Methods and compositions for overcoming resistance to biologic and chemotherapy

1. A method for inhibiting the proliferation of a hyperproliferative cell, comprising contacting the cell with a prodrug alone that is selectively converted to a toxin in the cell by an endogenous, intracellular enzyme and wherein the enzyme is overexpressed and amplified as a result of selection in vivo by chemotherapy, wherein the prodrug is an L- or D-compound of the formula:

and wherein R 1 is selected from the group consisting of Br, I, O-alkyl, O-aryl, O-heteroaryl, S-alkyl, S-aryl, S-heteroaryl, CN, OCN, SCN, NH 2 , NH-alkyl, N(alkyl) 2 , NHCHO, NHOH, NHO-alkyl, NH 2 CONHO, NHNH 2 , halovinyl and N 3 ;

wherein Q is selected from the group consisting of sugar groups, thio-sugar groups, carbocyclic groups, and 5′-monophosphate derivatives thereof; and

the compound being in any enantiomeric, diasteriomeric, stereoisomeric or anomeric form, including α- or β-anomeric forms.

2. The method of claim 1 , wherein Q is a furanosyl group of the formula:

wherein R 2 and R 3 are the same or different and are independently H or —OH.

3. The method of claim 1 , wherein Q is a β-D-ribofuranosyl group of the formula:

wherein R 2 and R 3 are the same or different and are independently H or —OH.

4. A method for treating a pathology characterized by hyperproliferative cells in a subject comprising administering to the subject a prodrug alone that is converted to a toxin in a hyperproliferative cell by an intracellular enzyme that is endogenously overexpressed or over-accumulated in the cell, wherein the prodrug is an L- or D-compound of the formula:

and wherein R 1 is selected from the group consisting of Br, I, O-alkyl, O-aryl, O-heteroaryl, S-alkyl, S-aryl, S-heteroaryl, CN, OCN, SCN, NH 2 , NH-alkyl, N(alkyl)2, NHCHO, NHOH, NHO-alkyl, NH 2 CONHO, NHNH 2 , halovinyl and N3;

wherein Q is selected from the group consisting of sugar groups, thio-sugar groups, carbocyclic groups, or the 5′ monophosphate derivative of the sugar groups, thio-sugar groups or carbocyclic groups; and

the compound being in any enantiomeric, diasteriomeric, stereoisomeric or anomeric form, including α- or β-anomeric forms.

5. The method of claim 4 , wherein the hyperproliferative cell is characterized by the endogenous overexpression of an intracellular enzyme related to resistance to chemotherapy.

6. The method of claim 4 , wherein the hyperproliferative cell is characterized as resistant to a chemotherapeutic drug.

7. The method of claim 4 , wherein the hyperproliferative cell is characterized as having an inactivated tumor suppressor function.

8. The method of claim 4 , wherein the endogeneous overexpression of an intracellular enzyme is the result of amplification of the gene coding for the enzyme.

9. The method of claim 4 , wherein the enzyme is amplified as a result of selection in vivo by chemotherapy.

10. The method of claim 4 , wherein the prodrug is a 5′-monophosphate uridine derivative.

11. The method of claim 4 , wherein the prodrug comprises a 2′ and/or 3′ substituted or unsubstituted uridine compound selected from the group consisting of 5-bromovinyl uridine, 5-bromovinyl uridine monophosphate, 5-bromovinyl 2′-deoxyuridine, and 5-bromovinyl-(2′-deoxyuridine monophosphate).

12. The method of claim 1 or 4 , wherein the sugar group is a monosaccharide cyclic sugar group selected from oxetenes, furanoses and pyranoses.

13. The method of claim 1 or 4 , wherein the sugar group is a threose, an erythrose, a ribose, an arabinose, a xylose, or a lyxose.

14. The method of claim 1 or 4 , wherein the sugar group is selected from the group consisting of deoxy-, keto- and dehydro-sugar groups.

15. The method of claim 1 or 4 , wherein the thiosugar is a sulfur analog of a monosaccharide cyclic sugar group selected from oxetenes, furanoses and pyranoses.

16. The method of claim 1 or 4 , wherein the sugar group is selected from the group consisting of threo-furanosyl, an erythro-furanosyl, a ribo-furanosyl, an arabinose, a xylose and a lyxose.

17. The method of claim 13 , wherein the sugar group is selected from the group consisting of deoxy-, keto- and dehydro-sugar groups.

18. The method of claim 1 or 4 , wherein the carbocyclic is a C 4 to C 6 -substituted or unsubstituted carbocyclic group.

19. The method of claim 18 , wherein the carbocyclic group is a 5′-monophosphate derivative of the substituted or unsubstituted carbocyclic group.

20. The method of claim 15 , wherein the thiosugar group is a 5′-monophosphate derivative of the thiosugar group.

21. A method for treating a pathology characterized by hyperproliferative cells in a subject comprising administering to the subject a composition consisting of a prodrug that is converted to a toxin in a hyperproliferative cell by an intracellular enzyme that is endogenously overexpressed or over-accumulated in the cell, wherein the prodrug is an L- or D-compound of the formula:

and wherein R 1 is selected from the group consisting of Br, I, O-alkyl, O-aryl, O-heteroaryl, S-alkyl, S-aryl, S-heteroaryl, CN, OCN, SCN, NH 2 , NH-alkyl, N(alkyl) 2 , NHCHO, NHOH, NHO-alkyl, NH 2 CONHO, NHNH 2 , halovinyl and N 3 ;

wherein Q is selected from the group consisting of sugar groups, thio-sugar groups, carbocyclic groups, and or the 5′ monophosphate derivative of the sugar groups, thio-sugar groups or carbocyclic groups; and

the compound being in any enantiomeric, diasteriomeric, stereoisomeric or anomeric form, including α- or β-anomeric forms.