Nucleosides for imaging and treatment applications

• US 6,677,314 B2
• Filed: 08/30/2001
• Issued: 01/13/2004
• Est. Priority Date: 10/30/1997
• Status: Expired due to Fees

• Current Assignee: United States Department Of Health And Human Services
• Original Assignee: United States Department Of Health And Human Services
• Inventors: Anderson, Lawrence, Collins, Jerry M., Klecker, Raymond W., Katki, Aspandiar G.
• Primary Examiner(s): Riley, Jezia
• Application Number:
  US09/941,550
• Publication Number:
  US 20020022001A1
• Time in Patent Office: 866 Days
• Field of Search: 514/1, 514/44, 435/6
• US Class Current: 514/44.00R
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• CPC Class Codes: C07H 21/00 Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids

Abstract

Methods of diagnosing and/or of treating tumors by administering a nucleoside analogue which is activated by thymidylate synthase and/or thymidine kinase enzyme into a diagnostic or toxic metabolite, and uridine analogue compounds, and compositions of same having a pharmaceutically acceptable carrier. For diagnostic applications, compounds containing a label and methods of use of such compounds are described

Claims

1. A method for selecting a uridine analogue for reducing or inhibiting the replication or spread of tumor cells, comprising the steps of:

providing a uridine analogue unsubstituted in the 5-position;

testing said uridine analog for activation by thymidylate synthase; and

selecting said uridine analog when found to be activated by thymidylate synthase.

2. A method according to claim 1, wherein the testing step comprises:

measuring cytotoxicity of said uridine analogue with respect to at least one cell line with a high expression of thymidylate synthase enzyme and at least one cell line with a low expression of thymidylate synthase enzyme; and

the selecting step comprises;

selecting said uridine analogue when the cytotoxicity measured with respect to the at least one cell line with a high expression of thymidylate synthase enzyme is greater than the cytotoxicity measured with respect to the at least one cell line with a low expression of thymidylate synthase enzyme.

3. A method according to claim 2, wherein the at least one cell line with a high expression of thymidylate synthase enzyme is selected from the group consisting of U937 cell line and CEM cell line.

4. A method according to claim 2, wherein the at least one cell line with a low expression of thymidylate synthase enzyme is selected from the group consisting of L1210 cell line and Raji cell line.

5. A method according to claim 1, wherein the uridine analog contains a radioisotope.

6. A method according to claim 5, wherein the radioisotope is ¹⁸F of ¹¹C.

7. The method of claim 1 wherein the uridine analogue is a compound of the following general formula:

wherein;

A=N, C;

B=H, hydroxy, halogen, acyl (C₁-C₆), alkyl, C₁-C₆), alkoxy (C₁-C₆)

D=O, S, NH₂; and

G=substituted or unsubstituted cyclic sugar, substituted or unsubstituted acyclic sugar, substituted or unsubstituted mono, di, or tri-phospho-cyclic-sugar phosphate;

substituted or unsubstituted mono, di, or tri-phospho-acyclic-sugar phosphate;

substituted or unsubstituted mono, di, or tri-phospho-cyclic sugar analogues, substituted or unsubstituted mono, di, or tri-phospho-acyclic sugar analogues wherein the substituents are alkyl (C₁-C₆) alkoxy (C₁ to C₆), halogen.

8. The method according to claim 7, wherein the compound contains a radioisotope.

9. The method according to claim 8, wherein the radioisotope is ¹⁸F or ¹¹C.

10. The method according to claim 7, wherein G comprises a positron emitting moiety.