁇ 1.7 % and a melting point of 56 0 C.
- copolymers have anticancer effect in terms of reducing or inhibiting the cell proliferation or growth rate of cancer cells and the reducing the DNA synthesis of cancer cells.
- This surprising effect may at least partly be due to the effect of the copolymers in binding to cell membranes and blocking the binding of different growth factors to their respective receptors on the membrane.
- the pharmaceutical composition of the invention preferably comprises a single amphiphilic block copolymer of the invention or a mixture of at least two such copolymers as the sole chemotherapeutic agents.
- Fig. 1 is a diagram illustrating the effects of PLURONIC ® F 127 on the growth rate of human breast cancer cell line MCF-7;
- Fig. 2 is a diagram illustrating the effects of PLURONIC ® F 127 on the growth rate of human breast cancer cell line SK-BR-3;
- Fig. 3 is a diagram illustrating the effects of PLURONIC ® F 127 on the growth rate of FCS-stimulated human vascular smooth muscle cells
- Fig. 4 is a diagram illustrating the effects of PLURONIC ® F 127 on the growth rate of unstimulated and FCS-stimulated rat aortic smooth muscle cells;
- Fig. 5 is a diagram illustrating a comparison of cell mediated cytotoxicity of PLURONIC ® F 127 and Triton X-100;
- Fig. 6 is a diagram illustrating relative cell growth inhibiting effect of different amphiphilic block copolymers on FCS-stimulated human vascular smooth muscle cells
- Fig. 7 is a diagram illustrating the correlation between growth rate inhibition of PLURONIC® F 127 on stimulated rat aortic muscle cells and the effect of PLURONIC® F 127 in blocking fibroblast growth factor binding to receptors on the smooth muscle cells;
- Fig. 8 is a diagram the effect of PLURONIC ® F 127 in blocking platelet derived growth factor binding to receptors on rat aortic smooth muscle cells
- Fig. 9 is a diagram illustrating cell density in a hollow fiber with U937/gtb cancer cells implanted in mice with or without treatment with PLURONIC® P105;
- Fig. 10 is a diagram illustrating cell density in a hollow fiber with H69 cancer cells implanted in mice with or without treatment with PLURONIC ® P 105;
- Fig. 11 is a diagram illustrating survival index of U937/gtb cancer cells exposed to different amphiphilic block copolymers
- Figs. 12A to 12O are diagrams illustrating survival index of U937/gtb cancer cells exposed to different amphiphilic block copolymers.
- Figs. 13A to 13C are diagrams illustrating survival index of different cancer cell lines exposed to PLURONIC ® P84, F127 or L121.
- the present invention generally relates to cancer treatment and in particular to the use of amphiphilic block copolymers for inhibiting and reducing the growth and proliferation rate of cancer cells
- the active anti-cancer compounds of the present invention are amphiphilic block copolymers of hydrophobic and hydrophilic monomers.
- the block copolymers therefore comprise at least one water-soluble (hydrophilic) part and at least one less water-soluble or even water-insoluble (hydrophobic) part.
- a central hydrophobic chain is surrounded by at least two hydrophilic side chains. More preferably, the central hydrophobic chain has a first chain end connected to at least one, preferably one or two, hydrophilic side chains and has a second chain end connected to at least one, preferably one or two, hydrophilic side chains.
- Formula (II) and (III) below schematically illustrate such preferred amphiphilic block copolymers: X-Y-Z (H)
- X, Xi, X2 and Z, Zi, Z2 represent a respective hydrophilic side chain and Y represents a hydrophobic central chain.
- X Z
- Xi X2
- the amphophilic block copolymers of the present inventions are block copolymers of ethylene oxide and propylene oxide.
- Several different such copolymer are available today from different manufactures, including the polymers PLURONIC ® and TETRONIC ® from BASF Corporation.
- PLURONIC ® is a copolymer of ethylene oxide (EO) and propylene oxide (PO) having the general structure (III) :
- n p.
- Table I below lists several PLURONIC ® polymers available from BASF and that can be used according to the present invention. Table I - PLURONIC® copolymers
- the alphabetical designation of the PLURONIC® product name denotes the physical form of the product at 25 °C, where "L” represents liquid, "P” represents paste and "F” represents solid form.
- the first digit or the two first digits in a three-digit product name multiplied by 300 indicates the approximate molecular weight of the hydrophobe central polypropylene oxide chain.
- the last digit, when multiplied by 10, indicates the approximate ethylene oxide content (in %) of the polymer. This ethylene oxide content can be calculated from equation (1):
- preferred PLURONIC ® copolymers of the present invention are therefore those that have a hydrophobic part that is at least about 2 000 g/mol, i.e. those PLURONIC ® polymers of Table I that have a three-digit product name or where the first digit in the product name is larger than six.
