Claims
- 1. A method of inhibiting carcinoma progression wherein matriptase plays a role in a subject in need of such inhibition comprising administering to a subject an effective amount of a compound comprising two groups capable of being positively charged at physiological pH, which can be the same or different, said groups being linked by a chemical moiety having a length of between 5 and 30 A.
- 2. The methods of claim 1, wherein the chemical moiety has a length of between 15 and 24 A.
- 3. The method of claim 1, wherein the positively charged groups are individually selected from the following groups:
- 4. The method of claim 1 wherein the compound is selected from the compounds of formulae I through VI which have the structures below, wherein X and Y are any substituents that are not detrimental to inhibition of matriptase
- 5. A method of inhibiting carcinoma progression wherein matriptase plays a role in a subject in need of such inhibition comprising administering to a subject an effective amount of a compound selected from the group consisting of compounds A, B, C, D, E, F, G:
- 6. The method of claim 5, wherein compound A to G is administered to a subject in a daily dose of between 0.1 and 500 mg for each kilogram of the subject's weight.
- 7. The method of claim 6, wherein compound A is administered to a subject in a daily dose of about 1.0-200 mg for each kilogram of the subject's weight.
- 8. The method of claim 5, wherein said compound inhibits carcinoma progression related protease cascade.
- 9. The method of claim 8, wherein inhibiting protease cascade comprises inhibiting matriptase activity.
- 10. The method of claim 9, wherein inhibiting matriptase activity comprises inhibiting activation of a substrate involved in carcinoma progression.
- 11. The method of claim 10, wherein the substrate is an extracellular matrix component, a growth factor or a protease.
- 12. The method of claim 10, wherein the substrate is HGF/SF or pro-uPA.
- 13. The method of claim 8, wherein inhibiting protease cascade comprises inhibiting the production of a protein fragment selected from the group consisting of the catalytically active fragment of HGF/SF produced by cleavage of HGF/SF and uPA produced by cleavage of pro-uPA.
- 14. A method of therapy which results in the inhibition of matriptase in a subject in need of such inhibition which comprises administering a therapeutically effective amount of at least one compound selected from the group consisting of compounds A, B, C, D, E, F, G:
- 15. The method of claim 13, wherein said compound antagonizes carcinoma progression related protease cascade.
- 16. The method of claim 13, wherein said method results in the inhibition of carcinoma progression.
- 17. A method of treating cancer comprising administering a therapeutically effective amount of at least one compound selected from the group consisting of compounds A, B, C, D, E, F, G:
- 18. The method of claim 16, wherein said cancer is selected from the group consisting of breast, ovarian, prostate, endometrial, colon, pancreatic, head and neck, gastric, renal, brain and CML.
- 19. The method of claim 16, wherein said compound is administered by a method selected from the group consisting of oral, intranasal, intraperitoneal, intravenous, intramuscular, intratumoral, rectal, and transdermal.
- 20. The method of claim 16, wherein the administered amount of said compound ranges from 0.01 mg to 200 mg/kg of the weight of said subject.
- 21. The method of claim 16, wherein the amount of said compound more preferably ranges from 0.5 mg to 50 mg/kg of the weight of said subject.
- 22. The method of claim 16, which further comprises the administration of another anticancer compound, radiation, or a compound that induces apoptosis.
- 23. A pharmaceutical composition which comprises a therapeutically effective amount of a compound selected from the group consisting of compounds A, B, C, D, E, F, G:
- 24. The composition of claim 22, which is suitable for administration via injection, orally, transdermally, intranasally, intraoculary, or rectally.
- 25. A method of treating malignancies, pre-malignant conditions, and pathologic conditions in a subject which are characterized by the expression of single-chain (zymogen) and/or two-chain (activated) form of matriptase comprising administering a therapeutically effective amount of a compound selected from the group consisting of compounds A, B, C, D, E, F, G:
- 26. The method of claim 24, wherein the malignancy and pre-malignant condition is a condition of the breast.
- 27. The method of claim 22, wherein the pre-malignant condition is selected from the group consisting of: atypical ductal hyperplasia of the breast, actinic keratosis (AK), leukoplakia, Barrett's epiethlium (columnar metaplasia) of the esophagus, ulcerative colitis, adenomatous colorectal polyps, erythroplasia of Queyrat, Bowen's disease, bowenoid papulosis, vulvar intraepithelial neoplasia (VIN), and displastic changes to the cervix.
- 28. A method of diagnosing cancer comprising exposing a tissue sample to an antibody or immunogenic fragment thereof which recognizes and binds to a product of matriptase mediated proteolysis of a matriptase substrate.
- 29. The method of claim 27, wherein the matriptase substrate is uPA or HGF/SF.
- 30. The method of claim 27, wherein the product is active urokinase or active HGF fragment obtained by cleavage of HGF/SF.
- 31. An in vivo method of diagnosing the presence of a pre-malignant lesion, a malignancy or other pathologic condition in a subject comprising the steps of:
(A) administering to a subject, that is to be tested for a pre-malignant or malignant lesion, or other pathologic condition, which is characterized by the presence of a product of matriptase mediated proteolysis of a substrate of matriptase, a labeled agent which recognizes and binds to the product of matriptase mediated proteolysis; and (B) imaging the subject for the localization of the labeled agent.
- 32. The method of claim 30, wherein the labeled agent is an antibody.
- 33. The method of claim 31, wherein the labeled antibody is a labeled monoclonal antibody.
- 34. The method of claim 32, wherein the agent is labeled with a radiolabel or a fluorescent label.
- 35. The method of claim 33, wherein the radiolabel is selected from the group consisting of: 62Cu, 99Te, 131I, 123I, 111In, 90Y, 188Re, and 186Re.
- 36. An in vitro method of diagnosing the presence of a pre-malignant lesion, a malignancy, or other pathologic condition, in a subject, which is characterized by the presence of a product of matriptase mediated proteolysis of a substrate of matriptase comprising the steps of:
(A) obtaining a biological sample from a subject that is to be tested for a pre-malignant lesion, a malignancy, or other pathologic condition; (B) exposing the biological sample to a labeled agent which recognizes and binds to the product of matriptase mediated proteolysis; and (C) determining whether said labeled agent bound to the biological sample.
- 37. The method of claim 35, wherein the biological sample is a sample comprising epithelial cells.
- 38. The method of claim 35, wherein the labeled agent is a labeled antibody.
- 39. The method of claim 37, wherein the labeled antibody is labeled with a radioisotope or a fluorescent label.
- 40. The method of claim 38, wherein the radioisotope is selected from the group consisting of: 62Cu, 99Te, 131I, 123I, 111In, 90Y, 188Re, and 186Re.
- 41. A method of treating cancer comprising administering a therapeutically effective amount of a bis-benzamidine compound.
- 42. The method of claim 41, wherein the bis-benzamidine compound is
- 43. The method of claim 41, wherein the bis-benzamidine compound is:
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application claims priority from U.S. Provisional Serial No. 60/213,073, filed Jun. 21, 2000, and is incorporated herein by reference in its entirety.
Provisional Applications (1)
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Number |
Date |
Country |
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60213073 |
Jun 2000 |
US |