EP0145711A1 - Complexe de cuivre pour le traitement du cancer - Google Patents

Complexe de cuivre pour le traitement du cancer

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Publication number
EP0145711A1
EP0145711A1 EP19830902217 EP83902217A EP0145711A1 EP 0145711 A1 EP0145711 A1 EP 0145711A1 EP 19830902217 EP19830902217 EP 19830902217 EP 83902217 A EP83902217 A EP 83902217A EP 0145711 A1 EP0145711 A1 EP 0145711A1
Authority
EP
European Patent Office
Prior art keywords
compound
copper
compound according
cells
copper salicylate
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Withdrawn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
EP19830902217
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German (de)
English (en)
Inventor
John R. J. Sorenson
Larry W. Oberley
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
INTERNATIONAL COPPER ASSOCIATION Inc
Original Assignee
INTERNATIONAL COPPER ASSOCIATION Inc
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by INTERNATIONAL COPPER ASSOCIATION Inc filed Critical INTERNATIONAL COPPER ASSOCIATION Inc
Publication of EP0145711A1 publication Critical patent/EP0145711A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/03—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
    • C07C65/05—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring o-Hydroxy carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/03—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
    • C07C65/05—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring o-Hydroxy carboxylic acids
    • C07C65/10—Salicylic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/32—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
    • C07F1/005—Compounds containing elements of Groups 1 or 11 of the Periodic Table without C-Metal linkages

Definitions

  • the present invention relates to a copper complex for treating cancer by decreasing tumor growth, increasing survival of a host, decreasing tumor metastasis and inducing morphological differentiation of cancerous cells.
  • a method for treatment of cancer using this complex is also disclosed.
  • Oxygen toxicity in aerobic organisms has been widely studied.
  • the enzyme SOD - superoxide dismutase plays a significant role in the defense against such toxicity.
  • Superoxide radical (0- 2 ) is generated in various biological reactions; this free radical anion is potentially damaging either because it is extremely reactive or because it can generate highly toxic species like OH.
  • Superoxide dismutase catalyses the dismutation of 0- 2 :
  • CuZnSOD The other enzyme contains manganese and is present in the matrix of the mitochondria (MnSOD). All normal mammalian cell types investigated contain these two types of the enzyme, except erythrocytes which lack MnSOD. However, in nearly all of the tumor systems studied so far, the level of CuZnSOD and MnSOD activities were diminished. There are a few exceptions for CuZnSOD activity, but no exception has been found in the case of MnSOD activity. In many tumor samples, the MnSOD content is reduced to a level where it cannot be detected.
  • Reduced MnSOD activity has been found in over fifty human, rat, mouse, spontaneous, transplanted virally- induced, chemically- induced, in vivo and in vitro tumors.
  • both CuZnSOD and MnSOD activities in over thirty types of human tumors have been found to be less than those in control organs, Westman, N.G. and Marklund, S.L., Copper and Zinc-Containing Superoxide Dismutase and Manganese-Containing Superoxide Dismutase in Human Tissues and Human Malignant Tumors, Cancer Res. 41:2962 (1981), hereby incorporated by reference.
  • loss of SOD activity is characteristic of a wide variety of human tumors and is not a phenomenon restricted to mouse and rat tumors.
  • cancer types characaterized by low SOD activity levels include: Morris hepatomas, H6 hepatoma, Novikoff hepatoma, C3H carcinoma, Lewis lung carcinoma. Walker carcinoma. Mammary adenocarcinoma, Ehrlich ascites,
  • EL 4 ascites Guerin T R ascites, S91 melanoma, B16 melantic melanoma.
  • Sarcoma 180 L1210 leukemia, L1210/6MP lymphoid leukemia, L1210/5FU lymphoid leukemia, P388 lymphoid leukemia, L1210/0 lymphoid leukemia, and Manning leukemia.
