WO2002007693A1 - Improved diagnostic method for detecting dysplastic epithelial tissue - Google Patents
Improved diagnostic method for detecting dysplastic epithelial tissue Download PDFInfo
- Publication number
- WO2002007693A1 WO2002007693A1 PCT/US2000/020017 US0020017W WO0207693A1 WO 2002007693 A1 WO2002007693 A1 WO 2002007693A1 US 0020017 W US0020017 W US 0020017W WO 0207693 A1 WO0207693 A1 WO 0207693A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- tissue
- cancerous
- precancerous
- diagnostic method
- epithelial tissue
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/006—Biological staining of tissues in vivo, e.g. methylene blue or toluidine blue O administered in the buccal area to detect epithelial cancer cells, dyes used for delineating tissues during surgery
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
- A61K49/0069—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form
- A61K49/0071—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form solution, solute
-
- 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
- G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
- G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
- G01N33/5076—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics involving cell organelles, e.g. Golgi complex, endoplasmic reticulum
- G01N33/5079—Mitochondria
-
- 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
Definitions
- This invention relates to an improved diagnostic method for in vivo detection of dysplastic epithelial tissue.
- the invention is an improved diagnostic method for detecting and/or delineating cancerous or precancerous epithelial tissue, with a reduced rate of false positives.
- the false positive rate of diagnostic methods that involve topical application of a dye that selectively stains cancerous and precancerous epithelial tissue is markedly reduced.
- cationic supravital dyes have the capability of selectively staining cancerous and precancerous cells of epithelial tissue, as well as cells that are abnormal due to dysplasia, hyperplasia, tumorigenesis and other active surface lesions.
- such dyes are disclosed in U.S. Patents Nos. 4,321,251 to Mashberg, 5,372,801 to Tucci, et al . r 5,882,627 to Pomerantz, and the pending International
- the mechanism of such selective staining has been shown to involve absorption or entry of the marking agent molecule into the mitochondria of the cancerous or precancerous epithelial cells.
- This selective staining of the mitochondria of cancerous tissue is apparently due to the higher electrical potential (negative charge on the inside of the membrane of cancerous mitochondrial cells as compared to normal cells.
- the mitochondrial marking agent also temporarily stains nearby non-cancerous tissue, it is released much more quickly from the normal tissue than from the mitochondria of the cancerous tissue.
- diagnosis of cancer is based on the continued retention of the dye in the cancerous tissue after it is autogenously released from the normal tissue.
- the temporary, less pronounced tendency of these dyes to stain normal tissue is due to binding of the dye with components of the extracellular matrix ("ECM") of epithelial tissue. Whereas the dye actually enters the mitochondria of cancerous and precancerous cells, it is only temporarily bound to components of the ECM, particularly to fibronectin.
- ECM extracellular matrix
- Temporary binding of cationic dyes and other mitochondrial marking agents to ECM components may be due to one or more of a variety of mechanisms.
- the mitochondrial marking agents may be temporarily bound to negatively charged ECM proteins by electrostatic attraction.
- hydrophobic interactions may take place between the ECM proteins and heterocyclic portions of the marking agent which exclude water.
- Other non-specific binding may occur by binding of various portions of the marking agent to ECM proteins that bind neutral charges.
- Such temporary binding of mitochondrial marking agents to ECM proteins can occur even outside of the tight junctions between epithelial cells, e.g., on the surface of the epithelium, as well as between and beneath cancerous cells.
- the undesired temporary binding of mitochondrial marking agents to ECM proteins can be largely prevented by pretreating the area of the epithelium to which the marking agent is to be applied with a non-toxic amphiphilic protein.
- the amphiphilic protein enters the various binding mechanisms to the ECM proteins, thus temporarily disabling them from binding the mitochondial marking agent when it is later applied.
- Such pretreatment of the epithelium with amphiphilic protein markedly reduces the occurrence of false positive reactions engendered by temporary binding of the mitochondrial marking agent to ECM proteins and the consequent appearance of "stained" areas on the normal epithelium which might be mistaken for cancerous or precancerous tissue.