- PLURONIC ® copolymers having a large hydrophilic content i.e. an approximate ethylene oxide content of about 80 % or more, have also been shown to have the least effective anti-cancer effect of the tested copolymers.
- These copolymers have an 8 as the last digit of the product name in Table I.
- the copolymer is less water soluble or even water insoluble.
- Such block copolymers may be less useful clinically as non- water based solvent then has to be used.
- both m, n and p in structure (I) are too low, such as L31, L42, L43, L44, L61, L62 and L63, i.e. a short relative hydrophobic block copolymer, the polymer becomes toxic for both cancerous and noncancerous cells. As a consequence, lower pharmaceutical concentrations must be used for such copolymers.
- PLURONIC ® copolymers include F127, P84, P105, P123, F87 and L121 and in particular F127.
- preferred amphiphilic copolymers of the present invention comprises at least two hydrophilic (polyethylene oxide) chains connected to a hydrophobic (polypropylene oxide) chain.
- Table II below lists some properties of available TETRONIC ® polymers. Table II - TETRONIC® copolymers
- TETRONIC ® 1307 is a currently preferred amphiphilic copolymer according to the present invention.
- the 1307 copolymer has efficient anti-cancer effect, while being water soluble and relatively non-toxic to non-proliferating cells.
- amphipathic (amphiphilic) block copolymers can be used according to the invention.
- a copolymer having a central polystyrene chain connected to respective side chains of polyethylene oxide has growth inhibitory effect.
- the present invention also encompassed other amphiphilic block copolymer besides those comprising a polyethylene oxide chain and multiple polyethylene oxide side chains.
- PLURONIC ® R is a copolymer in which the ethylene oxide and the propylene oxide have be changed places as compared to PLURONIC ® .
- the polymer has the following general structure: HO-(CH 2 CHCH3 ⁇ )k-(CH2CH 2 ⁇ ) q -(CH2CHCH 3 O)r-H (VI)
- TETRONIC ® R polymers are denoted TETRONIC ® R polymers.
- Table IV lists such polymers available from BASF Corporation.
- copolymers of the invention are effective inhibitors of cancer growth in vitro even at very low doses.
- the growth-inhibiting effect is furthermore more pronounced in rapidly growing cancer cells as compared to slowly growing cancer cells.
- at least some of the amphiphilic block polymers of the present invention do not have any cell proliferating affecting function on non-cancerous cells, unless they are stimulated by the addition of different growth factors.
- the copolymers can be used to reduce and normalize the growth rate of different types of cancer cell lines.
- the copolymers furthermore seem to reduce the high proliferation down to the normal growth rate but not further. As a consequence, non-cancerous cells will not be affected since they already proliferate at the low normal growth rate.
- the immune system of the (human) patient can more effectively handle and combat the cancer cells to eliminate the cancer.
- the copolymers of the present invention may also have affect in preventing or at least reducing the rate at which mutation arises in the cancer cells. This finding is extremely important since it reduces the risk of forming cancer cells that, due to mutations, are more prone to avoid or combat the inherent cancer defense mechanisms of a subject.
- the amphiphilic block copolymers can be provided as pharmaceutically acceptable formulations using formulation methods known to those of ordinary skill in the art. These formulations can be administered by standard routes. In general, the copolymer may be administered intravenously, intraperitoneally, subcutaneously, buccally, rectally, dermally, nasally, orally, tracheally, bronchially, topically, by any other patenteral route or via inhalation, in the form of a pharmaceutical preparation comprising the active ingredient in a pharmaceutically acceptable dosage form.
- a currently preferred administration route is an intravenous administration, in which the pharmaceutical medical composition comprises amphiphilic copolymer of the invention in a solution of a selected solvent.
- the copolymer-containing solution is injected once or preferably at multiple time instants to a person in need of cancer treatment. It could also be possible to employ a continuous or semi- continuous supply of the medicament from e.g. a medical pump or other administration equipment. Also administrations through so-called slow-release is possible and within the scope of the present invention.
- a local administration in or in connection with the tumor can be used to allow a relatively high local concentration of the active ingredient.
- This local administration can be accompanied by one or more systemic administrations.
- the formulations are prepared by uniformly and intimately bringing into associate the active ingredient with preferably liquid carriers or sometimes 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 ampoules and vials, and may be stored in a freeze-dried (lyophilized) conditions requiring only the addition of the sterile liquid carrier, for example, water for injections, immediately prior to use.
- aqueous media other media besides aqueous media can be used when injecting the pharmaceutics.
- a media is polyethylene glycol (PEG).
- PEG polyethylene glycol
- Other examples include oil-in- water or water-in-oil emulsions.
- a mineral oil or other oily substance such as Drakeol 6VR or Drakeol 5 (Penreco, Butler, PA) can be used as the oil phase of the emulsion.