  • This theory of excess free radicals with a deficiency of free radical scavengers in cancer cells has also been proposed by Georgieff, K.K., Free Radical Inhibitory Effect of Some Anticancer Compounds, Science 173:537-539 (1971), hereby incorporated by reference. Georgieff showed that various types of chemotherapeutic agents exhibit free radical inhibitory activity.
  • the present invention seeks to overcome the problems and disadvantages of the prior art. It has been discovered that copper complexes, which themselves act as 0- 2 scavengers, allow neoplastic cell to revert to its non- cancerous phenotype. These complexes also inhibit cancer cell growth in vivo, thereby prolonging the survival of tumor- bearing host organisms. Tumor metastasis is also reduced. The discovery is not only a significant advance but also an unexpected discovery in the art of treating cancer.
  • Native SOD has a molecular weight of about 32,000 and, as a result, does not penetrate well into cell membranes.
  • Cu(II) (3,5-diisopropylsalicylate) 2 ' CuDIPS, and other copper salicylate complexes are also 0- 2 scavengers and have a molecular weight that facilitates penetration into cell membranes.
  • Their smaller molecular size molecular weight between about 340 and about 1000, preferably between about 340 and about 600 for copper salicylate complexes and molecular weight between about
  • CuDIPS can mimic the action of lost SOD activity in tumor cells.
  • the use of copper salicylate complexes, their solvates, as well as mixtures thereof, for the treatment of cancer according to this invention is advantageous in that the overall treatment mechanism does not, as with various known methods, involve only cytot ⁇ xicity but, instead, focuses on the replacement of lost SOD activity in tumor cells to effectively halt cell division and subsequent tumor growth.
  • Such a non- cytotoxic approach to cancer therapy allows a continued regimen of treatment which is not, as with methods using cytotoxic compounds, limited by potential compounding of toxic effects.
  • This invention involves the effect of compounds with SOD activity on tumor growth and survival of tumor bearing mammals. Natural SOD and the subject copper salicylate complexes were found to have surprisingly different effects on these parameters.
  • Low SOD activity which is defined as SOD activity below that exhibited in a given normal, non- cancerous cell, characterizes various types of cancer. Copper salicylate complexes, their solvates, as well as mixtures thereof, are useful in treating such types of cancer.
  • the purpose of tumor therapy is to eliminate the tumor or to retard its growth, prevent metastasis and at the same time, prolong survival of a host. Inhibition of tumor metastasis is an important parameter in cancer control. Most primary tumors can be easily treated by various therapy regimens, but metastasis is usually difficult to prevent.
  • the tumor model used in the following experiment is Ehrlich carcinoma cells, which metastasized to the lungs, forming macroscopic nodules. Microscopic metastases are observed as early as the 10th day after transplantation of tumor cells in Tween 80- saline treated control animals. When mice treated with 5 daily doses of CuDIPS were killed on the 45th day after transplantation, only microscopic nodules were observed in the lungs. CuDIPS had delayed the process of metastasis in these Ehrlich tumor mice. However, lung metastases were the cause of death of these treated mice. Prolonged treatment further increased survival, possibly by suppressing metastases longer and thereby retarding tumor growth.
  • cancer types characterized by low SOD activity are advantageously treated using a copper salicylate complex in combination with known anti- cancer drugs.
  • a treatment mixture containing both CuDIPS and bis- dichloroethylN-nitroso urea (BCNU) is effective in prolonging survival of tumor- bearing host organisms, 2 Oberley, L.W., (unpublished observation).
  • Orgotein a generic name for CuZnSOD derived from bovine liver, is obtained from Diagnostic Data Incorporated, Mountain View, California. It is 98% pure CuZnSOD isolated from bovine liver and had 3,300 units of pure erythrocyte SOD activity/mg protein when assayed by the method of Beauchamp, C. and Fridovich, I., Superoxide Dismutase: Improved Assays and an Assay Applicable to Acrylamide Gel., Anal. Biochem. 44:276-287 (1971), hereby incorporated by reference. Orgotein was dissolved in USP grade nonpyrogenic sterile saline.
