Method of modulating the proliferation of medullary thyroid carcinoma cells

• US 20050124549A1
• Filed: 03/06/2002
• Published: 06/09/2005
• Est. Priority Date: 03/06/2001
• Status: Abandoned Application

• Current Assignee: Universita' Degli Studi Di Ferrara (Repubblica Italiana), Societe de Conseils de Recherches et d'Applications Scientifiques
• Original Assignee: Societe de Conseils de Recherches et d'Applications Scientifiques
• Inventors: Culler, Michael Dewitt, Uberti, Ettore Ciro Degli, Zatelli, Maria Chiara
• Application Number:
  US10/469,835
• Publication Number:
  US 20050124549A1
• Time in Patent Office: Days
• US Class Current: 424/1.690
• CPC Class Codes: A61K 38/08 Peptides having 5 to 11 amino acids A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 38/31 Somatostatins
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/02 of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin

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.

Claims

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-NH₂ (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-NH₂ (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-NH₂ (SEQ ID NO;

4); and

4-(2-Hydroxyethyl)-1-piperazine-2-ethanesulfonyl-D-Phe-cyclo(Cys-Tyr-D-Trp-Lys-Abu-Cys)-Thr-NH₂ (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-NH₂ (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-NH₂ (SEQ ID NO;

4); and

4-(2-Hydroxyethyl)-1-piperazine-2-ethanesulfonyl-D-Phe-cyclo(Cys-Tyr-D-Trp-Lys-Abu-Cys)-Thr-NH₂ (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 ¹²⁵I, ¹²⁷ I or ¹³¹I.