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WO2006053649A1 - Procede de detection du cancer - Google Patents

Procede de detection du cancer Download PDF

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Publication number
WO2006053649A1
WO2006053649A1 PCT/EP2005/011911 EP2005011911W WO2006053649A1 WO 2006053649 A1 WO2006053649 A1 WO 2006053649A1 EP 2005011911 W EP2005011911 W EP 2005011911W WO 2006053649 A1 WO2006053649 A1 WO 2006053649A1
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WIPO (PCT)
Prior art keywords
alkaloid
derivative
alkaloid derivative
cancer
present
Prior art date
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Ceased
Application number
PCT/EP2005/011911
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English (en)
Inventor
Wassyl Nowicky
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Individual
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Individual
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Publication of WO2006053649A1 publication Critical patent/WO2006053649A1/fr
Anticipated expiration legal-status Critical
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
    • G01N33/57488—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites involving compounds identifable in body fluids

Definitions

  • the present invention is in the fields of medicine and medical analytics and relates to a method of detection of tumorigenic development or cancer in an individual.
  • the well known anti-cancer drug Ukrain (e.g. WO 2003/041721 , WO 2004/082698) has been shown in vitro and in vivo to accumulate in cancer cells and tissues (Thakur et al., J Immunological Methods 1992, 152, 209-216). Due to its autofluorescence under UV irradition Ukrain can be detected in various tissues in vitro and in vivo (Nowicky et al, J Tumor Marker Oncology 1988, Vol.3; Nr.4).
  • the present invention is primarily based on the results of a study for determining and evaluating the pharmacokinetic data of the drug UKRAIN in humans, after a single intravenous administration at a dosage of 5 - 20 mg active ingredient per individual (1 - 5 ampoules each containing 5 mg Ukrain/5 ml) to healthy volunteers with the estimation of Ukrain concentrations in blood and renal Ukrain elimination.
  • the present invention relates to a simple urine and/or blood test applicable in the determination of cancer, particularly of solid tumours and metastases, in a human or animal body. It further relates to a test kit for early cancer diagnostics, as well as to the use of certain alkaloid derivatives for the diagnostic purposes, particularly for cancer diagnostics.
  • the invention is laid down in the independent claims, while further embodiments of the invention are disclosed and claimed in the dependent claims.
  • the present invention in its first aspect relates to a method of detecting cancer in an individual, which method comprises the following steps: - administering to said individual a dose of at least one alkaloid derivative that adheres to or accumulates in cancer cells or tissues; taking at least one blood and/or urine sample of said individual after said administration; determining the concentration of at least one alkaloid derivative in said blood and/or urine sample; and evaluating the concentration of said alkaloid derivative against corresponding mean values of healthy controls, preferably against the values given in Table 4,
  • the invention relates to such a method, wherein two or more samples are taken in intervals after said administration of said at least one alkaloid derivative.
  • the invention relates to a said method, wherein a concentration profile is established and evaluated against a corresponding concentration profile obtained from healthy controls.
  • the invention relates to a said method, wherein the alkaloid derivative is derived from an alkaloid present in the herb Chelidonium majus L.
  • the invention relates to a said method, wherein the alkaloid derivative comprises a mixture of compounds obtained by alkylation of some or all alkaloids present in the herb Chelidonium majus L.
  • the invention relates to a said method, wherein the alkaloid derivative has a quaternary nitrogen atom.
  • the invention relates to a said method, wherein the alkaloid derivative is a quaternary chelidonine or chelidonine derivative.
  • the invention relates to a said method, wherein as a fourth ligand to the quaternary nitrogen a residue selected from the group consisting of a -H, -OH, -SH, aliphatic, alkyl, aryl, aralkyl, alkyloxy, aryloxy, and a halogen residue is present.
  • the invention relates to a said method, wherein the concentration of the alkaloid derivative is determined by fluorescence measurement, preferably using UV irradiation, and/or by liquid chromatography, particularly by HPLC.
  • the invention relates to a diagnostic kit, suitable for carrying out the aforementioned method of cancer detection, which comprises on one hand a pharmaceutical preparation containing at least one alkaloid derivate that adheres to or accumulates in cancer cells or tissues, and on the other hand a test strip or another sampling device suitable for collecting said at least one alkaloid derivative from a blood or urine sample for subsequent analysis, particularly for visual, photometric or chromatographic analysis.