  • CuDIPS is synthesized using known methods. Sorenson, J.R.J., Copper Chelates as Possible Active Forms of the Antiarthritic Agents, J. Med. Chem. 19:135-148 (1976); Sorenson, J.R.J., Some Copper Coordination Compounds and their Antiinflammatory and Antiulcer Activities, Inflammation 1:317-331 (1976), hereby incorporated by reference.
  • CuDIPS is lipid soluble, and the LD 50 is 240 + 33 mg/kg when administered subcutaneously to rats.
  • CuDIPS is suspended in 10% Tween 80- saline ((Z) Sorbition mono- 9- ocladecinoate poly(oxy-1,2-ethonediyl)) solution.
  • reaction mixtures contain 0.05M potassium phosphate buffer (pH 7.8) with 10 -3 M diethylenetriaminepentaacetic acid, 10 - 4 M of xanthine,
  • 0- 2 scavenging ability of CuDIPS is determined by a similar assay method; the only difference is that dimethyl sulfoxide (DMSO) solvated potassium superoxide (KO 2 ) is used to generate 0- 2 instead of xanthine and xanthine oxidase.
  • DMSO dimethyl sulfoxide
  • K 2 solvated potassium superoxide
  • CuDIPS is dissolved in 10% Tween 80- saline. This alternate method is chosen due to the length of previous procedure and lipid insolubility of some of the reactants of the previous assay.
  • Reaction mixtures contain 1:20 dilution of a saturated KO 2 solution (20 mg KO 2 /ml of dimethyl sulfoxide), 5.6 x 10 -5 M of nitro blue tetrazolium, 1 unit of catalase and
  • Tumor models used in these experiments are Sarcoma 180 cells implanted in 8-12 week old standard CF1 female mice (Charles River Breeding Laboratory, Wilmington, Massachusetts) and Ehrlich carcinoma cells implanted in standard CBA/J female mice (Jackson Laboratory, Bar Harbor, Maine).
  • the tumor cells are maintained intraperitoneally in their respective hosts and are harvested and transferred weekly. Peritoneal fluid from these tumor hosts are centrifuged at 420xg for 2 minutes; the pellet is resuspended and washed three times in isotonic saline. The resulting pellet is diluted 1:5 with isotonic saline. Cell counts are done using a Coulter Model B cell counter.
  • Solid tumors are induced by implanting 5 X 10 6 cells intramuscularly into the right thigh of their respective hosts. Tumor growth is estimated by two dimensional measurements of the tumor thigh; group means and standard error of the means are plotted. The significance of differences between tumor growth curves is determined by a conventional Student's t- tests. Survival curves are analyzed by a conventional Mantel- Cox's Generalized Savage Test and a conventional Breslow's Generalized Wilcoxan test. The p values (probability that observation is due to chance alone) reported are the higher of the p values from these 2 tests.
  • the antitumor activity of Orgotein is studied in both tumor models.
  • a dose of 1.2 mg of Orgotein in 0.15 ml Tween 80- saline is injected intramuscularly at the tumor site.
  • a single dose is given to animals implanted with Sarcoma 180 cells at 1 hr, 5 days or 10 days after transplantation.
  • Mice implanted with Ehrlich carcinoma cells are also treated with Orgotein. 5 or 10 daily doses are administered instead of a single dose; Tween 80- saline treated mice are used as control.
  • Antitumor activity of CuDIPS is examined in mice with Ehrlich carcinoma only.
  • a daily dose of 0.5 or 1.0 mg in 0.2 ml of Tween 80- saline is administered intramuscularly at the tumor site for 5 days, 10 days, or every Monday, Wednesday, and Friday for a total of 10 or 18 doses with the first dose administration at 1 hr following implantation of tumor cells.
  • Another treatment schedule includes 5 daily doses beginning immediately after transplantation and an additional 5 daily doses starting on the 35th day after transplantation.
  • Each treatment group consists of 24 tumor bearing mice. Tween 80- saline injected mice are used as controls. Autopsies are performed on all dead animals.
