Methods for effecting regression of tumor mass and size in a metastasized pancreatic tumor
View Patent ↗The present invention relates generally to methods of inhibiting angiogenesis in a patient by administering an effective angiogenesis-inhibiting amount of a thrombin inhibitor, and to the treatment of disease states that result from uncontrolled cell proliferation by administering a thrombin inhibitor alone or co-administering a thrombin inhibitor with an anticancer or cytotoxic agent. Specifically, the thrombin inhibitors used in the methods of the present invention are hirudins.
1. A method of effecting regression of tumor mass and size in a metastasized pancreatic 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 of the metastasized pancreatic tumor in the subject.
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 8 , 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 pancreatic 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 of the pancreatic tumor in the subject.
12. The method of claim 11 , wherein said desulphatohirudin 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.