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Pharmacogenetics of target genes across doxorubicin disposition pathway: a review

Suman Lal1, Anupama Mahajan, Wei Ning Chen

  • 1Laboratory of Clinical Pharmacology, Division of Medical Sciences, Humphrey Oei Institute of Cancer Research National Cancer Centre, 11 Hospital Drive, Singapore 169610.

Current Drug Metabolism
|March 23, 2010
PubMed

Insights

Genetic variations in drug transporters and metabolizing enzymes influence doxorubicin treatment outcomes in Asian breast cancer patients. Understanding these pharmacogenetic factors is key to personalizing chemotherapy and reducing adverse effects like cardiomyopathy.

Area of Science:

  • Pharmacogenetics and Pharmacogenomics
  • Molecular Oncology
  • Personalized Medicine

Background:

  • Doxorubicin (Adriamycin) is a vital chemotherapy agent, but its efficacy and toxicity vary significantly among patients.
  • Tumor heterogeneity and advances in pharmacogenetics necessitate individualized anticancer therapies.
  • The pharmacogenetics of doxorubicin, particularly in diverse ethnic populations, remains incompletely understood.

Purpose of the Study:

  • To comprehensively review the pharmacogenetics of doxorubicin's biochemical pathway in Asian breast cancer patients.
  • To investigate the influence of genetic variants in key regulatory, transport, and metabolic genes on doxorubicin disposition.
  • To explore the role of ethnicity in doxorubicin pharmacogenetics and treatment individualization.

Main Methods:

  • Review of literature on pharmacogenetics of doxorubicin in Asian breast cancer patients.
  • Examination of genetic variants in Pregnane-X Receptor (PXR), drug transporters (SLC22A16, ABCB1, ABCG2, ABCC5, ABCB5, RLIP76), and metabolizing enzymes (CBR1, CBR3).
  • Discussion of the impact of functional genetic variants on doxorubicin pharmacokinetics and metabolite variability.

Main Results:

  • Functional genetic variants in PXR, drug transporters, and metabolizing enzymes are hypothesized to contribute to inter-individual variability in doxorubicin pharmacokinetics.
  • Ethnic differences in pharmacogenetics, particularly between Asian and Caucasian/African populations, impact chemotherapy predictive endpoints.
  • Genetic variations influence doxorubicin efficacy and the risk of adverse effects such as cardiomyopathy.

Conclusions:

  • Pharmacogenetic profiling of doxorubicin pathway genes in Asian populations is crucial for optimizing adjuvant chemotherapy.
  • Individualizing doxorubicin dosage based on genetic factors and non-genetic influences can maximize therapeutic benefits and minimize toxicity.
  • Further validation in diverse patient groups is essential for tailoring treatment regimens and improving clinical outcomes.

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