- amphiphilic protein to be applied as a pretreatment is not highly critical. All mucopolysaccharides are amphiphilic. However, for ease of handling and application, it is presently preferred to employ albumins (soluble in water) or globulins (soluble in dilute salt solutions). For example, serum albumin and milk proteins, such as casein, are effectively employed. Gluten proteins, such as wheat albumins and prolamins (soluble in aqueous alcohol) and glutenins (soluble in dilute acids and bases, detergents or reducing agents) are also effectively employed.
- amphiphilic protein pre-treatment composition is prepared:
- Flavor (IFF Raspberry IC563457) .5
- a toluidine blue 0 (“TBO”) stain compositio5 is prepared, having the following composition
- Flavor (IFF Raspberry IC563457) .20 Buffering Agent (sodium acetate trihydrate) 2.45 Preservative (hydrogen peroxide 30%) .41
- Pre-rinse and post-rinse solutions of 1 wt% acetic acid in purified water, sodium benzoate preservative and raspberry flavor are prepared.
- the patient is draped with a bib to protect clothing.
- Expectoration is expected, so the patient is provided with a 10-oz. cup, which can be disposed of in an infectious waste container or the contents can be poured directly into the center drain of a sink to avoid staining the sink.
- Environmental surfaces or objects which might be stained are draped or removed from the area.
- a visual oral cancer examination is conducted, without using any instruments which might cause nicks or cuts of soft tissues. Notations are made of the appearance of soft tissues and teeth.
- the patient rinses the oral cavity with approximately 15 ml of the of the pre-rinse solution for approximately 20 seconds and expectorates, to remove excess saliva and provide a consistent oral environment. This step is then repeated with additional pre-rinse solution.
- the patient then rinses and gargles with approximately 50 ml of the protein pretreatment composition for approximately 30 seconds and expectorates. This step is then repeated, except that the patient retains the protein pretreatment composition within the mouth for approximately two minutes, then expectorates.
- the patient then rinses with 15 ml of the post rinse solution and expectorates. This step is then repeated.
- the patient then rinses and gargles with water for 20 seconds and expectorates. This step is then repeated.
- Visual observations of the oral cavity are then made, using appropriate soft-tissue examination techniques, including retraction, well-balanced lighting and magnification, if necessary.
- the location, size, morphology, color and surface characteristics of suspect lesions, that have retained blue coloration are made and recorded.
- Example 1 The procedures of Examples 1-4 are repeated except that the protein pre-treat ent solution of Example 1 consists of globulins, casein, gluten albumin, wheat prolamin and glutenins in suitable pharmacologically acceptable solvents, with suitable flavorings. Equivalent results are obtained.
Abstract
Description
Claims
Priority Applications (12)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
BR0014130-5A BR0014130A (en) | 2000-07-20 | 2000-07-20 | Use of a mitochondrial marking agent to detect dysplastic epithelial tissue and use of an amphiphilic protein |
NZ517637A NZ517637A (en) | 2000-07-20 | 2000-07-20 | Diagnostic method for detecting dysplastic epithelial tissue using a prerinse composition containing a protein which binds to the extracellular matrix components |
PCT/US2000/020017 WO2002007693A1 (en) | 2000-07-20 | 2000-07-20 | Improved diagnostic method for detecting dysplastic epithelial tissue |
EP00950579A EP1301164A4 (en) | 2000-07-20 | 2000-07-20 | Improved diagnostic method for detecting dysplastic epithelial tissue |
IL14842900A IL148429A0 (en) | 2000-07-20 | 2000-07-20 | Improved diagnostic method for detecting dysplastic epithelial tissue |
