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Related Experiment Videos

A mouse-based strategy for cyclophosphamide pharmacogenomic discovery.

James W Watters1, Ellen F Kloss, Daniel C Link

  • 1Washington Univ. School of Medicine, Dept. of Medicine, Campus Box 8069, St. Louis, MO 63110, USA.

Journal of Applied Physiology (Bethesda, Md. : 1985)
|September 13, 2003
PubMed
Summary

Inbred mice reveal genetic factors influencing chemotherapy response. This study identifies significant variations in cyclophosphamide sensitivity and hematopoietic progenitor cell mobilization across mouse strains, aiding cancer pharmacogenomics.

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Area of Science:

  • Pharmacogenomics
  • Genetics
  • Toxicology

Background:

  • Understanding the genetic basis of chemotherapy response is crucial for personalized cancer treatment.
  • Traditional human familial studies face ethical and technical limitations in cancer pharmacogenomics.
  • Inbred mouse models offer a robust system to investigate complex genetic traits in drug response.

Purpose of the Study:

  • To explore the utility of inbred mouse strains for studying the genetic determinants of response to the cytotoxic agent cyclophosphamide.
  • To assess phenotypic variation in response to cyclophosphamide across multiple inbred mouse strains.
  • To identify candidate genes and genetic variations associated with cyclophosphamide pharmacogenomics.

Main Methods:

  • Phenotypic assessment of cyclophosphamide response in up to 19 inbred mouse strains, including in vitro hematopoietic progenitor cell toxicity and in vivo progenitor cell mobilization.

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  • Evaluation of sex-based differences and dominance patterns in progenitor cell mobilization using F1 hybrid animals.
  • Genetic analysis of three cytochrome P-450 genes involved in cyclophosphamide metabolism, including resequencing and polymorphism identification in eight strains.

    • Main Results:

    • Significant inter-strain variation observed in both in vitro hematopoietic progenitor cell toxicity (2-fold) and in vivo progenitor cell mobilization (75-fold).
    • Males exhibited higher hematopoietic progenitor cell mobilization than females; low-mobilization was dominant in F1 hybrids.
    • Twenty-six polymorphisms were identified in three cytochrome P-450 genes, with distinct haplotype patterns observed across strains.

    Conclusions:

    • Inbred mouse strains exhibit substantial phenotypic and genotypic variation in response to cyclophosphamide.
    • This variation provides a valuable genetic framework for discovering genes that influence cyclophosphamide pharmacogenomics.
    • The study highlights the potential of mouse models to overcome limitations in human cancer pharmacogenomic research.