- the aqueous phase can be physiologic phosphate buffered saline or other physiologic salt solution.
- the ratio of oil to water is preferably between approximately 80:20 and 1: 100.
- Formulations of suitable for oral administration may be presented 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 or emulsion in an aqueous liquid or a non-aqueous liquid.
- 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.
- 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 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.
- 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 maximum allowable dosage that can be used according to the present invention depends, among others, on the toxicity of the particular amphiphilic block copolymer, its anti-cancer effect, i.e. growth rate inhibitory effect, and the administration route.
- the maximum allowable concentration of an amphiphilic copolymer can be estimated according the toxicity study- described in the Example section of the present document. The result from such a toxicity study in mice or some other animal can then be correlated to estimated maximum allowable concentrations for other animals, including humans, using techniques well known in the art.
- the dosage conversion factor table of Freireich et al. [17] can be used. According to that conversion factor table, a conversion factor from mouse to man of about 1/ 12 is suggested, implying that if a maximum polymer concentration of X % is allowable in mice, the corresponding estimated maximum concentration in humans is about X/ 12 %.
- toxicity studies in mouse have shown that a maximum polymer concentration of about 30 % w/w can safely be injected in mouse without any side effects. This would then correspond to a concentration limit of about 2.5 % w/w for human administration.
- Some of the above listed amphiphilic copolymers of the present invention, including PLURONIC ® have underwent clinical phase studies and extensive toxicity investigations.
- concentrations used for administration of the polymers can non- inventively be determined by the person skilled in the art based on the above-described procedures. It is expected that a polymer concentration of up to 30 % w/w, such as up to 25, 20, 25 or 10 % w/w, or up to 7.5 % w/w, preferably 0.001 to 5 w/w %, more preferably at least 0.01 % w/w, such as at least 0.1 w/w % can be suitable concentrations.
- Suitable concentrations can be those that give a mean blood concentration below 5 % w/w, probably less than 2.5 % w/w and especially less than 1 % w/w.
- a preferred concentration range is between 0.0001 % w/w and 1 % w/w polymer, such as more than 0.01 % w/w, or more than 0.1 % w/w.
- the present invention can be used in connection with animal subjects, preferably mammal subjects and more preferably human subjects.
- the active copolymers of present invention can be utilized for reducing the growth rate of tumors of different cancer lines and types.
- the present invention is applicable on several different types of cancers, including, but not limited to, human sarcomas and carcinomas, e.g.
- fibrosarcoma myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, enothelio sarcoma, lymphangio sarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung
- ALL acute lymphocytic leukemia
- acute myelocytic leukemia myeloblastic, promyelocytic, myelomonocytic, monocytic and erytholeukemia
- chronic leukemias chronic myelocytic leukemia, chronic granulocytic leukemia and chronic lymphocytic leukemia
- polycythemia vera lymphoma
- lymphoma Hodgkin's disease and non-Hodgkin's disease
- multiple myeloma Waldenstrom's macroglobulinemia and heavy chain disease.
- the pharmaceutical composition of the present invention can include one of the amphiphilic block copolymers of the invention.
- the composition comprises a mixture of at least two amphiphilic block copolymers of the invention.
- the present invention can be used as a complement to other traditional cancer treatment techniques, e.g. irradiation, chemotherapy, hormone treatment, etc., to combat cancer in a patient.
- the polymers of the invention may advantageously be used in connection with other chemo therapeutic drugs.
- at least one such chemotherapeutic drug can be administered simultaneously with or sequentially relative administration of at least one amphiphilic copolymer of the present invention.
- Suitable chemotherapeutic agents include:
- alkylating agents such as cisplatin, carboplatin, oxaplatin, mechloethamine, cyclophosphamide, chlorambucil:
- anti-metabolites such as methotrexate, azathioprine, mercaptopurine, thioguanine, fludarabine, pentostatin, cladribine, 5-fluorouracil, floxuridine, cytostine arabinoside;
- anthracyclines such as daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone;
- vinca alkaloids such as vincristine, vinblastine, vinorelbine, vindesine
- phodophyllotoxin such as etoposide, teniposide
- taxanes such as paclitaxel, docetaxel
- topoisomerase inhibitors such as irinotecan, topotecan, amsacrine, etoposide, etoposide phosphate, teniposide.
- the copolymers are preferably water soluble so that they, upon administration or in vitro, can reach and interact with the cancer cells.
- the hydrophobic part of the copolymers may then penetrate into the cell membrane and bind thereto.
- the hydrophilic parts prevent to copolymer from fully entering into the membrane. This means that the copolymers will typically be anchored in the cell surface. Once fixed in the membrane, the copolymers may exert their cell growth inhibiting action in different ways.