  • the test strip may be of a nature such as to adsorb quaternary alkaloids or alkaloid derivatives from a liquid sample, whereafter the adsorbed alkaloid derivative is subjected in situ to a colour-generating chemical reaction or is photometrically analysed under UV-light, e.g. using a UV-spectrophotometer.
  • the invention relates to a diagnostic kit, wherein the alkaloid derivative is derived from an alkaloid present in the herb Chelidonium majus L.
  • the invention relates to a diagnostic kit, wherein the alkaloid derivative comprises a mixture of compounds obtained by alkylation of some or all alkaloids present in the herb Chelidonium majus L.
  • the invention relates to a diagnostic kit, wherein the alkaloid derivative has a quaternary nitrogen atom. In a further embodiment the invention relates to a diagnostic kit, wherein the alkaloid derivative is a quaternary chelidonine or a quaternary chelidonine derivative.
  • the invention relates to a diagnostic kit, wherein the instruction manual comprises information relating to a method claimed in any one of claims 1 to 7.
  • the invention relates to the general use of an alkaloid derivative that adheres to or accumulates in cancer cells or tissues, as a diagnostic tool in the detection of cancer.
  • the invention relates to a said use, wherein the alkaloid derivative is derived from an alkaloid present in the herb Chelidonium majus L.
  • the invention relates to a said use, wherein the alkaloid derivative comprises a mixture of compounds obtained by alkylation of some or all alkaloids present in the herb Chelidonium majus L.
  • the invention relates to a said use, wherein the alkaloid derivative has a quaternary nitrogen atom.
  • the invention relates to a said use, wherein the alkaloid derivative is a quaternary chelidonine or chelidonine derivative.
  • the invention also relates to a method of cancer localization in a human body, the method comprising administering to an individual a composition comprising at least one metal-stained alkaloid derivative that adheres to or accumulates in cancer cells, and detecting the metal-stained alkaloid derivative after distribution in the body by means of physical, particularly imaging, detection methods.
  • the invention relates to such a method, wherein the metal is selected from the group consisting of titanium, platinum and gold.
  • the invention relates to alkaloid derivatives as disclosed hereinbefore and hereinafter.
  • test substance UKRAIN was administered undiluted as an aqueous solution by intravenous injection to 6 healthy men at a dose of 20 mg (i.e. 20 ml injection solution).
  • any other galenic form for oral or parenteral administration may also be suitable.
  • Plasma concentrations of the test substance were determined 5, 15, 30, 45, 60, 90, 120, 150, and 180 min after administration. Urine was collected and the test substance concentration was determined in intervals over a period of 24 hours after administration.
  • Y-axis Log10 of plasma concentrations of Ukrain in micrograms/ml
  • X-axis time after administration, in minutes.
  • FIG. 1 Renal excretion of Ukrain; Ukrain concentrations in urine samples.
  • Y-axis Renal excretion of Ukrain in percent of admininstered dose
  • X-axis time after administration, in hours.
  • the test substance applied was UKRAIN as commercially available in 5mg/5ml ampoules from Nowicky Pharma (Austria).
  • the active ingredient is a mixture of alkaloid derivatives obtained in a process of chemical derivatization of an alkaloid extract of the herb Chelidonium majus L using thiotepa (a cytostatic thiophosphorous acid derivative) as an alkylating agent.
  • a process of manufacture of UKRAIN is disclosed, e.g., in WO 03/041721 .
  • the main active ingredient is a quaternary chelidonine derivative.
  • test substance was provided in liquid form at a concentration of 5mg active ingredients per 5 ml carrier solution.
  • the clear solution had a pH-value of 3.49, a density of 0.9968 and a yellow colour.
  • the solution was stable over the entire period of experimentation when stored at room temperature and protected from light.
  • test substance UKRAIN was administered undiluted. A slow bolus intravenous administration was performed once in the morning into the cubital vein over 5 minutes.
  • Insyte-W® 18G i.v. catheter/needle units Becton
  • Table 1 Demographic data for six volunteers
  • Urine was collected during 24 hours after administration of the test substance. Volume and time of each urination as well as the total volume of urine collected in the periods of 0 - 4, 4 - 8, 8 -12, 12 -16 and 16 - 24 h were registered.
  • Samples (8 ml of perchloric acid extracts of plasma; or 1 1 ml in case of urine) were injected into the pre-column and the pre-column rinsed with 1 ml of water to eliminate the rest of perchloric acid. Samples were then eluted from the pre- column by 2M KOH containing 20 per cent (v/v) of ethanol: the first 150 ⁇ l fraction was discarded, subsequent 300 ⁇ l fraction was collected, neutralized with 50 ⁇ l of 5M H 3 PO 4 , and 100 ⁇ l aliquots were injected into the HPLC system.
