Nucleosides for imaging and treatment applications
AssigneeThe Gov. of the USA respresented by the Secretary of Health and Human Services
InventorsRaymond W. Klecker, Lawrence Anderson, Aspandiar G. Katki, Jerry M. Collins
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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.
Claims35
A method of treating tumors, comprising:
- administering a uridine analogue selected according to claim 30 in an effective amount to reduce or inhibit replication or spread of tumor cells.
A method of alleviating cytopathic effects associated with tumors, comprising administering to an afflicted patient an effective amount of a uridine analogue selected according to claim 30 such that said cytopathic effects are alleviated.
A method of treating cancer, comprising:
- administering a uridine analogue selected according to claim 30 in an effective amount to reduce or inhibit the replication or spread of said cancer cells.
A method of diagnosing tumors which are resistant to thymidylate synthase inhibitors, comprising the steps of:
- (a) administering a uridine analogue selected according to claim 30 prior to obtaining biopsy specimens;
- (b) obtaining biopsy specimens;
- and
- (c) analyzing DNA from the biopsy specimens for extent of analogue incorporation.
A method of diagnosing tumors which are resistant to thymidylate synthase inhibitors, comprising the steps of:
- (a) administering to said tumors uridine analogue selected according to claim 30;
- wherein said uridine analogue is labeled with a positron emitter;
- and
- (b) measuring DNA incorporation by external imaging.
The method of claim 30 wherein the uridine analogue is a compound of the following general formula:
- 6
- 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-C6), halogen.
A method of treating cancer comprising:
- administering to a cancer patient a therapeutically effective amount of a composition comprising a uridine analogue selected according to claim 30 and a pharmaceutically acceptable carrier.
A composition for reducing or inhibiting the replication or spread of tumor cells, comprising:
- a uridine analogue selected according to claim 30 and a pharmaceutically acceptable carrier.
A method of treating undesirable tumors in a human or animal, comprising:
- administering to the human or animal having undesirable tumors a composition comprising a tumor-inhibiting amount of a uridine analogue selected according to claim 30.
A method of reducing or inhibiting replication of tumor cells, comprising the step of:
- administering a therapeutically-effective amount of a uridine analogue selected according to claim 30 alone or in combination with other pharmaceutical agents and/or other drugs used to inhibit tumor growth.
A method for assessing the adequacy of treatment of tumors with thymidylate synthase inhibitors, comprising the steps of:
- (a) administering a uridine analogue selected according to claim 30 wherein said uridine analogue is labeled with a positron emitter;
- and
- (b) determining an extent of maximum thymidylate synthase inhibition and persistence of thymidylate synthase inhibition over time between doses by external imaging.
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.
A compound of the formula:
- 8
- wherein:
- A=N, C;
- B=H, hydroxy, halogen, acyl (C1-C6), alkyl alkoxy (C1-C6)
- D=O, S, NH2;
- E=H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, halogen, or any substituent which is readily cleaved in the body to generate one of the before listed groups;
- at least one of W, X, Y, Z is a label or a label containing moiety having sufficient isotopic activity for imaging and the remainder of W, X, Y, Z=H, hydroxy, halogen, alkyl (C1-C6) substituted alkyl (C1-C6), alkoxy (C1-C6), substituted alkoxy (C1-C6);
- J=C, S;
- and
- K=O, C.
[CANCELED]
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.
Dependencies are inferred from the claim text.