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 analysis 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.

Description

CROSS-REFERENCES TO RELATED APPLICATIONS[0001]This application is a Divisional App. and claims the benefit of the filing date of a U.S. Non-Provisional application Ser. No. 10 / 927,904, filed Aug. 26, 2004, which claims the benefit of the filing date of U.S. Provisional Appl. Ser. No. 60 / 514,423, filed Oct. 24, 2003 and to U.S. Provisional App. Ser. No. 60 / 560,752, filed on Aug. 29, 2003.DESCRIPTION OF THE TEXT FILE SUBMITTED ELECTRONICALLY[0002]The contents of the text file submitted electronically herewith are incorporated herein by reference in their entirety: A computer readable format copy of the Sequence Listing (filename: CYPR 028 03US SubSeqList_ST25.txt, date recorded: Apr. 7, 2009, file size 13 kilobytes).FIELD OF THE INVENTION[0003]This invention relates generally to medical genetics and, more specifically, to methods for optimizing clinical responsiveness to chemotherapy.BACKGROUND OF THE INVENTION[0004]Folate (folic acid) is a vitamin that is essential for the life-susta...

AI Technical Summary

Benefits of technology

"The present invention provides methods for optimizing clinical responsiveness to chemotherapy and arthritis therapy in individuals by genotyping them at polymorphic sites in genes involved in these processes. The methods involve identifying the presence or absence of a variant allele at the polymorphic site and calculating a pharmacogenetic index based on the presence or absence of the variant allele. The pharmacogenetic index is indicative of a characteristic clinical responsiveness to the chemotherapy or arthritis therapy. The methods can be used to optimize the effectiveness of chemotherapy or arthritis therapy for an individual."

Problems solved by technology

Despite its structural similarity to folic acid, methotrexate cannot be used as a cofactor by enzymes that require folate, and instead competes with the folate cofactor for enzyme binding sites, thereby inhibiting protein and DNA biosynthesis and, hence, cell division.

Although methotrexate is among the best tolerated of the disease-modifying anti-rheumatic drugs (DMARDs), a major drawback of methotrexate therapy is a troublesome inter-patient variability in the clinical response and an unpredictable appearance of side effects including gastrointestinal disturbances, alopecia, elevation of liver enzymes, and bone marrow suppression (Weinblatt et al., Arthritis Rheum.

Thus, the lack of efficient therapeutic drug monitoring of methotrexate therapy and difficulty of rapidly individualizing methotrexate dose-maximizing response hampers effective patient treatment.

Moreover, a recent study of children with acute lymphoblastic leukemia has suggested that the A variant may be associated with poor clinical outcomes as compared with patients having the G / G genotype; individuals carrying the A / A genotype presented higher plasma concentrations of methotrexate compared to those with the G / G or G / A genotypes (Laverdiere et al., supra, 2002).

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