Nucleosides for imaging and treatment applications

• US 6,753,309 B2
• Filed: 04/16/2002
• Issued: 06/22/2004
• 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:
  US10/122,173
• Publication Number:
  US 20020165199A1
• Time in Patent Office: 798 Days
• Field of Search: 514/1, 514/44
• US Class Current: 514/1
• 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 of diagnosing tumors which are resistant to thymidylate synthase inhibitors, comprising the steps of:

(a) administering a uridine analogue selected by a method comprising 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 prior to obtaining biopsy specimens;

(b) obtaining biopsy specimens; and

(c) analyzing DNA from the biopsy specimens for extent of analogue incorporation.

2. A method of diagnosing tumors which are resistant to thymidylate synthase inhibitors, comprising the steps of:

(a) administering to said tumors a uridine analogue labeled with a positron emitting isotope selected by a method comprising 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; and

(b) measuring DNA incorporation in said tumor by external imaging.

3. The method of claim 2 wherein the positron emitter is ⁸F or ¹¹C.

4. The method of claim 2 wherein the external imaging is accomplished by using positron emission tomography.

5. A method of diagnosing tumors which are resistant to thymidylate synthase inhibitors, comprising the steps of:

(a) administering to the tumor isotopically-labeled IdUrd;

(b) preparing biopsy specimens of the tumor; and

(c) determining the extent of dehalogenation of IdUrd by thymidylate synthase enzyme by examination of DNA of the tumor specimens.

6. The method of claim 5 wherein the isotopic label is selected from the group consisting of radioisotopes ⁴C and ³H and stable isotopes ¹³ C, ²H and ⁵N.

7. The method of claim 5 wherein examination of DNA of the tumor specimens comprises digesting DNA, recovering isotopically labeled dThd and determining the fraction of material derived from IdUrd in DNA.

8. The method of claim 5, wherein the isotopically labeled IdURD comprises IdUrd labeled with a radioisotope and examination of DNA of the tumor specimens comprises measuring radioactivity of the DNA.

9. The method of claim 5, wherein the isotopically labeled IdURD comprises IdUrd labeled with a non-radioactive isotope and examination of DNA of the tumor specimens mass spectrometric analysis.