- the amphiphilic copolymers can bind to growth factors and thereby inactivating them or at least prevent them from binding to and activating growth receptors in the cancer cell membranes. This has been seen in experiments with one of the amphiphilic block copolymers of the invention that is able to block the binding of Fibroblast Growth Factor 2 (FGF2, also denoted basic FGF) and Platelet Derived Growth Factor (PDGF) to the respective receptors on cell membranes.
- FGF2 Fibroblast Growth Factor 2
- PDGF Platelet Derived Growth Factor
- amphiphilic copolymer could block growth receptors in the membrane and prevent these receptors from pairing together, which are often necessary for forwarding a signal into the cell.
- the amphiphlic copolymers can bind to growth receptors and thereby inactivating them or at least partly block them and thereby preventing growth factors from binding to and activating the receptors.
- amphiphilic block copolymers of the present invention have previously been used in connection of anti-neoplastic agents.
- a combination of a selected PLURONIC ® polymer and polyethylene oxide can be used to decrease the toxicity of an anti-neoplastic agent and for increasing the anti-cancer activity by i) increasing the stability of the agent in the blood stream, ii) making the agent more soluble or iii) improving the transport of the agent across cell membranes.
- PLURONIC® block copolymers affects several distinct drug resistance mechanisms including inhibition of drug efflux transporters, abolishing drug sequestration in acidic vesicles and inhibiting the gluthion/ glutathione S-transferase detoxification system. All these mechanisms of drug resistance are energy-dependent and therefore ATP depletion induced by PLURONIC ® block copolymers in multidrug-resistant cancer cells is considered as the reason for the chemosensitization experienced through the combined administration of anthracycline antibiotics and PLURONIC® copolymers.
- amphiphilic block copolymers such as PLURO NIC ® copolymers
- an effective anti-cancer medicament can comprise an amphiphilic block copolymer of the present invention without any of the prior art chemotherapeutical agents and still being effective in preventing or treating cancer.
- a first aspect of the invention relates to a pharmaceutical composition comprising an amphiphilic block copolymer of the present invention as anti- cell proliferation or anti-cell-growth agent.
- This aspect also relates to the use of an amphiphilic block copolymer of the invention in the manufacture of an anti-cell-proliferation or anti-cell-growth medicament.
- the invention also encompassed an in vitro method of modulating, i.e. reducing or even inhibiting, the proliferation rate or growth rate of a cell, preferably a cancer cell. This method involves contacting the cell, preferably the cancer cell, with an amphiphilic block copolymer.
- the amphiphilic block copolymer is preferably added in the culture medium used for the cell.
- a further embodiment relates to an in vivo method of modulating, i.e. reducing, proliferation rate or cell growth rate of a cell, preferably a cancer cell.
- the method involves administering a pharmaceutical composition according the first aspect of the invention to a subject, where this subject is an animal subject, preferably a mammalian subject and more preferably a human subject.
- a second aspect of the invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising an amphiphilic block copolymer of the present invention as chemotherapeutic agent for treating or preventing cancer with the proviso that the amphiphilic block copolymer is not PLURONIC® F68 (average molecular weight 8 400 g/mol, average ethylene oxide content of 81.8 ⁇ 1.9 %, a melt point of 52 °C and an average Brookfield viscosity of 1 000 cps at 77 °C and average chemical structure of HO-(CH 2 CH 2 O) 8 O-(CH(CH 3 )CH 2 O) 2 ?- (CH2CH2 ⁇ )80-H).
- PLURONIC® F68 average molecular weight 8 400 g/mol, average ethylene oxide content of 81.8 ⁇ 1.9 %, a melt point of 52 °C and an average Brookfield viscosity of 1 000 cps at 77 °C and average chemical structure of HO-(CH 2 CH 2 O)
- Another embodiment relates to the use of an amphiphilic block copolymer as chemotherapeutic agent (active anti-cancer agent) in the manufacture of a medicament for treating or preventing cancer with the proviso that the block copolymer is not PLURONIC ® F68.
- This aspect also relates to a method of treating or preventing cancer in a subject, preferably a mammalian subject and more preferably a human subject. The method involves administering a pharmaceutical composition according to the second aspect to the subject.
- a third aspect of the invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising an amphiphilic block copolymer of the present invention for reducing or inhibiting a growth rate of cancer cells in a subject, preferably mammalian subject and more preferably a human subject, suffering from cancer.
- An embodiment of this aspect relates to the use of an amphiphilic block copolymer of the invention in the manufacture of a medicament for inhibiting or reducing the growth rate of cancer cells in the subject suffering from cancer.
- This aspect also relates to a method of reducing a growth rate of cancer cells in a subject suffering from cancer, where the method involves administering the pharmaceutical composition of the third aspect to the subject.