  • Tissues from the tumor masses and organs are excised and processed by known histologic techniques and stained with hematoxylin and eosin.
  • Orgotein is administered to CF1 and CBA mice one hour after intramuscular implantation of Sarcoma 180 cells and Ehrlich carcinoma cells, respectively.
  • tissue homogenates from these two types of solid tumor contain reduced amounts of total SOD activity and diminished amounts of MnSOD activity as compared to that from normal leg muscle of the mice without tumor cell implantation.
  • these models appear to be representative in their SOD activity of the total class of tumors.
  • Orgotein is assayed to have 49,500 + 300 units of SOD activity/mg protein by the xanthine- xanthine oxidase method.
  • 1.2 mg of Orgotein is given to mice with Sarcoma 180 tumors at 1 hour after tumor cell implantation, a reduction in tumor size is observed, as indicated in Chart I (p less than 0.05 between 11 and 27 days); after 27 days, the growth curves are the same.
  • Table II and Chart II show the survival times of these tumor bearing mice; there is a 23% increase in mean survival time in the Orgotein treated group (p less than 0.1). Viability of the Sarcoma 180 cells (2.5 x 10 7 cells/ml) is unchanged when they are incubated in 0.8 mg/ml Orgotein for one hour, showing that the effect of Orgotein is probably not due to cytotoxicity.
  • Orgotein show no difference histologically from those developed from untreated cells. Histologic studies of the tumors from the Orgotein treated group show evidence of the development of a prominent fibroblast response in the area surrounding the tumor in some, but not all, of these animals on the 5th day after inoculation of tumor cells.
  • CuDIPS has a mean of 17,400 ⁇ 1,800 units of
  • Ehrlich carcinoma cells (25 x 10 7 cells/ml) are incubated with 5 mg/ml of CuDIPS for one hour, no toxicity is indicated. Preliminary dose study indicates that about
  • Chart III shows the difference in tumor growth when the tumor bearing mice are treated with CuDIPS (p less than 0.001) for 5 days.
  • Table III summarizes the differences in survival times in the various treatment groups (p less than 0.0001 for all groups).
  • Chart IV shows the survival curves of CuDIPS- treated groups.
  • mice were given 5 doses of Tween 80 (O); 5 daily doses of CuDIPS (•); 10 daily doses of CuDIPS ( ⁇ ); CuDIPS on Mondays, Wednesdays, and Fridays for a total of 10 ( ⁇ ) or 18 ( ⁇ ) doses; or 10 daily doses of CuDIPS on days 0- 4 and 35-39 ( ⁇ ).
  • CuSO 4 at a dose of 0.5 mg in 0.1 ml of Tween 80- saline is also given to CBA mice implanted with Ehrlich carcinoma cells for 5 days after transplantation. A continuous loss of weight of the tumor bearing mice is observed and death is caused by massive lung metastasis. In contrast to the above results, no weight loss was observed when mice are treated with various doses of CuDIPS, indicating that its effects are most likely not due to toxicity of the copper compounds.
  • copper compounds have antineoplastic activity which prolongs survival of tumor bearing mice. Most of these compounds are cytotoxic; they prevent the development of tumors by cell killing.
  • CuDIPS has been shown to be a potent anti- inflammatory agent. This compound is also non- toxic to the host at the dose levels used.
  • the advantage of this 0- 2 scavenger over Orgotein is its small molecular size, which enables it to penetrate cell membranes and enter organelles, thus replacing the lost SOD activity within the tumor cells.
  • the reduction in the size of the Ehrlich carcinomas in CBA mice after treatment with CuDIPS means that CuDIPS has a marked beneficial effect on this tumor model. Because Orgotein exerts no effect on tumor growth in this model, and both compounds are 0- 2 scavengers, these different antitumor activities may be due to differences in ability to penetrate cell membranes. Thus, intracellular localization of the added 0- 2 scavengers may be responsible for the observed antitumor effect.
  • CuDIPS inhibits cell population growth and induces morphological differentiation of mouse neuroblastoma cells in vitro.
