Method of modulating the proliferation of medullary thyroid carcinoma cells

Abstract

The present invention is directed to a method of decreasing the rate of proliferation of medullary thyroid carcinoma cells which comprises contacting medullary thyroid carcinoma cells with one or more SSTR2 agonist.

1 . A method of modulating the rate of proliferation of medullary thyroid carcinoma cells which comprises contacting MTC cells with one or more SSTR2 agonist and one or more SSTR5 agonist, wherein said SSTR2 agonist reduces the rate of proliferation of the MTC cells and said SSTR5 agonist attenuates the SSTR-2 agonist-induced reduction in cellular proliferation rate.  
     
     
         2 . A method according to  claim 1  wherein said SSTR-5 agonist is D-Phe-Phe-Trp-D-Trp-Lys-Thr-Phe-Thr-NH 2  (SEQ ID NO: 1) or a pharmaceutically acceptable salt thereof.  
     
     
         3 . A method of decreasing the rate of proliferation of medullary thyroid carcinoma cells which comprises contacting said medullary thyroid carcinoma cells with one or more SSTR2 agonist or a pharmaceutically acceptable salt thereof.  
     
     
         4 . A method according to  claim 3  wherein said SSTR-2 agonist is a SSTR-2 selective agonist or a pharmaceutically acceptable salt thereof.  
     
     
         5 . A method according to  claim 3  wherein said SSTR-2 agonist or pharmaceutically acceptable salt thereof has a Ki value for SSTR-5 that is at least 2 times higher than it has for SSTR-2.  
     
     
         6 . A method according to  claim 3  wherein said SSTR-2 agonist or pharmaceutically acceptable salt thereof has a Ki value for SSTR-5 that is at least 5 times higher than it has for SSTR-2.  
     
     
         7 . A method according to  claim 3  wherein said SSTR-2 agonist or pharmaceutically acceptable salt thereof has a Ki value for SSTR-5 that is at least 10 times higher than it has for SSTR-2.  
     
     
         8 . A method according to  claim 3  wherein said SSTR-2 agonist or pharmaceutically acceptable salt thereof has a Ki value of less than 5.  
     
     
         9 . A method according to  claim 3  wherein said SSTR-2 agonist or pharmaceutically acceptable salt thereof has a Ki value of less than 1.  
     
     
         10 . A method according to  claim 3  wherein said SSTR-2 selective agonist is a compound selected from the list consisting of: 
 D-Nal-cyclo[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH 2  (SEQ ID NO:2);    cyclo[Tic-Tyr-D-Trp-Lys-Abu-Phe] (SEQ ID NO:3);    4-(2-Hydroxyethyl)-1-piperazinylacetyl-D-Phe-cyclo(Cys-Tyr-D-Trp-Lys-Abu-Cys)-Thr-NH 2  (SEQ ID NO:4); and    4-(2-Hydroxyethyl)-1-piperazine-2-ethanesulfonyl-D-Phe-cyclo(Cys-Tyr-D-Trp-Lys-Abu-Cys)-Thr-NH 2  (SEQ ID NO:5);    or a pharmaceutically acceptable salt thereof.    
     
     
         11 . A method of treating medullary thyroid carcinoma which comprises administering to a patient in need thereof an effective amount of a SSTR2 agonist or a pharmaceutically acceptable salt thereof.  
     
     
         12 . A method according to  claim 11  wherein said SSTR2 agonist comprises an SSTR2 selective agonist, or a pharmaceutically acceptable salt thereof.  
     
     
         18 . A method according to  claim 11  wherein said SSTR-2 agonist or pharmaceutically acceptable salt thereof is a compound selected from the list consisting of: 
 D-Nal-cyclo[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH 2  (SEQ ID NO:2);    cyclo[Tic-Tyr-D-Trp-Lys-Abu-Phe] (SEQ ID NO:3);    4-(2-Hydroxyethyl)-1-piperazinylacetyl-D-Phe-cyclo(Cys-Tyr-D-Trp-Lys-Abu-Cys)-Thr-NH 2  (SEQ ID NO:4); and    4-(2-Hydroxyethyl)-1-piperazine-2-ethanesulfonyl-D-Phe-cyclo(Cys-Tyr-D-Trp-Lys-Abu-Cys)-Thr-NH 2  (SEQ ID NO:5);    or a pharmaceutically acceptable salt thereof.    
     
     
         19 . A method according to  claim 11 , wherein said SSTR-2 agonist or pharmaceutically acceptable salt thereof comprises a Tyr(I) residue, wherein the iodine atom of said Tyr(I) residue comprises a radioactive iodine isotope.  
     
     
         20 . A method according to  claim 11  or  claim 19 , wherein said medullary thyroid carcinoma cells have formed metastases outside the thyroid.  
     
     
         21 . A method according to  claim 20 , wherein said metastases are present in the lymph, the lung, the liver, the brain, or in bone.  
     
     
         22 . A method of  claim 21 , wherein said iodine is  125 I,  127  I or  131 I.