EP1511493A1 - Utilisation de composes de peroxovanadium en tant que suppresseurs de croissance de cellules tumorales - Google Patents

Utilisation de composes de peroxovanadium en tant que suppresseurs de croissance de cellules tumorales

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Publication number
EP1511493A1
EP1511493A1 EP03727051A EP03727051A EP1511493A1 EP 1511493 A1 EP1511493 A1 EP 1511493A1 EP 03727051 A EP03727051 A EP 03727051A EP 03727051 A EP03727051 A EP 03727051A EP 1511493 A1 EP1511493 A1 EP 1511493A1
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EP
European Patent Office
Prior art keywords
bpv
peroxide
cells
oxygen
phen
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Withdrawn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
EP03727051A
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German (de)
English (en)
Inventor
Robert Faure
Pierre Savard
Charles Doillon
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.)
Universite Laval
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Universite Laval
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Filing date
Publication date
Application filed by Universite Laval filed Critical Universite Laval
Publication of EP1511493A1 publication Critical patent/EP1511493A1/fr
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention relates to the use of low dosage levels of peroxovanadium compounds, such as potassium bisperoxo(1,10-phenanthroline)oxovanadate [bpV(phen)], potassium bisperoxo(pyridine-2-carboxylato)oxovanadate [bpV(pic)] and potassium bisperoxo(2,2'-bipyridyl) oxovanadate [bpV(bipy)], for preventing and suppressing tumour growth in a mammal.
  • peroxovanadium compounds such as potassium bisperoxo(1,10-phenanthroline)oxovanadate [bpV(phen)], potassium bisperoxo(pyridine-2-carboxylato)oxovanadate [bpV(pic)] and potassium bisperoxo(2,2'-bipyridyl) oxovanadate [bpV(bipy)
  • Synthetic peroxovanadium (pV) compounds are structurally versatile molecules which are potent inhibitors of phosphotyrosyl phosphatases (PTPs) (1). These compounds contain one oxo Iigand, one or two peroxo groups, one ancillary Iigand, all coordinated to vanadium. They are stable in aqueous solution at physiological pH when shielded from light. Their mode of action lies in the modulation of the activity of cellular transduction pathways involved in the progression of pathological conditions. Their effects are transitory and disappear within a few days after administration(2),
  • Phosphotyrosine phosphatases are enzymes which remove phosphates from tyrosine residues of proteins. They are involved in several cell functions regulating proliferation, differentiation and metabolism. Their number is estimated at about 100 in the human genome (3). These enzymes function by engulfing in their catalytic site phosphates located on the tyrosine residues of target proteins. The mechanisms underlying the inhibition of PTPs and the specificity of peroxo-anionic compounds towards inhibition of PTPs have been characterized. The inhibiting potential of PTPs by pVs is a 100 to a 1000 times more powerful than that of oxovanadate (1).
  • the possibility of manipulating the ancillary ligands of pVs is important in regulating potency and specificity (1).
  • the ancillary ligands are more or less hydrophilic or hydrophobic and provide the molecule with a specific mode of action and distribution for the different PTPs. These ligands allow for the specific targeting of certain PTPs.
  • the use described in the present invention is aimed at obtaining a cytostatic effect meaning that tumour cells remain alive but stop dividing so as to prevent or arrest the growth of an invading tumour.
  • peroxovanadium compounds can obtain a cytostatic effect at dosage levels much lower than those proposed in International Patent Publication WO 00/57860 thereby minimising side-effects of the drug while improving the therapeutic outcomes of patients.
  • the present invention provides the use of peroxovanadium compounds, at low dosages, as antitumorigenic agents, for example in the treatment of cancer, such as breast cancer and prostate cancer. It has been found that a low dosages, these compounds can prevent or arrest further tumour growth.