  • the neuroblastoma cell clone NBP 2 provided by Dr. K. N. Prasad (University of Colorado), is maintained according to the procedure of Prasad and Hsie, Prasad, K. N. and Hsie, A. N., Nature New Biol. 233:141 (1971), hereby incorporated by reference.
  • Cells are grown as a monolayer in 75 cm 2 Falcon plastic tissue culture flasks containing F- 12 medium supplemented with 10% gamma globulin- free new born calf serum, penicillin (100 U/ml) and streptomycin (100 ⁇ g/ml). Cultures are maintained in a humidified atmosphere of 5% CO 2 in a water jacketed incubator at 37oC. The cells are harvested with 0.25%
  • CuDIPS was synthesized using known methods. Fifty- thousand cells were seeded in each 60 mM plastic petri dish containing 5 ml of the growth medium. Cells are treated with CuDIPS 24 hours after seeding. CuDIPS is dissolved in ethanol to give a final concentration of 10, 25, or 50 yg/ml of copper compound in the medium. The concentration of ethanol in the medium is kept constant at 1% in all the treated and control dishes. Culture dishes containing 1% ethanol serve as controls. One day after the start of treatments and daily afterwards, fresh drug and medium are provided in each dish. To avoid possible degradation, CuDIPS is dissolved in ethanol immediately before use. The experiment is done in triplicate. Three days after the initial treatments the number of cells and percent differentiation of cells are scored in each dish.
  • CuDIPS also induces morphological differentiation in neuroblastoma cells. Although the induction of differentiation is not observed at a concentration of 10 ⁇ g/ml, at a concentration level of 25 ⁇ g/ml, 22.4 ⁇ 2.6 percent of the neuroblastoma cells differentiated. A treatment concentration of 50 ⁇ g/ml, produces an average of 74.2 + 4.9 percent differentiated cells after 3 days of treatment. This represents more than 9 times the percentage of differentiated cells in controls. The majority of cells treated with 50 ⁇ g/ml of CuDIPS morphologically resembles mature neural cells.
  • a variety of copper salicylate complexes exhibit antineoplastic activity in CBA/J female mice implanted with Ehrlich carcinoma cells.
  • the degree of tumor growth inhibition positively correlated with the degree of lipid solubility of the particular copper salicylate complex.
  • Tumors are induced in inbred CBA/J female mice (The Jackson Laboratory, Bar Harbor, Maine) by implantation of Ehrlich carcinoma cells. Tumor cells are maintained intraperitoneally in their hosts and are harvested and transferred weekly. Solid tumors are induced by intramuscular injections of 5 X 10 6 cells into the right thighs of hosts. Cells are enumerated with a Coulter Model B counter. Tumor growth is estimated by two-dimensional measurements of the thighs; group means and standard errors are calculated. The significance of differences between tumor growth curves is determined by
  • Copper salicylates are synthesized by known methods. Aqueous solutions of sodium salicylates are prepared by combining equivalent amounts of sodium hydroxide and the corresponding salicylic acid. To this solution is added 0.5 equivalents of copper chloride. The resulting precipitates are collected by filtration, washed with water, dried in vacuo for 24 hours at 50°, and submitted for elemental analysis. The analytical values agree with the calculated values within + 0.4%.
  • mice implanted with Ehrlich carcinoma cells are treated with copper chelates suspended in 10% Tween 80- saline solution just prior to administration. All treatments are delivered by 0.1 ml intramuscular injections at the site of cell implantation.
  • a daily dose of 0.5 to 1.0 mg copper chelate in 0.1 ml of 10% Tween 80- saline is administered for 5 days, 10 days, or every Monday, Wednesday, and Friday for a total of up to 12 doses, with the first dose given 1 hour after inoculation of cells.
  • Another schedule includes five daily doses beginning 1 hour after transplantation.
  • Each treatment group consists of 24 tumor- bearing mice. Mice given Tween 80- saline injections are used as controls.