- a fourth aspect of the invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising an amphiphilic block copolymer represented by formula (IV):
- m, n and p are each integer numbers, preferably multiple integers numbers for treating or preventing cancer in a subject, preferably mammalian subject and more preferably a human subject, with the proviso that the cancer is not colon cancer or rectal cancer.
- An embodiment teaches the use of an amphiphilic block copolymer represented by formula (IV) as a chemotherapeutic agent in the manufacture of a medicament for treating or preventing cancer in a subject with the proviso that said cancer is not colon or rectal cancer.
- This aspect also relates to a method of treating or preventing cancer different from colon cancer and rectal cancer in a subject by administering the pharmaceutical composition of the fourth aspect to the subject.
- a fifth aspect of the invention relates a method, including an in vitro method, of blocking binding of a growth factor to a growth factor receptor on a cell membrane of a cell.
- the method comprises contacting the cell with an amphiphilic block copolymer according to the present invention.
- amphiphilic block copolymers In the experiments different amphiphilic block copolymers are used.
- the PLURONIC ® and TETRONIC ® polymers were obtained from BASF Corporation.
- the amphiphilic block copolymer denoted DORVAL 1 is a variant of a PLURONIC ® polymer but with the central propylene oxide chain exchanged for a corresponding polystyrene chain. That block copolymer was ordered from Polymer Source Inc., Canada.
- PLURONIC® F 127 was tested on cell growth of human breast cancer cell lines cultured in vitro. The growth rate was measured with incorporation of 3 H-thymidine. An aggressively growing breast cancer cell line, MCF-7, and a more slowly growing breast cancer cell line, SK-BR-3, were examined.
- PLURONIC ® F127 markedly reduced growth of both breast cancer cell lines.
- the effect was most pronounced in the rapidly growing cancer (MCF-7) were 1 % PLURONIC ® F 127 reduced cell proliferation by approximately 80 %.
- the effect was also pronounced in SK- BR-3 were the growth was reduced by approximately 60 %.
- FCS a growth stimulus
- FCS increased proliferation in SK-BR-3 but not in MCF-7, probably because MCF-7 by itself proliferates at maximum rate.
- PLURONIC® F127 was increased in FCS- stimulated cells compared to unstimulated cells.
- PLURONIC ® F 127 was effective as an inhibitor of proliferation even at the lowest concentration tested (0.01 % w/w). DNA synthesis inhibition on stimulated smooth muscle cells
- the dissected vessel was cut open and the endothelial was scraped off by a scalpel.
- the vessel was turned and further adventitia was scraped off.
- the endothelial was removed by flushing the vessel lumen with 0.1 % Triton X-100 for 10 s, followed by- flushing with DMEM (Dulbecco's Modified Eagle's Medium) culture medium.
- DMEM Dulbecco's Modified Eagle's Medium
- the vessel was hacked into smaller pieces, about 1x 1 mm.
- the vessel pieces were transferred to cell culture bottle with DMEM supplemented with 10 % FCS and 1 % antibiotic for incubation in 10 days.
- the DMEM medium was also supplemented with 10 % human serum (NHS).
- the spent culture medium was pipetted off and discarded.
- the cells were rinsed twice by addition of PBS (10 ml/ 75 cm 2 flask) to the flasks, while being careful not to disturb the cell monolayer.
- the monolayer is rinsed by gently rocking the flask back and forth.
- the PBS was removed and discarded.
- Trypsin (3.5 ml/ 75 cm 2 flask) was added to the flasks and the flasks were rocked gently to ensure that the entire monolayers were covered with the trypsin solution.
- the flasks were incubated about 3-5 minutes until the cells began to detach. 3.5 ml 10 % FCS was added per flask to "neutralize" the trypsin and the solutions were pipetted up and down until the cells were dispersed into a single cell suspension. The solution was centrifuged at 300 g for 5 minutes and the supernatant was removed and discarded. The cell pellet was solved in DMEM and transferred to two new culture flasks.
- the cell growth rate (DNA synthesis) experiments were then conducted in the same way as for the two breast cancer cell lines described above.
- Fig. 3 illustrates the results on growth rate modulation of PLURONIC ® F 127 on human vascular smooth muscle cells. It is seen that PLURONIC ® F 127 has a dose-dependent proliferation rate inhibition on the FCS-stimulated muscle cells. Comparative results were also obtained from rat and rabbit vascular smooth muscle cells.
- Vascular smooth muscle cells from rat aorta were obtained using the above- described procedure. 5 000 rat aorta cells in 200 ⁇ l DMEM supplemented by 10 % FCS were seeded per well in a CellTiter 96TM AQueous plate (Promega). The cells were allowed to incubate for about 1 day. The medium was pipetted off and discarded and exchanged by 200 ⁇ l DMEM with 0.1 % FCS per well.
