Methods for effecting regression of tumor mass and size in a metastasized tumor

Abstract

The present invention relates generally to methods of effecting regression of tumor size and mass of a metastasized tumor in a subject by administering an effective amount of a desulphatohirudin variant.

1 . A method of effecting regression of tumor mass and size in a metastasized tumor in a subject, the method comprising administering to the subject a pharmaceutical formulation comprising an effective amount of a desulphatohirudin variant selected from the group consisting of a) SEQ ID NO:1 wherein Xaa at 27, 36 and 47 are each Lys, Xaa at 51 is His and Xaa at 62-65 is the peptide residue Glu-Tyr-Leu-Gln (SEQ ID NO:2) Xaa at 66 not present, b) SEQ ID NO:1 wherein Xaa at 27 is Ile or Glu and Xaa at 36, 47, 51 and 62-66 are as defined in a), c) SEQ ID NO:1 wherein Xaa at 36 is Ile or Glu and Xaa at 27, 47, 51 and 62-66 are as defined in a), d) SEQ ID NO:1 wherein Xaa at 47 is Ile or Glu and Xaa at 27, 36, 51 and 62-66 are as defined in a), and e) SEQ ID NO:1 wherein Xaa at 51 is Leu or Asp and Xaa at 27, 36, 47 and 62-66 are as defined in a), to effect regression in the subject of a metastasized tumor selected from the group consisting of adrenocortical cancer, cervical cancer, colon cancer, endometrial cancer, esophogeal cancer, eye cancer, gallbladder cancer, gastric cancer, head and neck cancer, laryngeal cancer, liver cancer, myeloproliferative disorders, neck cancer, nonmelanoma skin cancer, ovarian cancer and testicular cancer. 
     
     
         2 . The method of  claim 1 , wherein said desulphatohirudin variant is SEQ ID NO. 1, wherein Xaa at 27, 36 and 47 are each Lys, Xaa at 51 is His and Xaa at 62-65 is the peptide residue Glu-Tyr-Leu-Gln (SEQ ID NO:2) Xaa at 66 not present. 
     
     
         3 . The method of  claim 1  wherein the pharmaceutical formulation is administered via injection. 
     
     
         4 . The method of  claim 3 , wherein the pharmaceutical formulation is systemically injected. 
     
     
         5 . The method of  claim 3 , wherein the pharmaceutical formulation is locally injected. 
     
     
         6 . The method of  claim 1 , wherein the desulphatohirudin variant is co-administered with a cytotoxic agent comprising an anthracycline selected from the group consisting of doxorubicin and daunorubicin and the co-administration results in increased therapeutic effect as compared to administration of the cytotoxic agent alone. 
     
     
         7 . The method of  claim 1 , wherein the pharmaceutical formulation further includes potassium phosphate. 
     
     
         8 . The method of  claim 1 , wherein the pharmaceutical formulation further includes a divalent or trivalent metal ion. 
     
     
         9 . The method of  claim 1 , wherein the pharmaceutical formulation further includes a sugar. 
     
     
         10 . The method of  claim 1 , wherein the pharmaceutical formulation provides a sustained-release profile in vivo. 
     
     
         11 . A method of treating a prevascularized metastasized tumor in a subject, comprising administering to the subject a pharmaceutical formulation consisting essentially of an effective amount of a desulphatohirudin variant selected from the group consisting of a) SEQ ID NO:1 wherein Xaa at 27, 36 and 47 are each Lys, Xaa at 51 is His and Xaa at 62-65 is the peptide residue Glu-Tyr-Leu-Gln (SEQ ID NO:2) Xaa at 66 not present, b) SEQ ID NO:1 wherein Xaa at 27 is Ile or Glu and Xaa at 36, 47, 51 and 62-66 are as defined in a), c) SEQ ID NO:1 wherein Xaa at 36 is Ile or Glu and Xaa at 27, 47, 51 and 62-66 are as defined in a), d) SEQ ID NO:1 wherein Xaa at 47 is Ile or Glu and Xaa at 27, 36, 51 and 62-66 are as defined in a), and e) SEQ ID NO:1 wherein Xaa at 51 is Leu or Asp and Xaa at 27, 36, 47 and 62-66 are as defined in a), to effect regression in the subject of a metastasized tumor a metastasized tumor selected from the group consisting of adrenocortical cancer, cervical cancer, colon cancer, endometrial cancer, esophogeal cancer, eye cancer, gallbladder cancer, gastric cancer, head and neck cancer, laryngeal cancer, liver cancer, myeloproliferative disorders, neck cancer, nonmelanoma skin cancer, ovarian cancer and testicular cancer. 
     
     
         12 . The method of  claim 11 , wherein said desulphatohirudin variant is SEQ ID NO. 1, wherein Xaa at 27, 36 and 47 are each Lys, Xaa at 51 is His and Xaa at 62-65 is the peptide residue Glu-Tyr-Leu-Gln (SEQ ID NO:2) Xaa at 66 not present. 
     
     
         13 . The method of  claim 11 , wherein the desulphatohirudin variant is co-administered with a cytotoxic agent comprising an anthracycline selected from the group consisting of doxorubicin and daunorubicin such that the co-administration results in increased therapeutic effect as compared to administration of the cytotoxic agent alone.