Methods for controlling angiogenesis and cell proliferation

Abstract

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 for repressing the growth of a tumor in a subject, comprising administering to the subject an amount of a PEGylated hirudin effective to inhibit the growth of the tumor. 
     
     
         2 . The method of  claim 1 , wherein the administration of the PEGylated hirudin effects a reduction in the size or volume of the tumor. 
     
     
         3 . The method of  claim 1 , wherein the tumor is a prevascularized tumor. 
     
     
         4 . The method of  claim 1 , wherein the tumor is a metastasized tumor. 
     
     
         5 . The method of  claim 1 , wherein the PEGylated hirudin is administered systemically. 
     
     
         6 . The method of  claim 1 , wherein the PEGylated hirudin is administered locally. 
     
     
         7 . The method of  claim 6 , wherein the PEGylated hirudin is administered by intratumoral injection. 
     
     
         8 . The method of  claim 1 , wherein the tumor is of a type selected from the group consisting of: brain cancer, bladder cancer, breast cancer, colon cancer, colorectal cancer, rectal cancer, head and neck cancer, liver cancer, lung cancer, myeloma, prostate cancer, ovarian cancer adrenocortical cancer, bone cancer, cervical cancer, endometrial cancer, esophageal cancer, eye cancer, gallbladder cancer, gastric cancer, laryngeal cancer, melanoma, neck cancer, nonmelanoma skin cancer, pancreatic cancer, and testicular cancer. 
     
     
         9 . The method of  claim 1 , further comprising administering to the subject an anticancer or cytotoxic agent. 
     
     
         10 . The method of  claim 9 , wherein the anticancer or cytotoxic agent is selected from the group consisting of antimetabolites, antimicrotubule agents, alkylating agents, platinum agents, anthracyclines, antibiolitics, and topoisomerase inhibitors. 
     
     
         11 . The method of  claim 10 , wherein the anticancer or cytotoxic agent is selected from the group consisting of 5-fluorouracil, methotrexate, fludarabine, vincristine, vinblastine, taxanes, paclitaxel, docetaxel, cyclophasphamide, melphalan, biochoroethylnitrosurea, hydroxyurea, cisplatin, carboplatin, oxaliplatin, JM-216, CI-973, doxorubicin, daunorubicin, mitomycin, idarubicin, adriamycin, daunomycin, etoposide, camptothecins, estramustine phosphate, and prednimustine. 
     
     
         12 . A method for inhibiting angiogenesis in a subject, comprising administering to the subject an effective amount of a PEGylated hirudin to prevent or reduce angiogenesis of a tissue of the subject. 
     
     
         13 . The method of  claim 12 , wherein the tissue is a solid tumor. 
     
     
         14 . The method of  claim 12 , wherein the PEGylated hirudin is administered systemically. 
     
     
         15 . The method of  claim 12 , wherein the PEGylated hirudin is administered locally. 
     
     
         16 . A method for repressing metastasis of a tumor in a subject, comprising administering to the subject an amount of a PEGylated hirudin effective to inhibit metastasis of the tumor. 
     
     
         17 . The method of  claim 16 , wherein the PEGylated hirudin is administered systemically. 
     
     
         18 . The method of  claim 16 , further comprising administering to the subject an anticancer or cytotoxic agent. 
     
     
         19 . A pharmaceutical composition for treating cancer, comprising a PEGylated hirudin, an anticancer or cytotoxic agent that differs therefrom, and a pharmaceutically acceptable carrier. 
     
     
         20 . A kit for use in cancer treatment, comprising:
 a first pharmaceutical composition containing a PEGylated hirudin and a pharmaceutically acceptable carrier; and   a second pharmaceutical composition containing an anticancer or cytotoxic agent.