- cell DMEM medium negative control
- DMEM medium with 10 % FCS positive control
- copolymer having the highest hydrophilic content i.e. F38, F68, F108 and T908, showed the lowest cell growth inhibiting effect on the FCS-stimulated smooth muscle cells.
- the copolymer F87 had similar effect as F127, while P105 achieved the highest inhibitory effect under the present experimental settings.
- Test experiments were conducted to determine whether the growth rate inhibitory effect of PLURO NIC ® F 127 might be mediated through the blocking of the binding of different growth factors to respective receptors on rat aorta smooth muscle cells.
- Rat aorta cells prepared as previously described added in culture medium (+ 10 % FCs) to wells of a 24-well microtiter plate at a concentration of about 5 000 cells per well. The plate was incubated over night to allow the cells to form a layer of the well bottoms. The culture medium was then replaced with culture medium supplemented with 0.1 % FCS and allowed to incubate for two days.
- the culture medium was then removed and the wells were washed twice with PBS.
- 150 ⁇ l NaCl solution with different concentrations of PLURONIC ® F 127 (2, 1, 0.1, 0.01, 0.001 and 0.0001 % w/w) was added together with 1 ⁇ l ⁇ 5 I- FGF2 (Radioactively labeled Fibroblast Growth Factor 2) or 1 ⁇ l 125 I-PDGF (Platelet Derived Growth Factor) diluted in a buffer solution (0.237 M NaCl, 0.0054 M KCl, 0.00044 M KH 2 PO 4 , 0.00126 M CaCl 2 , 0.00018 M MgSO 4 , 0.020 M HEPES and 0.3 % BSA) and incubated in 30 minutes at 37 0 C.
- PLURONIC ® F 127 Radioactively labeled Fibroblast Growth Factor 2
- 1 ⁇ l 125 I-PDGF Platinum Derived Growth Factor
- Fig. 7 illustrates the corresponding binding blocking effect of the F 127 polymer on radioactively labeled PDGF.
- the blocking of this growth factor binding to receptors in the cell membrane can be at least one of the mechanisms of the growth rate inhibition of the amphophilic block copolymers of the present invention.
- mice Ten NMRI albino mice, weighing about 25 g at arrival, were used for the experiment.
- the animals were obtained from Scanbur BK, and were conditioned for one week before start of the study.
- the animals were provided with food and water ad libitum
- the active substance PLURONIC ® P105 was provided in two bulk solutions of 10 and 50 % by weight, respectively, of the copolymer in NaCl (9 mg/1) for 10 % solution and in NaCl (9 mg/1) and PEG for the 50 % solution.
- the animals were separated in five groups and were treated i.v. in a tail vein, once daily for 5 days.
- the injected volume for all groups was 150 ⁇ l. The injections were performed during 10 seconds.
- Body weights were to be recorded before the first administration and at day 6.
- the animals were observed for clinical signs of toxicity (fur quality, salivation, lacrimation, diarrhea, respiration, motor disturbances, apathy, tremor, convulsions and coma) during 0-30 minutes and at 1, 2, 3, 4, 8, 24, 48 and 72 hours after administration of the test substance.
- mice treated with 10 % PLURONIC ® P 105 and 2 mice treated with 50 % PLURONIC ® P 105 were found to tolerate the repeated treatment well but those treated with 50 % P 105 showed edematous and haemolytic tails already at the second injection. In addition, these two animals showed decreased motor behavior and were subsequently euthanized at the third day after start of treatment. At this point it was decided to treat 6 mice with the 50 % formulation diluted with saline to 40 %, 30 % and 20 %.
- mice Animals injected with the 20 % and 30 % dilutions were found to tolerate the treatment well. Table VI - weight gain of mice
- mice Eighteen NMRI albino male mice, weighing about 25 g at arrival, were used for the experiment. The animals were obtained from Scanbur BK, and were conditioned for one week before start of the study. The animals were provided with food and water ad libitum
- the filling of the fibers was performed at Uppsala University Hospital, Department of Clinical Pharmacology.
- the fibers were loaded with the following tumor cells: yellow fibers with U936/gtb and blue fibers with H69.
- the animals were separated into three groups and were treated as follows intravenously in a tail vein once daily for 5 days starting immediately after implantation:
- the current study aims at investigating the cytotoxic activity of different PLURONIC ® and TETRONIC ® copolymers.
- As model systems a well defined panel of 10 selected human tumor cell lines and one additional prostate cancer cell lines are used. Three compounds, selected after screening in the sensitive lymphoma cell line U937/gtb, are investigated in all cell lines.
- a model system used in this study is a cell line panel of ten human tumor cell lines [3]. This concept originates from the National Cancer Institute (NCI) in the U.S., where a cell line panel with approximately 60 different cell lines (representing most forms of human cancer) is commonly used to define the activity profile of a new compound [4].
