great ming! > St. Jude article co-authored by T. Frudakis
:Blood. 2007 Jan 30; [Epub ahead of print]
Ancestry and pharmacogenetics of antileukemic drug toxicity.
Kishi S,
Cheng C,
French D,
Pei D,
Das S,
Cook EH,
Hijiya N,
Rizzari C,
Rosner GL,
Frudakis T,
Pui CH,
Evans WE,
Relling MV.
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, United States.
Treatment-related toxicity in acute lymphoblastic leukemia (ALL) cannot only be life-threatening but may affect relapse risk. In 240 patients, we determined whether toxicities were related to 16 polymorphisms in genes linked to the pharmacodynamics of ALL chemotherapy, adjusting for age, race (self-reported or via ancestry-informative markers), sex and disease risk group (lower vs. higher-risk therapy). Toxicities (gastrointestinal, infectious, hepatic, and neurological) were assessed in each treatment phase. During the induction phase, when drugs subject to the steroid/cytochrome P4503A pathway predominated, genotypes in that pathway were important: vitamin D receptor (odds ratio [OR] 6.85 [95% confidence interval 1.73-27.0]) and cytochrome P4503A5 (OR 4.61 [1.11-19.2]) polymorphisms were related to gastrointestinal toxicity and infection, respectively. During the consolidation phase, when antifolates predominated, the reduced folate carrier polymorphism predicted gastrointestinal toxicity (OR 10.4 [1.35-80.4]) as it also did during continuation (OR 2.01 [1.06-4.11]). In all three treatment phases, a glucuronosyltransferase polymorphism predicted hyperbilirubinemia (p = 0.017, < 0.0001, and < 0.0001, respectively) and methotrexate clearance (p = 0.028), which was also independently associated with hyperbilirubinemia (p = 0.026). The genotype-phenotype associations were similar whether analyses were adjusted by self-reported race or ancestry-informative genetic markers. Germline polymorphisms are significant determinants of toxicity of antileukemic therapy.
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