  • the dosage levels will be 0.001 to less than 15 per mg of body weight per day and most preferably 1 to 10 mg/kg of body weight/day. In serum concentration, the dosage levels are preferably between 1 and 50 ⁇ M.
  • the molecules also contain an ancillary Iigand, which includes any molecule capable of binding the transition metal atom (usually, through bonds involving oxygen and nitrogen).
  • an ancillary Iigand which includes any molecule capable of binding the transition metal atom (usually, through bonds involving oxygen and nitrogen).
  • Phenanthroline, picolinic acid, bipyridine, oxalic acid, 4,7-dimethyl-phenanthroline and peptides are examples of such ligands.
  • Peroxo vanadate complexes include complexes such as the following: methavanadate (VO3 " ), orthovanadate (VO4 3 "), salts thereof, vanadyl compounds (VO 2+ ) like vanadyl acetyl acetonate and vanadyl sulfate.
  • Most preferred peroxides comprise the following: t-butylhydroperoxide, benzoyl peroxide, m-chloroperoxibenzoic acid, cumene hydroperoxide, peracetic acid, hydroperoxiloneic acid, ethyl peroxide, pyridine peroxide and hydrogen peroxide.
  • Y is oxygen or hydroxyl
  • Z and Z' are independently selected from oxygen and peroxide and at least one of them is peroxide;
  • L and L' are any group which can donate an electron pair.
  • Y is oxygen
  • Z and Z' are peroxide
  • L and L' are the nitrogen atoms of 1 ,10-phenanthroline.
  • Y is oxygen, Z and Z' are peroxide and L and L' are nitrogen or oxygen atoms of picolinic acid. In yet another preferred embodiment, Y is oxygen, Z and ⁇ are peroxide and L and L' are nitrogen atoms of 2,2'-bipyridine.
  • the present invention relates to the inhibiting action on tumour growth of bpV(phen), demonstrating efficiency in vivo.
  • bpV(phen) has also the capacity to inhibit the migration of tumour cells in vitro.
  • FIG. 1 Peroxovanadium compounds inhibit the proliferation of endothelial cells.
  • Human umbilical vein endothelial cells (HUVECs) were extracted with collagenase-controlled digestion. Pure HUVECs were used before the fourth passage (trypsin-EDTA at each passage). The cells were analyzed for their capacity to incorporate di-acetyl LDL and to be labelled with factor Vlll-related antigen.
  • Endothelial cells were plated at a density of 2500 cells/cm2 in a sterile plate coated with gelatin.
  • FIG. 2 Illustration of the antitumour activity of bpV(phen) in vitro using PC3 prostate cancer cells.
  • Collagen gels containing the PC3 cells were prepared according to the method of Esdale and Bard (1972) (reference 10). Briefly, stock collagen solution (3.5mg/ml in acetic acid 0.02N; Rat tail) was added to a mixture composed of culture medium (5x), fetal bovine serum (FBS), bicarbonate (0.26M), and was neutralized with 0.1 N NaOH. A cell suspension (1.42 x 10 6 cells/ml) was mixed into the collagen-medium mixture to obtain a final concentration of 2.5x10 5 cells/ml.
  • culture medium 5x
  • FBS fetal bovine serum
  • bicarbonate 0.26M
  • a DMEM medium having a normal concentration of glucose and without phenol red, was used. After gelification (within 1h) of the collagen mixture containing the cells, the gels were removed from their culture wells (mould) and interwoven into a receptor hole prepared in a fibrin gel, as previously described (6).
  • the fibrin gel was made from a 0.3 % fibrinogen solution in Hank's balanced salt solution. Fibrin was allowed to polymerize with thrombin (stock solution at 1.75mg/ml) at a ratio of 1 :003 v/v fibrin to thrombin.
  • the collagen-fibrin complexes were then covered with serum-supplemented medium according to the cell types.
  • An inhibitor of plasminogen activator (Trasylol, Parke Davies) was added into the medium at 10 ⁇ l/ml (100U/ml). Cell behavior was periodically monitored over 15 days of culture.
  • Figure 3 Illustration of the antitumour activity of bpV(phen) in vitro using ZR-75 breast cancer cells. Experiments were done as described for the figure 2 except that DMEM medium having a high glucose concentration and without phenol red was used. 10% FBS was used instead of 5% FBS. The media was supplemented with 10 "9 M estradiol (final concentration).