- NCI National Cancer Institute
- the cell line panel can successfully classify agents as being related to a specific mechanistic group (e.g. antimetabolites, alkylators, topoisomerase II inhibitors) by the use of correlation analysis [5]. It has earlier been demonstrated that a more limited number (10) of human tumor cell lines representing defined kinds of cytotoxic drug resistance can successfully be used for the initial evaluation and preliminary mechanistic classification of anticancer agents [6] .
- Tumor cells can gain resistance to cytotoxic drugs, and examples of known resistance mechanisms are the P-glycoprotein (Pgp) and multidrug resistance associated protein (MRP), increased activity of cellular detoxification systems, altered function of nuclear target enzymes like topoisomerase II (topo II) as well as altered tubulin binding/ function and subcellular redistribution of the drug.
- Pgp P-glycoprotein
- MRP multidrug resistance associated protein
- the cell line panel used contains cell lines expressing some of these phenotypes [3].
- the drug efflux pumps, e g Pgp and MRP display low specificity for substrates and thus contribute to decreased sensitivity to agents of various classes, e g vinca alkaloids, anthracyclins, taxanes, epipodophyllotoxines and other drugs [7].
- the cell lines included were the myeloma cell line RPMI 8226/ S and its sublines 8226/Dox40 and 8226/LR-5 (kind gifts from W.S. Dalton, Dept of Medicine, Arizona Cancer Center, University of Arizona, Arlington, AZ), the lymphoma cell lines U-937/gtb and U-937-Vcr (kind gifts from K.
- the 8226/Dox40 was selected for doxorubicin resistance and shows the classical MDR phenotype with overexpression of P-glycoprotein 170 (Pgp; [10].
- the 8226/ LR-5 was selected for melphalan resistance, proposed to be associated with increased levels of GSH [H].
- the U-937-Vcr was selected for vincristine resistance, proposed to be tubulin associated [12].
- the H69AR selected for doxorubicin resistance, expresses a MDR phenotype proposed to be mediated by MRP [13].
- the CEM/VM-1 selected for teniposide resistance, expresses an atypical MDR, which is proposed to be topoisomerase II (topoll) associated [14].
- the exact mechanism of resistance for the primary resistant ACHN cell line is not known and may be multifactorial [15].
- the cell lines were grown in complete culture medium described below at 37 0 C in humidified atmosphere containing 5 % CO2.
- the 8226/Dox40 was treated once a month with doxorubicin at 0.24 ⁇ g/ml and the 8226/LR-5 at each change of medium with melphalan at 1.53 ⁇ g/ml.
- the U-937-Vcr was continuously cultured in presence of 10 ng/ml of vincristine and the H69AR was alternately fed with drug free medium and medium containing 0.46 ⁇ g/ml of doxorubicin.
- the CEM/VM-1 cell line was cultured in drug free medium without any loss of resistance for a period of 6-8 months. The resistance patterns of the cell lines were routinely confirmed in control experiments.
- Human prostate cancer PC-3 cells were obtained from the American Type Culture Collection (Rockville, MD). They were grown in Dulbecco's modified Eagle medium supplemented with 10 % fetal bovine serum, penicillin G and streptomycin. Table VIII - Human tumor cell lines
- a complete medium consisting of carbonate buffered culture medium RPMI- 1640 (HyClone, Cramlington, UK) supplemented with 10 % inactivated FCS, 2 mM glutamine, 50 ⁇ g/ml of streptomycin and 60 ⁇ g/ml of penicillin was used throughout for cell lines.
- FDA Sigma, St Louis, MO
- DMSO DMSO and kept frozen (-20 0 C) as a stock solution protected from light.
- test compounds were dissolved according to the Table IX below.
- Copolymer Amount agent (g) PEG (g) NaCl (9mg/l) (g) 95 % EtOH (g)
- Tumor cells were seeded in the drug prepared 96-well plates at a cell density of about 20 000 cells/well.
- a fluorometric microculture cytotoxicity assay (FMCA) based on measurement of fluorescence generated from hydrolysis of FDA to fluorescein by cells with intact plasma membranes and as previously described in detail [16] were used.
- the plates were incubated at 37 0 C in humidified atmosphere containing 5 % CO2 for 72 hours. At the end of the incubation period the plates were centrifuged (1000 rpm, 5 minutes) and the medium was removed by aspiration. After one wash in PBS, 100 ⁇ l/well of FDA dissolved in a physiological buffer (10 ⁇ g/ml) was added.
- the plates were incubated for 45 minutes and the generated fluorescence from each well was measured in a 96- well scanning fluorometer (Fluoroscan II, Labsystems Oy, Helsinki, Finland). The fluorescence is proportional to the number of intact cells in the well.
- Quality criteria for a successful analysis included a fluorescence signal in the control wells of more than five times mean blank val ⁇ e, a mean coefficient of variation (CV) in the control wells of less than 30 % and more than 70 % tumor cells in the cell preparation prior to incubation. Experiments were performed twice, mean values are used throughout.