  • the column used was 3x150 mm, packed with Diasorb 130 Ci 6 T (Elsico, Moscow, Russia), 8 ⁇ m.
  • the mobile phase composition was 0.5M KH 2 PO 4 , pH adjusted to 2.65 with H 3 PO 4 , 10 mM sodium octylsulfonate, 15 per cent (v/v) of acetonitrile and the flow rate was 0.4 ml/min.
  • Detection was done by fluorescence, excitation wavelength 360 nm, emission wavelength 455 nm. Chromatograms were processed using MultiChrom system (MultiChrom, Moscow, Russia; AD converter MultiChrom-1 ; program version 2.67). External standard quantitation was used.
  • MultiChrom system MultiChrom, Moscow, Russia; AD converter MultiChrom-1 ; program version 2.67. External standard quantitation was used.
  • Table 6 Parameters of pharmacokinetics of the test substance after a single intravenous administration to healthy volunteers (6 men, age 27 - 44 years) at a dose of 20 mg calculated using two-compartment model were the following:
  • Ukrain is not metabolised during residence in a human body.
  • prior publications e.g. Nowicky et al., J Tumor Marker Oncol, 3(4), p.463-65,19878
  • Ukrain has a high affinity towards cancer and malignant tumor cells and accumulates in the cell nuclei of such cancer and tumor cells.
  • Evaluating the blood elimination and/or urinary excretion values or profiles of Ukrain of a patient against the corresponding values or profiles, respectively, of healthy volunteers as presented herein allows to make reliable predictions on a possible cancer state of said patient.
  • the data obtained from cancer patients so far allow to conclude that any significant reduction in the Ukrain concentrations in the blood and/or urine samples of the cancer patients as compared to the corresponding values of healthy volunteers ("controls"), such as the ones given in Tables 2 to 5 and particularly in Table 4, may thus provide a simple and easy to do analytical and diagnostic method for the detection of cancer in a human individual.
  • the values obtained from cancer patients may be lower by 10 to 80 %, i.e. indicating less excretion from and more accumulation inside the body of one or more alkaloid derivatives present in the drug Ukrain, thus further indicating the presence of cancer cells in said individual's body.
  • the fourth ligand of the quaternary nitrogen is selected from the group consisting of a -H, -OH, -SH, aliphatic, alkyl, aryl, aralkyl, alkyloxy, aryloxy, and a halogen residue.
  • alkaloid detection using fluorescence measurements or gel chromatographic methods
  • further methods of alkaloid detection may be applied without deviating from the spirit of the present invention.
  • radio-labeled alkaloid derivatives may be applied which can easily be traced, e.g. by scintillation counting of sample preparations.
  • Another method of detection of malignant tumorigenic development or of established cancer in a patient comprises administration of metal-stained alkaloid derivatives, e.g. metal-stained Ukrain, to cancer patients followed by subsequent detection of the metal-stained alkaloids using conventional imaging methods, e.g. using X-ray or magnetic resonance methods. Since certain quaternary alkaloids, for instance those reported in WO 03/041721 , WO 2004/082698 or in the European patent application Nr.
  • EP 04022299.4 preferably quaternary alkaloids derived by alkylation of one or more alkaloids present in the herb Chelidonium majus L., adhere to or accumulate in cancer cells and tissues, as hereinbefore described, it is possible to localize the metal stained alkaloid derivatives, hence cancer cells or tissue inside the human body.
  • Stable means that metal particles are attached to the alkaloid derivatives in a way such as to stably remain attached during passage of said alkaloid derivatives through the humoral system of the body until the final destination , i.e. cancer cells, is reached.
  • Suitable metals are those that are substantially inert under the physiological conditions of the humoral system of the body and which can be easily traced by physical, particularly imaging, detection methods.
  • Preferred metals are titanium, platinum and particularly gold. Since the water- soluble, quaternary alkaloids have been found to rather qickly distribute within the body and also to rather qickly eliminate from the body via renal exrection, it will be sufficient in most cases to take the proper measurements within a period of 30 minutes to 4 hours post administration of the stained alkaloid derivative(s). However, in some cases it may be useful to make measurements even after 4 hours post administration. Typically, the stained alkaloid derivative preparation will be administered by intravenous injection.
  • This method is far less harmful and hazardous to a patient than conventional methods using radioisotope-labelling and subsequent cancer localization using known imaging methods.

