Methods for Optimizing Clinical Responsiveness to Methotrexate Therapy Using Metabolite Profiling and Pharmacogenetics

Abstract

The present invention provides methods for optimizing clinical responsiveness to chemotherapy in an individual through genotypic analysis of polymorphisms in at least one gene. The methods of the present invention may further comprise determining the level of at least one long-chain methotrexate polyglutamate (MTXPG) in a sample obtained from the individual. The present invention also provides methods for generating a pharmacogenetic index for predicting clinical responsiveness to chemotherapy in an individual through genotypic analysts of polymorphisms in at least one gene. In addition, the present invention provides methods for optimizing therapeutic efficacy of chemotherapy in an individual by calculating the level of at least one long-chain MTXPG in a sample obtained from the individual.

1 - 50 . (canceled) 
     
     
         51 . A method for optimizing clinical responsiveness to methotrexate (MTX) therapy in a human with rheumatoid arthritis, comprising genotyping a nucleic acid sample from the human at nucleotide 347 in a 5-aminoimidazole carboxamide-ribonucleotide transformylase (ATIC) gene; wherein the presence of homozygous variant G residues at nucleotide 347 in the ATIC gene is indicative of superior clinical responsiveness of rheumatoid arthritis in said human to said methotrexate therapy compared to human subjects that do not have homozygous variant G residues at nucleotide 347 in the ATIC gene. 
     
     
         52 . The method of  claim 51 , wherein the method comprises determining a methotrexate polyglutamate (MTXPG) level in a sample from the human, wherein a human with a level of less than about 40 nmol/L MTXPG in the sample is subjected to the genotyping at nucleotide 347 in the ATIC gene. 
     
     
         53 . The method of  claim 52 , wherein the nucleic acid sample comprises red blood cells. 
     
     
         54 . The method of  claim 51 , wherein the method further comprises
 (b) treating the human by
 (i) administering a standard dose of MTX to a human that has homozygous variant G residues at nucleotide 347 in the ATIC gene; 
 (ii) administering a higher than standard dose of MTX to a human patient that does not have homozygous variant G residues at nucleotide 347 in the ATIC gene; or 
 (ii) treating a human patient that does not have homozygous variant G residues at nucleotide 347 in the ATIC gene with a therapeutic other than MTX.