- SI survival index
- Concentration-effect data from both the cell line panel were fitted to a sigmoidal dose-response equation with variable slope, using non-linear regression in the GraphPad Prism software (GraphPad Software, San Diego, CA). 0 and 100 % cell survival was set as maximum effect and baseline, respectively, and the EC50 (concentration giving 50 % effect) was predicted by the curve fitting. Resistance factors were calculated as the ratio between the EC50 in the resistant and parental cell line in the cell line pairs [3].
- the compounds retained their cytotoxic activity after 4 weeks storage in microtiterplates at -70 °C.
- the concentration-effect curves were similar when using plates that had been stored for 4 weeks and when using freshly prepared plates (not shown) .
- the concentration-effect curves for all tested compounds in U937gtb are shown in Fig. 11.
- the respective tested copolymers are individually depicted in the Figs. 12A to 12O.
- the IC50-values are shown in Table X below. When samples dissolved in NaCl/ EtOH and PEG/ NaCl/ EtOH were compared similar results were obtained (not shown).
- Copolymer IC50 (% w/w)
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BRPI0710564-9A BRPI0710564A2 (en) | 2006-04-24 | 2007-04-23 | polymer-based anti-cancer agents |
CN2007800147589A CN101432005B (en) | 2006-04-24 | 2007-04-23 | Polymer-based anti-cancer agents |
AU2007241593A AU2007241593B2 (en) | 2006-04-24 | 2007-04-23 | Polymer-based anti-cancer agents |
MX2008013576A MX2008013576A (en) | 2006-04-24 | 2007-04-23 | Polymer-based anti-cancer agents. |
US12/298,437 US20090252702A1 (en) | 2006-04-24 | 2007-04-23 | Polymer-based anti-cancer agents |
JP2009507625A JP2009534464A (en) | 2006-04-24 | 2007-04-23 | Polymeric anticancer agent |
EP20070748057 EP2012804A4 (en) | 2006-04-24 | 2007-04-23 | Polymer-based anti-cancer agents |
CA002648007A CA2648007A1 (en) | 2006-04-24 | 2007-04-23 | Polymer-based anti-cancer agents |
IL194342A IL194342A0 (en) | 2006-04-24 | 2008-09-25 | Polymer-based anti-cancer agents |
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CA (1) | CA2648007A1 (en) |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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US20130065887A1 (en) * | 2011-02-28 | 2013-03-14 | Mickie Bhatia | Treatment of Cancer with Dopamine Receptor Antagonists |
WO2020180549A1 (en) * | 2019-03-05 | 2020-09-10 | Dow Global Technologies Llc | Inducing caspase activity |
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AU6898996A (en) * | 1995-08-21 | 1997-03-12 | Cytrx Corporation | Compositions and methods for growth promotion |
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US20040170674A1 (en) * | 1998-08-03 | 2004-09-02 | Easterling W. Jerry | Noninvasive methods for treating hemangiomas |
KR20010100194A (en) * | 2000-03-13 | 2001-11-14 | 박호군 | Composition and formulation for solubilization of various compounds and preparation method thereof |
CA2407700A1 (en) * | 2000-04-28 | 2001-11-08 | Alexander V. Kabanov | Compositions and methods for inducing activation of dendritic cells |
JP2003533454A (en) * | 2000-05-12 | 2003-11-11 | スプラテック ファーマ インコーポレイテッド | Compositions of non-ionic block copolymers for treating autoimmune, proliferative, and inflammatory diseases and methods of using the same |
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US5234683A (en) * | 1985-06-18 | 1993-08-10 | Emory University | Method of stimulating the immune system |
US5047236A (en) * | 1986-05-15 | 1991-09-10 | Emory University | Method of treating stroke |
WO1996007420A1 (en) * | 1994-09-03 | 1996-03-14 | The University Of Nottingham | Macrophage stimulating composition comprising a non-ionic surfactant |
WO2000024407A1 (en) * | 1998-10-27 | 2000-05-04 | Inra - Institut National De La Recherche Agronomique | Non-fermented osmotic laxative for treating and preventing colorectal cancers |
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WO2020180549A1 (en) * | 2019-03-05 | 2020-09-10 | Dow Global Technologies Llc | Inducing caspase activity |
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RU2432168C2 (en) | 2011-10-27 |
MX2008013576A (en) | 2009-01-07 |
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ZA200808329B (en) | 2010-05-26 |
RU2008146073A (en) | 2010-05-27 |
IL194342A0 (en) | 2009-08-03 |
EP2012804A4 (en) | 2012-07-04 |
EP2012804A1 (en) | 2009-01-14 |
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US20090252702A1 (en) | 2009-10-08 |
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