Methotrexate adjuvants to reduce toxicity and methods for using the same

Abstract

Methods are provided for using methotrexate (MTX) active agents in which reduced host toxicity is observed. Aspects of the methods include administering to a subject an effective amount of an MTX active agent in conjunction with a MTX toxicity-reducing adjuvant, such as a 2,2′-anhydropyrimidine, a derivative thereof or a uridine phosphorylase inhibitor. Also provided are compositions and kits that find use in practicing embodiments of the invention. The methods and compositions find use in a variety of applications, including the treatment of a variety of different disease conditions.

What is claimed is: 
     
       1. A kit for use in treating a host suffering from a cellular proliferative disease condition, said kit comprising:
 (a) an MTX active agent; and 
 (b) an MTX toxicity-reducing adjuvant, wherein said MTX toxicity-reducing adjuvant is a 2,2′-anhydropyrimidine or derivative thereof. 
 
     
     
       2. The kit according to  claim 1 , wherein said 2,2′-anhydropyrimidine or derivative thereof is a compound of formula (I): 
       
         
           
           
               
               
           
         
       
       or the pharmaceutically acceptable salts, solvates, hydrates, and prodrug forms thereof, and stereoisomers thereof;
 wherein: 
 each R 1 , R 2 , R 3 , and R 4  is independently selected from the group consisting of hydrogen, substituted or unsubstituted heteroatom, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, carbohydrate, nucleic acid, amino acid, peptide, dye, fluorophore and polypeptide. 
 
     
     
       3. The kit according to  claim 2 , wherein each R 1 , R 2 , R 3 , and R 4  is independently selected from selected from the group consisting of hydrogen, hydroxyl, sulfyhydryl, amino, hydroxymethyl, methoxy, halogen, pseudohalogen, and a substituted or unsubstituted lower hydrocarbon containing 1 to 20 carbons. 
     
     
       4. The kit according to  claim 3 , wherein said lower hydrocarbon is selected from the group consisting of alkyl, alkenyl, alkanoyl, aryl, aroyl, aralkyl and alkylamino, and esters thereof. 
     
     
       5. The kit according to  claim 2 , wherein R 1  is hydrogen, flourine, methyl, ethyl, propyl, benzyl, or 2-bromovinyl; R 2  is hydrogen, hydroxyl flourine, methyl, ethyl, propyl, benzyl, benzoyl, benzoyloxy, or 2-bromovinyl; and each R 3  and R 4  is independently selected from the group consisting of hydroxyl and benzoyloxy. 
     
     
       6. The kit according to  claim 2 , wherein R 1  is hydrogen or methyl; R 2  is hydrogen; and each R 3  and R 4  is independently selected from the group consisting of hydroxyl and benzoyloxy. 
     
     
       7. The kit according to  claim 2 , wherein R 1  is hydrogen or methyl; R 2  is hydrogen, R 3  is hydroxyl or benzoyloxy; and R 4  is hydroxyl. 
     
     
       8. The kit according to  claim 1 , wherein said 2,2′-anhydropyrimidine or derivative thereof is selected from the group consisting of: 2,2′-anhydro-5-methyluridine; 3′-O-benzoyl-2,2′-anhydrouridine; 3′-O-benzoyl-2,2′-anhydro-5-methyluridine; 5′-O-benzoyl-2,2′-anhydrouridine; and 5′-O-benzoyl-2,2′-anhydro-5-methyluridine. 
     
     
       9. The kit according to  claim 1 , wherein said 2,2′-anhydropyrimidine or derivative thereof is 2,2′-anhydro-5-methyluridine. 
     
     
       10. The kit according to  claim 1 , wherein said 2,2′-anhydropyrimidine or derivative thereof is 3′-O-benzoyl-2,2′-anhydro-5-methyluridine. 
     
     
       11. The kit according to  claim 1 , wherein said 2,2′-anhydropyrimidine or derivative thereof is 5′-O-benzoyl-2,2′-anhydro-5-methyluridine. 
     
     
       12. The kit according to  claim 1 , wherein said 2,2′-anhydropyrimidine or derivative thereof comprises a stereoisomer. 
     
     
       13. The kit according to  claim 12 , wherein said stereoisomer is selected from the group consisting of 2,2′-anhydro-1-(β-D-arabinofuranosyl)-5-methyluracil; 3′-O-benzoyl-2,2′-anhydro-1-(β-D-arabinofuranosyl)-uracil; 3′-O-benzoyl-2,2′-anhydro-1-(β-D-arabinofuranosyl)-5-methyluracil; 5′-O-benzoyl-2,2′-anhydro-1-(β-D-arabinofuranosyl)-uracil; and 5′-O-benzoyl-2,2′-anhydro-1-(β-D-arabinofuranosyl)-5-methyluracil. 
     