JP2002513430A JP2004504615A (en) | 2000-07-20 | 2000-07-20 | Improved diagnostic method for detecting dysplastic epithelial tissue |
CN00813014A CN1374855A (en) | 2000-07-20 | 2000-07-20 | Improved diagnostic method for detecting dysplastic epithelial tissue |
MXPA02002644A MXPA02002644A (en) | 2000-07-20 | 2000-07-20 | Improved diagnostic method for detecting dysplastic epithelial tissue. |
US10/069,836 US6967015B1 (en) | 2000-07-20 | 2000-07-20 | Diagnostic method for detecting dysplastic epithelial tissue |
AU18402/01A AU785490B2 (en) | 2000-07-20 | 2000-07-20 | Improved diagnostic method for detecting dysplastic epithelial tissue |
TW089116023A TWI281412B (en) | 2000-07-20 | 2000-08-09 | Improved method for detecting dysplastic epithelial tissue |
NO20021355A NO20021355L (en) | 2000-07-20 | 2002-03-19 | Improved diagnostic method for the detection of dysplastic epithelial tissue |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/US2000/020017 WO2002007693A1 (en) | 2000-07-20 | 2000-07-20 | Improved diagnostic method for detecting dysplastic epithelial tissue |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2002007693A1 true WO2002007693A1 (en) | 2002-01-31 |
Family
ID=21741605
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2000/020017 WO2002007693A1 (en) | 2000-07-20 | 2000-07-20 | Improved diagnostic method for detecting dysplastic epithelial tissue |
Country Status (10)
Country | Link |
---|---|
US (1) | US6967015B1 (en) |
EP (1) | EP1301164A4 (en) |
JP (1) | JP2004504615A (en) |
CN (1) | CN1374855A (en) |
AU (1) | AU785490B2 (en) |
IL (1) | IL148429A0 (en) |
MX (1) | MXPA02002644A (en) |
NO (1) | NO20021355L (en) |
TW (1) | TWI281412B (en) |
WO (1) | WO2002007693A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1214101A1 (en) * | 2000-02-28 | 2002-06-19 | Zila, Inc. | Method for detecting and killing epithelial cancer cells |
WO2004035091A1 (en) * | 2002-10-14 | 2004-04-29 | Fluoron Gmbh | Production of a dye for colouring cells in the human or animal body |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006036149A1 (en) * | 2004-09-28 | 2006-04-06 | Zila Pharmaceuticals, Inc. | Methods for detecting abnormal epithelial tissue |
AU2004324049A1 (en) * | 2004-09-30 | 2006-04-20 | Zila Biotechnology, Inc. | Light-directed method for detecting and aiding further evaluation of abnormal mucosal tissue |
AU2008350867B2 (en) | 2007-09-29 | 2014-08-28 | Timothy James Williams | Composition and method to modify sperm function and increase male gender ratio in mammals |
ES2915263T3 (en) | 2011-06-17 | 2022-06-21 | Roche Diagnostics Hematology Inc | Solution and procedure for the histoprocessing of biological samples |
CN105510321A (en) * | 2011-12-29 | 2016-04-20 | 闫文广 | Detection agent composition for epithelial tissue tumor cells and preparing method thereof |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4321251A (en) * | 1979-12-19 | 1982-03-23 | The United States Of America As Represented By The Department Of Health And Human Services | Detection of malignant lesions of the oral cavity utilizing toluidine blue rinse |
US5882627A (en) * | 1996-01-16 | 1999-03-16 | Zila Pharmaceuticals, Inc. | Methods and compositions for in-vivo detection of oral cancers precancerous conditions |
US6086852A (en) * | 1997-11-13 | 2000-07-11 | Zila, Inc. | In vivo stain composition, process of manufacture, and methods of use to identify dysplastic tissue |
Family Cites Families (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE69229471T2 (en) * | 1991-10-31 | 1999-11-25 | Zila Inc | BIOLOGICAL DYE COMPOSITION, PROCESS FOR ITS PRODUCTION AND USE FOR MARKING THE OUTLINE OF EPITHELIC CARSINOMAS |
JPH07507812A (en) * | 1993-01-14 | 1995-08-31 | ジラ・インコーポレーテッド | Screening method for epithelial cancer and kit for the screening |
JPH08196272A (en) * | 1995-01-23 | 1996-08-06 | Asahi Chem Ind Co Ltd | Hybridoma 29d38 |
US5925552A (en) * | 1996-04-25 | 1999-07-20 | Medtronic, Inc. | Method for attachment of biomolecules to medical devices surfaces |
