Biochemistry - Nucleotide Metabolism

Pharmacogenetic testing: proofs of principle and pharmacoeconomic implications.

Dervieux, T M et al., 2005. Mutat Res 573(1-2):180-94.

Several proofs of principle have established that pharmacogenetic testing for mutations altering expression and functions of genes associated with drug disposition and response can decrease the "trial-and-error" dosing and reduce the risk of adverse drug reactions. These proofs of principle include thiopurine methyltransferase and thiopurine therapy, dihydropyrimidine dehydrogenase/thymidylate synthase and 5-fluorouracil therapy, folate enzyme MTHFR and methotrexate therapy, UGT1A1 and irinotecan therapy and CYP450 2C9 and S-warfarin therapy. These evidences advocate for the prospective identification of mutations associated with drug response, serious adverse reactions and treatment failure. More recent evidence with the HLA basis of hypersensitivity to the retroviral agent abacavir demonstrates the potential of pharmacogenetic testing and its pharmacoeconomic implications. With the convergence of rising drug costs and evidence supporting the clinical benefits of pharmacogenetic testing, it will be important to demonstrate the improved net health outcomes attributed to the additional costs for this testing.

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Comments:

Although the title suggest pharmacogenomics, this is an excellent overview of genomics as applied to Biochemistry as well as Pharmacology.  It is very well illustrated and explains the role of genetic polymorphisms for the enzymes in biochemical pathways that metabolize xenobiotics, especially chemotherapeutic drugs.  The latter include 5-flurouracil, thiopurines, methotrexate and irinotecan, plus the anti-clotting agent warfarin and the anti-HIV drug abacavir.

Pyrimidine pathways in health and disease.

Loffler, M et al., 2005. Trends Molec. Med. 11(9):430-437.

Abstract

Genetic defects involving enzymes essential for pyrimidine nucleotide metabolism have provided new insights into the vital physiological functions of these molecules in addition to nucleic acid synthesis. Such aberrations disrupt the haematological, nervous or mitochondrial systems and can cause adverse reactions to analogue therapy. Regulation of pyrimidine pathways is also known to be disrupted in malignancies. Nine genetic defects have now been identified but only one is currently treatable. Diagnosis is aided by the accumulation of specific metabolites. Recently, progress has been made in understanding the molecular mechanisms underlying inborn errors of pyrimidine metabolism, together with the key clinical issues and the implications for the future development of novel drugs and therapeutic strategies.

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Comparative genomics reveals novel biochemical pathways.

Piskur, J et al., 2007. Trends in Genet. 23(8):369-372.

Abstract

How well do we understand which enzymes are involved in the primary metabolism of the cell? A recent study using comparative genomics and postgenomics approaches revealed a novel pathway in the most studied organism, Escherichia coli. The analysis of a new operon consisting of seven previously uncharacterized genes thought to be involved in the degradation of nucleic acid precursors shows the impact of comparative genomics on the discovery of novel pathways and enzymes.

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Thiopurine methyltransferase (TPMT) genotype and early treatment response to mercaptopurine in childhood acute lymphoblastic leukemia.

Stanulla, M et al., 2005. J. Amer. Med. Assn. 293(12):1485-1489.

Abstract

Context Early response to multiagent chemotherapy, including mercaptopurine, as measured by minimal residual disease is an important prognostic factor for children with acute lymphoblastic leukemia (ALL). Thiopurine methyltransferase (TPMT) is involved in the metabolism of mercaptopurine and subject to genetic polymorphism, with heterozygous individuals having intermediate and homozygous mutant individuals having very low TPMT activity. Objective To assess the association of TPMT genotype with minimal residual disease load before and after treatment with mercaptopurine in the early treatment course of childhood ALL. Design, Setting, and Patients TPMT genotyping of childhood ALL patients (n = 814) in Germany consecutively enrolled in the ALL-BFM (Berlin-Frankfurt-Munster) 2000 study from October 1999 to September 2002. Minimal residual disease was analyzed on treatment days 33 and 78 for risk-adapted treatment stratification. A 4-week cycle of mercaptopurine was administered between these 2 minimal residual disease measurements. Patients (n = 4) homozygous for a mutant TPMT allele, and consequently deficient in TPMT activity, were treated with reduced doses of mercaptopurine and, therefore, not included in the analyses. Main Outcome Measures Minimal residual disease load before (day 33) and after (day 78) mercaptopurine treatment. Loads smaller than 10-4 were defined as negative. Results Patients (n = 55) heterozygous for allelic variants of TPMT conferring lower enzyme activity had a significantly lower rate of minimal residual disease positivity (9.1%) compared with patients (n = 755) with homozygous wild-type alleles (22.8%) on day 78 (P = .02). This translated into a 2.9-fold reduction in risk for patients with wild-type heterozygous alleles (relative risk, 0.34; 95% confidence interval, 0.13-0.86). Conclusions TPMT genotype has a substantial impact on minimal residual disease after administration of mercaptopurine in the early course of childhood ALL, most likely through modulation of mercaptopurine dose intensity. Our findings support a role for minimal residual disease analyses in the assessment of genotype-phenotype associations in multiagent chemotherapeutic trials.

Journal Link  | PMID