     
       14. The kit according to  claim 1 , wherein said MTX active agent and MTX toxicity-reducing adjuvant are present as separate compositions. 
     
     
       15. The kit according to  claim 1 , wherein said MTX active agent and MTX toxicity-reducing adjuvant are present in the same composition. 
     
     
       16. A kit for use in treating a host suffering from a cellular proliferative disease condition, said kit comprising:
 (a) instructions for using a MTX toxicity-reducing adjuvant 2,2′-anhydropyrimidine or derivative thereof in treating a cellular proliferative disorder, and 
 (b) a pharmaceutical composition including one or more of a MTX active agent, a MTX toxicity-reducing adjuvant, or a combination thereof, wherein said MTX toxicity-reducing adjuvant is a said 2,2′-anhydropyrimidine or derivative thereof. 
 
     
     
       17. The kit according to claim 16, wherein said instructions discuss use of the 2,2′-anhydropyrimidine or derivative thereof in combination with a cytotoxic agent. 
     
     
       18. The kit according to claim 16, wherein said instructions discuss use of the 2,2′-anhydropyrimidine or derivative thereof in combination with a MTX active agent. 
     
     
       19. The kit according to claim 16, wherein said instructions discuss use of the 2,2′-anhydropyrimidine or derivative thereof in combination with radiation treatment. 
     
     
       20. The kit according to claim 16, wherein said 2,2′-anhydropyrimidine or derivative thereof is a compound of formula (I): 
       
         
           
           
               
               
           
         
         or the pharmaceutically acceptable salts, solvates, hydrates, and prodrug forms thereof, and stereoisomers thereof; 
       
       wherein:
 each R 1 , R 2 , R 3 , and R 4  is independently selected from the group consisting of hydrogen, substituted or unsubstituted heteroatom, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, carbohydrate, nucleic acid, amino acid, peptide, dye, fluorophore and polypeptide. 
 
     
     
       21. The kit according to claim 20, wherein each R 1 , R 2 , R 3 , and R 4  is independently selected from selected from the group consisting of hydrogen, hydroxyl, sulfyhydryl, amino, hydroxymethyl, methoxy, halogen, pseudohalogen, and a substituted or unsubstituted lower hydrocarbon containing 1 to 20 carbons. 
     
     
       22. The kit according to claim 21, wherein said lower hydrocarbon is selected from the group consisting of alkyl, alkenyl, alkanoyl, aryl, aroyl, aralkyl and alkylamino, and esters thereof. 
     
     
       23. The kit according to claim 21, wherein R 1  is hydrogen, flourine, methyl, ethyl, propyl, benzyl, or 2-bromovinyl; R 2  is hydrogen, hydroxyl flourine, methyl, ethyl, propyl, benzyl, benzoyl, benzoyloxy, or 2-bromovinyl; and each R 3  and R 4  is independently selected from the group consisting of hydroxyl and benzoyloxy. 
     
     
       24. The kit according to claim 21, wherein R 1  is hydrogen or methyl; R 2  is hydrogen; and each R 3  and R 4  is independently selected from the group consisting of hydroxyl and benzoyloxy. 
     
     
       25. The kit according to claim 21, wherein R 1  is hydrogen or methyl; R 2  is hydrogen, R 3  is hydroxyl or benzoyloxy; and R 4  is hydroxyl. 
     
     
       26. The kit according to claim 20, wherein said 2,2′-anhydropyrimidine or derivative thereof is selected from the group consisting of: 2,2′-anhydro-5-methyluridine; 3′-O-benzoyl-2,2′-anhydrouridine; 3′-O-benzoyl-2,2′-anhydro-5-methyluridine; 5′-O-benzoyl-2,2′-anhydrouridine; and 5′-O-benzoyl-2,2′-anhydro-5-methyluridine. 
     
     
       27. The kit according to claim 20, wherein said 2,2′-anhydropyrimidine or derivative thereof is 2,2′-anhydro-5-methyluridine. 
     
     
       28. The kit according to claim 20, wherein said 2,2′-anhydropyrimidine or derivative thereof is 3′-O-benzoyl-2,2′-anhydro-5-methyluridine. 
     
     
       29. The kit according to claim 20, wherein said 2,2′-anhydropyrimidine or derivative thereof is 5′-O-benzoyl-2,2′-anhydro-5-methyluridine.