  • FIG. 4 figures 4A and 4B, illustrate the antitumour activity of bpV(phen) in vivo.
  • FIG. 5 In vitro antitumour activity of lymphocytes pretreated with bpV(phen).
  • PC-3 cancer cells embedded in a collagen gel grew as a "primary tumour". Some cells migrated from the primary tumour toward the fibrin gel, forming front edges that can be quantified. Small clumps of cells progressively appear in the fibrin gel and we assume that these cell extension are representative of the invasive potential of the cancer cells.
  • PC-3 cells migrated slightly from the primary tumour and formed extensive secondary tumours in the fibrin gel.
  • no secondary tumour was observed and there was no migration front.
  • the primary tumours appeared less dense than in the control.
  • animal is meant to signify human beings, primates, domestic animals (such as horses, cows, pigs, goats, sheep, cats, dogs, guinea pigs, mice, birds, fish etc.).
  • therapeutic agent should be taken in a broad sense so as to also include a combination of at least two such therapeutic agents.
  • the prescribing medical professional will ultimately determine the appropriate form and dosage for a given patient, and this can be expected to vary according to the chosen therapeutic regimen, the response and condition of the patient as well as the severity of the disease.
  • compositions within the scope of the present invention should contain the active agent (e.g. compound) in an amount effective to achieve the desired therapeutic effect while avoiding adverse side effects.
  • the compounds of the present invention can be administered to mammals (e.g. humans) in doses ranging from 0.001 to less than 15 per kg of body weight per day of the mammal which is treated and most preferably 1 to 10 mg/kg body weight/day.
  • Pharmaceutically acceptable preparations and salts of the active agent are within the scope of the present invention and are well known in the art
  • the dosage will be adapted by the clinician in accordance with conventional factors such as the extent of the disease and different parameters from the patient. Typically, 0.001 to less than 15 mg/kg/day will be administered to the mammal.
  • ZR-75 hormone-dependent cancer (ductal carcinoma) with oestrogen receptors (ATCC, USA is depository)
  • PC-3 adenocarcinoma (grade IV) with bone metastasis (ATCC, USA is depository).
  • ZR-75-1 human breast cancer ZR-75-1 human breast cancer cells obtained from the American Tissue Culture Collection (Rockville, MD) were cultured in phenol red-free RPMI 1640. The cells were supplemented with 2mM L- glutamine, 1 mM Na-pyruvate, 100 IU penicillin/ml, 100 ⁇ g streptomycin/ml, and 10% (v/v) fetal bovine serum and incubated under a humidified atmosphere comprised of 95% air and 5% CO 2 at 37°C.
  • mice Female homozygous HSD nu/nu athymic mice (50 days old) were obtained from Harlan Sprague Dawley Inc. (Indianapolis, IN). Five mice were housed per vinyl cage, which was equipped with air filter lids and kept in laminar air flow hoods under pathogen-limiting conditions. The photoperiod was composed of a period of 14h of light and a period of 10h of darkness. Cages, bedding, and food (Agway Pro-Lab R-M-H diet #4018) were autoclaved prior to use. Water was acidified to pH of 2.8, autoclaved, and provided ad libitum.
  • E 2 oestrogen
  • mice bearing tumours of an average area of 15 mm 2 were randomly assigned to 3 groups, each group containing more than 15 mice.
  • OVX animals first received the most potent natural estrogen, to initiate cell proliferation and the development of tumours. Thereafter, the E 2 implants were replaced by Ei implants as a model for post-menopausal women in which Ei is the main circulating estrogen that is converted into E 2 in peripheral tissues.
  • mice On day 0 of the experiment (5 weeks after inoculation), the E releasing implants were removed from the animals in Group 1 only. All mice received a daily administration of bpV(phen) over a period of 42 days (i.p., 100 ⁇ l, in a 2 blind manner). Groups 1 and 2 received PBS, Group 3 received 2.5 mg/Kg bpV(phen).
