Effect of race on vincristine‐associated neurotoxicity in pediatric acute lymphoblastic leukemia patients

Renbarger, Jamie L.; McCammack, Kevin; Rouse, Caroline E.; Hall, Stephen D.

doi:10.1002/pbc.21435

Cited by 110 publications

(97 citation statements)

References 13 publications

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“…90 The frequency of the risk allele was lower in individuals with African ancestry compared with the other ancestral groups, consistent with a lower incidence of vincristine neuropathy in African American patients. 91 A candidate-gene study found that variants in ABCB1, ACTG1, and CAPG were associated with vincristine neurotoxicity during ALL therapy, 92 although other candidate-gene studies found no associations with ABCB1 variants, despite its likely role in vincristine transport. 93,94 Although CYP3A5 affects vincristine metabolism, candidate-gene studies indicate that there are conflicting data on its association with neuropathy.…”

Section: Vincristinementioning

confidence: 99%

Inherited genetic variation in childhood acute lymphoblastic leukemia

Moriyama

Relling

Yang

2015

Blood

123

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Although somatically acquired genomic alterations have long been recognized as the hallmarks of acute lymphoblastic leukemia (ALL), the last decade has shown that inherited genetic variations (germline) are important determinants of interpatient variability in ALL susceptibility, drug response, and toxicities of ALL therapy. In particular, unbiased genome-wide association studies have identified germline variants strongly associated with the predisposition to ALL in children, providing novel insight into the mechanisms of leukemogenesis and evidence for complex interactions between inherited and acquired genetic variations in ALL. Similar genome-wide approaches have also discovered novel germline genetic risk factors that independently influence ALL prognosis and those that strongly modify host susceptibility to adverse effects of antileukemic agents (eg, vincristine, asparaginase, glucocorticoids). There are examples of germline genomic associations that warrant routine clinical use in the treatment of childhood ALL (eg, TPMT and mercaptopurine dosing), but most have not reached this level of actionability. Future studies are needed to integrate both somatic and germline variants to predict risk of relapse and host toxicities, with the eventual goal of implementing genetics-driven precision-medicine approaches in ALL treatment.

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Section: Vincristinementioning

confidence: 99%

Inherited genetic variation in childhood acute lymphoblastic leukemia

Moriyama

Relling

Yang

2015

Blood

123

View full text Add to dashboard Cite

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“…Individuals who express CYP3A5 may metabolize vincristine more efficiently than nonexpressers, resulting in lower vincristine exposure and thus potentially less drug efficacy and toxicity. Clinical data demonstrate less vincristineinduced peripheral neuropathy in African Americans, and a recent retrospective study in children diagnosed with acute lymphoblastic leukemia and treated with vincristine revealed greater neuropathy in children with CYP3A5 low expresser genotypes (Renbarger et al, 2008;Egbelakin et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

The Relative Contributions of CYP3A4 and CYP3A5 to the Metabolism of Vinorelbine

et al. 2013

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Vinorelbine is a semisynthetic vinca alkaloid used in the treatment of advanced breast and non-small cell lung cancers. Vincristine, a related vinca alkaloid, is 9-fold more efficiently metabolized by CYP3A5 than by CYP3A4 in vitro. This study quantified the relative contribution of CYP3A4 and CYP3A5 to the metabolism of vinorelbine in vitro using cDNA-expressed human cytochrome P450s (P450s) and human liver microsomes (HLMs). CYP3A4 and CYP3A5 were identified as the P450s capable of oxidizing vinorelbine using a panel of human enzymes and selective P450 inhibitors in HLMs. For CYP3A4 coexpressed with cytochrome b 5 (CYP3A4+b 5 ) and CYP3A5 +b 5 , the Michaelis-Menten constants for vinorelbine were 2.6 and 3.6 mM, respectively, but the V max of 1.4 pmol/min/pmol was common to both enzymes. In HLMs, the intrinsic clearance of vinorelbine metabolism was highly correlated with CYP3A4 activity, and there was no significant difference in intrinsic clearance between CYP3A5 high and low expressers. When radiolabeled vinorelbine substrate was used, there were clear qualitative differences in metabolite formation fingerprints between CYP3A4+b 5 and CYP3A5+b 5 as determined by NMR and mass spectrometry analysis. One major metabolite (M2), a didehydro-vinorelbine, was present in both recombinant and microsomal systems but was more abundant in CYP3A4+b 5 incubations. We conclude that despite the equivalent efficiency of recombinant CYP3A4 and CYP3A5 in vinorelbine metabolism the polymorphic expression of CYP3A5, as shown by the kinetics with HLMs, may have a minimal effect on systemic clearance of vinorelbine.

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“…For example, in an ALL pediatric study, the mortality rates of African-American children with vincristine combination chemotherapy were 42% greater than those of Caucasian children after correcting for known prognostic factors such as compliance, clinical presentation, and tumor characteristics (Pollock et al, 2000). In addition, in a retrospective analysis with ALL patients, Caucasian children compared with African-American children were more likely to experience vincristine-associated neurotoxicity (Renbarger et al, 2008). Thus, interracial variability in vincristine exposure due to differences in metabolism may in part explain the differences in clinical outcomes between African-American and Caucasian children.…”

mentioning

confidence: 99%

Apparent High CYP3A5 Expression Is Required for Significant Metabolism of Vincristine by Human Cryopreserved Hepatocytes

Dennison¹,

Mohutsky²,

Barbuch³

et al. 2008

J Pharmacol Exp Ther

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Vincristine is metabolized to one primary metabolite, M1, by cDNA-expressed CYP3A4 and CYP3A5 and by CYP3A enzymes in human liver microsomes. For both systems, CYP3A5 is predicted to mediate approximately 80% of the CYP3A metabolism for individuals with high CYP3A5 expression (at least one CYP3A5*1 allele). In the current study, the role of CYP3A5 was quantified in the metabolism of vincristine with human cryopreserved hepatocytes. The hepatocytes were genotyped for common CYP3A5 allelic variants (CYP3A5*3, CYP3A5*6, and CYP3A5*7) to predict CYP3A5 expression. For each hepatocyte preparation, the rates of vincristine depletion and metabolite formation were quantified. Whereas human hepatocytes with predicted low CYP3A5 expression did not detectably metabolize vincristine, human hepatocytes with predicted high CYP3A5 expression metabolized vincristine to one primary metabolite, M1. In paired experiments using cryopreserved hepatocytes from the same donor, vincristine was incubated with intact cells and cell lysates supplemented with NADPH. The rates of M1 formation were 4 to 69-fold higher for the cell lysates compared with the intact cells. For one representative donor, the intact cells had a 3-fold higher K m value and a 3-fold lower V max value for M1 formation compared with the cell lysates. Thus, the rate of M1 formation in the hepatocytes may be influenced by the rate of vincristine translocation across the plasma membrane. We conclude that genetically determined CYP3A5 expression in human cryopreserved hepatocytes plays a major role in vincristine metabolism.

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Effect of race on vincristine‐associated neurotoxicity in pediatric acute lymphoblastic leukemia patients

Abstract: The data support the hypothesis pharmacogenetic polymorphisms in CYP3A5 expression contribute to variability in vincristine metabolism and neurotoxicity.

Cited by 110 publications

References 13 publications

Inherited genetic variation in childhood acute lymphoblastic leukemia

Inherited genetic variation in childhood acute lymphoblastic leukemia

The Relative Contributions of CYP3A4 and CYP3A5 to the Metabolism of Vinorelbine

Apparent High CYP3A5 Expression Is Required for Significant Metabolism of Vincristine by Human Cryopreserved Hepatocytes

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