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  • Health & Medical Sciences (AREA)
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Abstract

L'invention concerne un procédé de diagnostic destiné à détecter un cancer dans le corps d'un être humain, ce procédé étant basé sur la détermination de la concentration d'un dérivé alcaloïde qui adhère aux cellules cancéreuses ou s'accumule dans celles-ci dans des échantillons de sang et/ou d'urine des individus par administration orale ou parentérale du dérivé alcaloïde à cet individu, une réduction de ces valeurs de concentration par rapport aux valeurs correspondant aux individus sains indique la présence de cellules cancéreuses dans le corps de l'individu. L'invention concerne en outre un nécessaire de diagnostic destiné à mettre en oeuvre le procédé, et à utiliser ces dérivés alcaloïdes en tant qu'outils de diagnostic dans le diagnostic du cancer. L'invention concerne enfin un procédé de localisation du cancer dans un corps humain, ce procédé étant basé sur l'administration de dérivés alcaloïdes imprégnés de métal à un patient atteint d'un cancer et la détection ultérieure de celui-ci au moyen des procédés de détection physique connus.
PCT/EP2005/011911 2004-11-19 2005-11-08 Procede de detection du cancer Ceased WO2006053649A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP04027574 2004-11-19
EP04027574.5 2004-11-19

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WO2006053649A1 true WO2006053649A1 (fr) 2006-05-26

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015144900A1 (fr) * 2014-03-27 2015-10-01 Nowicky Wassili Procédé de diagnostic servant au dépistage du cancer

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2110533A (en) * 1981-07-13 1983-06-22 Nowicky Wassili Compositions containing alkaloid derivatives
US4816462A (en) * 1982-05-18 1989-03-28 Nowicky Wassili Method for diagnosing and for the therapeutic treatment of tumors and/or infectious diseases of different types with alkaloid-compounds
US5399338A (en) * 1991-05-01 1995-03-21 University Of New Mexico Enhancement of abnormal tissue uptake of antibodies, tumor-specific agents or conjugates thereof for diagnostic imaging or therapy
US5567593A (en) * 1992-07-28 1996-10-22 Beljanski; Mirko Cytodiagnostic method using alstonine as a selective marker, and diagnostic kit containing marker
WO2000006143A1 (fr) * 1998-07-27 2000-02-10 Texas Pharmaceuticals, Inc. Hyperthermie intracellulaire induite chimiquement
WO2003041721A1 (fr) * 2001-11-15 2003-05-22 Nowicky Wassili Processus de reaction d'alcaloides et utilisation des produits de reaction dans la preparation de medicaments

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2110533A (en) * 1981-07-13 1983-06-22 Nowicky Wassili Compositions containing alkaloid derivatives
US4816462A (en) * 1982-05-18 1989-03-28 Nowicky Wassili Method for diagnosing and for the therapeutic treatment of tumors and/or infectious diseases of different types with alkaloid-compounds
US5399338A (en) * 1991-05-01 1995-03-21 University Of New Mexico Enhancement of abnormal tissue uptake of antibodies, tumor-specific agents or conjugates thereof for diagnostic imaging or therapy
US5567593A (en) * 1992-07-28 1996-10-22 Beljanski; Mirko Cytodiagnostic method using alstonine as a selective marker, and diagnostic kit containing marker
WO2000006143A1 (fr) * 1998-07-27 2000-02-10 Texas Pharmaceuticals, Inc. Hyperthermie intracellulaire induite chimiquement
WO2003041721A1 (fr) * 2001-11-15 2003-05-22 Nowicky Wassili Processus de reaction d'alcaloides et utilisation des produits de reaction dans la preparation de medicaments

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DOROSHENKO Y M ET AL: "A method for determination of Ukrain in blood plasma for monitoring and pharmacokinetic study", DRUGS UNDER EXPERIMENTAL AND CLINICAL RESEARCH, vol. 26, no. 5-6, 2000, pages 163 - 170, XP008060482, ISSN: 0378-6501 *
DOROSHENKO Y M ET AL: "The dynamics of concentration of the main fluorescent component of Ukrain in the tissues and blood plasma of rats with W-256 tumor after a single intravenous injection", DRUGS UNDER EXPERIMENTAL AND CLINICAL RESEARCH, vol. 26, no. 5-6, 2000, pages 171 - 177, XP008060378, ISSN: 0378-6501 *
JAGIELLO-WOJTOWICZ E ET AL: "Preliminary pharmacokinetic studies of Ukrain in rats", DRUGS UNDER EXPERIMENTAL AND CLINICAL RESEARCH, vol. 24, no. 5-6, 1998, pages 309 - 311, XP008060484, ISSN: 0378-6501 *
NOWICKY J W ET AL: "MACROSCOPIC UV-MARKING THROUGH AFFINITY", JOURNAL OF TUMOR MARKER ONCOLOGY, vol. 3, no. 4, 1988, pages 463 - 466, XP008060373, ISSN: 0886-3849 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015144900A1 (fr) * 2014-03-27 2015-10-01 Nowicky Wassili Procédé de diagnostic servant au dépistage du cancer

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