  • PC-3 Human prostate adenocarcinoma (PC-3) in the athymic mice: Male Balb/c nude (nu/nu) were purchased at 4-6 weeks of age from Charles Rivers Inc. Mice were housed under pathogen free conditions and maintained on a 12-h light/12- h dark cycle with food and water supplied ad libitum.
  • the hormono-independent PC3 human tumour cells were from the American Tissue Cuture Collection. Cells were grown in DMEM in the presence of 5 % foetal bovine serum. Cells were collected at confluence, included in a matrix (1.0 X 10 6 cells /ml; 30 % Matrigel). An equal volume of the tumour cell suspension was injected s.c. in the right flank of each mouse.
  • mice with palpable tumours were divided into five groups (18 mice/group) for the treatment study. All mice in each treatment group had tumour of similar size at the start of treatment.
  • bpV(phen) was dissolved and diluted in phosphate buffered saline (PBS) at pH 7.4.
  • PBS phosphate buffered saline
  • a 5mg/Kg dose of bpV(phen) was administed daily by i.p. for 39 days.
  • Taxol was used as a positive control, at the dose of 20mg/Kg and injected i.p. at every three days.
  • a control group of 10 animals was injected with PBS.
  • tumour volume length X (width) 2 X 0.53.
  • the treatment period was completed after 39 days, when the PBS treated group of mice had large tumours, requiring that the animals be sacrificed according to the Animal Care Procedures. On the final day of the study, the mice were sacrificed by carbon dioxyde inhalation. The s.c. tumours was removed and weighed.
  • Tumour growth curves are presented in terms of treatment group means and SEs. Statistical significance of treatment effect was assessed by repeated measures ANOVA after applying a power transformation to equalize residual variances and linearize the tumour growth curves.
  • the cells embedded in the collagen gel grew as a "primary tumour”. Some cells migrated from the primary tumour towards the fibrin gel, forming front edges. Small clumps of cells were observed in the fibrin gel; in this model they represent "secondary tumours”. Their extension and numbers are representative of the invasive potential of the cancer cells.
  • PC-3 In control experiments, PC-3 cells migrated slightly from the primary tumour and formed extensive secondary tumours in the fibrin gel. In the presence of 2 ⁇ M bpV(phen), a decrease in the size of the secondary tumour was observed and the migration front from the primary tumour was similar to that seen in the control gels. In the presence of 5 and 10 ⁇ M bpV(phen), there was no migration front and there were no secondary tumours in the fibrin gel. In addition, the primary tumours appeared clearer than in the control ( Figure 2).
  • ZR-75-1 In control experiments ZR-75-1 cells migrated into the fibrin as small spheroidal secondary tumours, with a limited and sparsely visible migration front.
  • ZR-75-1 human breast cancer The tumour size in the control group, having not received Ei replacement therapy, did not increase.
  • the tumour size in the animals in the other control groups having received Ei replacement therapy was found to have increased significantly (p ⁇ 0.05) from 15 to 26 mm 2 on day 42.
  • the daily administration of bpV(phen) do not resulted in increase of tumour size (p ⁇ 0.05).
  • the results show that bpV(phen) has the capacity to inhibit the progression of tumours in vivo ( Figure 4A).
  • PC-3 Human prostate adenocarcinoma (PC-3) in the athymic mice: Daily administration of bpV(phen) caused a significant (p ⁇ 0.001) 59 % suppression of the final tumour compared with PBS-treated control animals ( Figure 4B). No death were observed among the vehicle-treated controls or bpV(phen), and, on average these mice gained 1.5 and 1.7 grams in body weight respectively, relative to their weight at the initiation of the treatment.
  • Lymphocytes with anti-tumour activity can be isolated from patients and grown in vitro for use in cell-tranfer therapies (8).