US6194573B1 (en) * | 1997-11-13 | 2001-02-27 | Zila, Inc. | Process for manufacture of in vivo stain composition |
AU3102699A (en) * | 1998-03-19 | 1999-10-11 | Board Of Regents, The University Of Texas System | Fiber-optic confocal imaging apparatus and methods of use |
US6649144B1 (en) * | 2000-02-28 | 2003-11-18 | Zila, Inc. | Method for detecting and killing epithelial cancer cells |
GR1004180B (en) * | 2000-03-28 | 2003-03-11 | ����������� ����� ��������� (����) | Method and system for characterization and mapping of tissue lesions |
US6376525B1 (en) * | 2000-09-15 | 2002-04-23 | Qingzhong Kong | Method and composition for treating cancer using cellular organelle crystallizing agents |
CA2392213A1 (en) * | 2000-09-26 | 2002-04-04 | Zila, Inc. | Method for early prediction of the onset of invasive cancer |
US20040146919A1 (en) * | 2002-05-18 | 2004-07-29 | Burkett Douglas D. | Method for early prediction of the onset of invasive cancer |
WO2003072826A1 (en) * | 2001-12-14 | 2003-09-04 | Zila, Inc. | Stain-directed molecular analysis for cancer prognosis and diagnosis |
US20030017158A1 (en) * | 2002-03-08 | 2003-01-23 | Bernal Samuel D. | Method for detecting and killing epithelial cancer cells |
-
2000
- 2000-07-20 MX MXPA02002644A patent/MXPA02002644A/en not_active Application Discontinuation
- 2000-07-20 US US10/069,836 patent/US6967015B1/en not_active Expired - Fee Related
- 2000-07-20 WO PCT/US2000/020017 patent/WO2002007693A1/en active IP Right Grant
- 2000-07-20 JP JP2002513430A patent/JP2004504615A/en active Pending
- 2000-07-20 CN CN00813014A patent/CN1374855A/en active Pending
- 2000-07-20 EP EP00950579A patent/EP1301164A4/en not_active Withdrawn
- 2000-07-20 IL IL14842900A patent/IL148429A0/en unknown
- 2000-07-20 AU AU18402/01A patent/AU785490B2/en not_active Ceased
- 2000-08-09 TW TW089116023A patent/TWI281412B/en not_active IP Right Cessation
-
2002
- 2002-03-19 NO NO20021355A patent/NO20021355L/en not_active Application Discontinuation
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4321251A (en) * | 1979-12-19 | 1982-03-23 | The United States Of America As Represented By The Department Of Health And Human Services | Detection of malignant lesions of the oral cavity utilizing toluidine blue rinse |
US5882627A (en) * | 1996-01-16 | 1999-03-16 | Zila Pharmaceuticals, Inc. | Methods and compositions for in-vivo detection of oral cancers precancerous conditions |
US6086852A (en) * | 1997-11-13 | 2000-07-11 | Zila, Inc. | In vivo stain composition, process of manufacture, and methods of use to identify dysplastic tissue |
Non-Patent Citations (1)
Title |
---|
See also references of EP1301164A4 * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1214101A1 (en) * | 2000-02-28 | 2002-06-19 | Zila, Inc. | Method for detecting and killing epithelial cancer cells |
EP1214101A4 (en) * | 2000-02-28 | 2005-04-13 | Zila Inc | Method for detecting and killing epithelial cancer cells |
WO2004035091A1 (en) * | 2002-10-14 | 2004-04-29 | Fluoron Gmbh | Production of a dye for colouring cells in the human or animal body |
DE10255601B4 (en) | 2002-10-14 | 2012-10-25 | Fluoron Gmbh | Use of a triphenylmethane dye for the manufacture of a stain for retinal and vitreous surgery |
DE10255601C5 (en) * | 2002-10-14 | 2017-10-19 | Fluoron Gmbh | Use of a triphenylmethane dye for the manufacture of a stain for retinal and vitreous surgery |
Also Published As
Publication number | Publication date |
---|---|
IL148429A0 (en) | 2002-09-12 |
TWI281412B (en) | 2007-05-21 |
EP1301164A4 (en) | 2005-10-05 |
US6967015B1 (en) | 2005-11-22 |
NO20021355D0 (en) | 2002-03-19 |
CN1374855A (en) | 2002-10-16 |
EP1301164A1 (en) | 2003-04-16 |
NO20021355L (en) | 2002-03-19 |
AU1840201A (en) | 2002-02-05 |
AU785490B2 (en) | 2007-11-15 |
MXPA02002644A (en) | 2003-10-14 |
JP2004504615A (en) | 2004-02-12 |
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