  • Cu(II)(3,5-diisopropylsalicylate) 2 (CuDIPS), having the highest degree of lipid solubility of the tested compounds, is found to be most effective in reducing tumor growth.
  • Cu(II) 2 (aspirinate) 4 is 50 mg/kg following intramuscular administration, while its LD 50 is determined to be 760 mg/kg in rats and greater than 320 mg/kg in mice, following subcutaneous injection.
  • An intramuscular dose of 25 mg/kg of CuS is found to be an effective dose, while LD 50 values of 440 mg/kg, and greater than 320 mg/kg were reported following subcutaneous administration to mice, Sorenson, J.R.J., Rauls, D.O., Ramakrishna, K. Stull, R.E. and Voldeng, A. N., "Anticonvulsant Activity of Some Copper Complexes" in Trace Substances in Environmental Health, XIII university of Missouri Press, Columbia, Mo, pp.
  • the effective intramuscular dose of CuDIPS is 25 mg/kg while reported LD 50 values are 240 mg/kg in rats and greater than 320 mg/kg in mice following subcutaneous administration. Also, if these complexes cause cell death, a significant number of normal muscle cells would have been killed with treatment. Finally, there is no difference in the number of cells killed when Ehrlich cells were incubated at 37°C for one hour with medium containing 5 mg of CuDIPS per milliliter of saline.
  • the copper complexes In the treatment of human cancer patients, the copper complexes would be administered to patients in dosages and according to regimens that would be therapeutically effective in replacing lost SOD activity in the cancerous cells.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Complexes de cuivre présentant une activité analogue à celle de la superoxyde-dismutase dans les cellules de mammifères. Les complexes de cuivre, qui agissent comme coprécipitants de radicaux superoxydes (O2), sont utilisés dans le traitement du cancer en remplaçant l'activité perdue de la superoxyde-dismutase, caractérisant les systèmes tumoraux. Le faible poids moléculaire des complexes de cuivre ainsi que leur solubilité dans les lipides facilitent la pénétration des membranes cellulaires. En fonction du type spécifique de complexe de cuivre utilisé, le traitement peut résulter en une réduction de la croissance de la tumeur, en un accroissement de la survie de l'organisme hôte, en une réduction des métastases tumorales ou de la différenciation morphologique induite des cellules cancéreuses. Les complexes de cuivre utilisés selon l'invention comprennent des complexes de salicylates de cuivre, leurs solvates ainsi que des mélanges de ces composés. Un procédé de traitement du cancer utilisant des complexes de cuivre est également décrit.
EP19830902217 1983-06-10 1983-06-10 Complexe de cuivre pour le traitement du cancer Withdrawn EP0145711A1 (fr)

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Application Number Priority Date Filing Date Title
PCT/US1983/000913 WO1984004922A1 (fr) 1983-06-10 1983-06-10 Complexe de cuivre pour le traitement du cancer

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EP0145711A1 true EP0145711A1 (fr) 1985-06-26

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WO2012046214A2 (fr) 2010-10-08 2012-04-12 Universita´ Degli Studi Di Camerino Composition comprenant un larvicide photoactivable

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EP0493642A1 (fr) * 1991-01-02 1992-07-08 Takeo Dr. Takayanagi Nouveaux dérivés de sulfonyle
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FR2901274B1 (fr) * 2006-05-19 2010-09-17 Coordination De Rech S Therape Nouveaux complexes metalliques, procede pour leur preparation et leur utilisation therapeutique
CN101284010B (zh) * 2008-04-25 2010-12-15 中山大学 具有双阳离子侧臂的二(2,2’-联吡啶)合铜配合物在制备超氧离子自由基清除剂中的应用
WO2017049529A1 (fr) 2015-09-24 2017-03-30 Innolife Co., Ltd. Composition pharmaceutique comprenant une tétramine de chélation de cuivre et utilisation de celle-ci
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Publication number Priority date Publication date Assignee Title
WO2012046214A2 (fr) 2010-10-08 2012-04-12 Universita´ Degli Studi Di Camerino Composition comprenant un larvicide photoactivable

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