  • the incubation of immune cells with the PTP inhibitor bpV(phen) augments their activation state (9). Therefore, the re-administration of bpV(phen)-activated immune cells to cancer patients may enhance the immune response towards tumour cells.
  • the results described below demonstrate the efficacy of a method in which a peroxometallic compound (bpV(phen) is used ex vivo on autologous immune cells in order to stimulate the potency of these cells and once returned into blood circulation of cancer patients fight invasion malignant cells.
  • prostate cancer cells (PC-3; American Type Culture Collection, Rockville MD) were grown in DMEM medium with 5 % fetal bovine serum, 2 mM L-glutamine, and antibiotics. They were, incubated under a humidified atmosphere of 95 % air/5% CO 2 at 37 ° C.
  • Collagen gels containing the PC-3 cells were prepared according the method of Esdale and Bard (10). The cell- embedded collagen gels were laid down onto a layer of fibrin gel, and anchored by a second layer of fibrin gel. The top of the collagen gel was not fully covered with fibrin gel in order to allow direct contacts between the cancer cells in collagen and the splenocytes.
  • leucocytes Prior to the molding of the cancer invasion system, leucocytes were isolated from spleen of either healthy mice or mice bearing PC- 3 tumours. They were treated in vitro with bpV(phen) (25 M) for 24 hr. Thereafter, treated cells were washed, counted and seeded (10 6 cells per gel) on the cancer cells-embedded gels. Untreated leukocytes seeded on the top of the cancer invasion system (same concentration) were used as a control experiment. Medium was renewed periodically. During the whole experiment, most leucocytes remained on the top of the gels, and have a normal morphology. Cell behavior was periodically observed for 7 days of culture, then recorded (by photography).
  • bpV dosage compositions of the present invention may be used as vaccines for eliciting an immuno response from a mammal.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne l'utilisation de composés de peroxovanadium comme agents antitcancéreux. Ces composés conviennent, à faible doses, comme agents antitcancéreux dans le traitement de cancers, tels que le cancer du sein ou le cancer de la prostate. L'on a découvert que, même à faible doses, ces composés peuvent empêcher ou arrêter l'évolution d'une tumeur.
EP03727051A 2002-05-17 2003-05-15 Utilisation de composes de peroxovanadium en tant que suppresseurs de croissance de cellules tumorales Withdrawn EP1511493A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CA002386759A CA2386759A1 (fr) 2002-05-17 2002-05-17 Usages therapeutiques des composes peroxometalliques
CA2386759 2002-05-17
PCT/CA2003/000738 WO2003097068A1 (fr) 2002-05-17 2003-05-15 Utilisation de composes de peroxovanadium en tant que suppresseurs de croissance de cellules tumorales

Publications (1)

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EP1511493A1 true EP1511493A1 (fr) 2005-03-09

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EP03727051A Withdrawn EP1511493A1 (fr) 2002-05-17 2003-05-15 Utilisation de composes de peroxovanadium en tant que suppresseurs de croissance de cellules tumorales

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EP (1) EP1511493A1 (fr)
AU (1) AU2003233285A1 (fr)
CA (2) CA2386759A1 (fr)
WO (1) WO2003097068A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003031930A2 (fr) * 2001-10-09 2003-04-17 The Johns Hopkins University Phosphatase associee a une metastase

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000057860A2 (fr) * 1999-03-26 2000-10-05 Centre For Translational Research In Cancer Composes de peroxovanadium utilises comme agents antineoplasiques dans le traitement du cancer
CA2280249A1 (fr) * 1999-08-12 2001-02-12 Universite Laval Composes de vanadium utilises comme facteurs anti-angiogeniques et comme inhibiteurs de production d'endotheline

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO03097068A1 *

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CA2525672A1 (fr) 2003-11-27
AU2003233285A1 (en) 2003-12-02
WO2003097068A1 (fr) 2003-11-27
CA2386759A1 (fr) 2003-11-17

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