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Glutathione S-transferase (GSTM1, GSTT1 and GSTA1) polymorphisms and outcomes after treatment for acute myeloid leukemia: pharmacogenetics in Southwest Oncology Group (SWOG) clinical trials

Leukemia volume 20, pages 2169–2171 (2006)Cite this article

The prognosis for older patients with acute myeloid leukemia (AML) is poor, with overall survival (OS) rates of approximately 10% at 4–5 years, and high morbidity owing to adverse therapeutic outcomes. Therefore, identification of effective, yet less toxic, therapies is essential and could be elucidated through the application of pharmacogenetics to treatment trials. Although clinical outcomes in adult AML patients may be partially explained by recognized prognostic markers, including age, cytogenetics and de novo versus secondary disease, it is possible that inherited polymorphisms in enzymes that activate or detoxify chemotherapeutic agents, as well as those that protect from reactive oxygen species (ROS) generated by therapy, may account for some of the variability in toxicity and efficacy of treatment.

Anthracycline antibiotics, such as daunorubicin, are used in the treatment of leukemia, and are known to generate high levels of ROS, including hydrogen peroxide and hydroxyl radicals,1 which are highly destructive to cells. Glutathione S-transferases (GSTs), which are active in detoxification of organic epoxides, hydroperoxides and unsaturated aldehydes, including reactive purine and pyrimidine bases and lipid peroxidases produced by reactive oxidant damage to DNA and lipids, respectively,2 are induced under conditions of oxidative stress. Variability in GSTs owing to genetic polymorphisms resulting in reduced activity of GSTA1 and total gene deletions of GSTM1 and GSTT1 could thereby alter protection of both tumor and normal cells from ROS, and impact treatment outcomes.

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Acknowledgements

This investigation was supported in part by the following PHS Cooperative Agreement Grant numbers awarded by the National Cancer Institute, DHHS: CA38926, CA32102, and from a grant from the Southwest Oncology Group Hope Foundation.

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Authors and Affiliations

  1. Department of Epidemiology, Roswell Park Cancer Institute, Buffalo, NY, USA

    J R Weiss, K B Moysich & C B Ambrosone

  2. Southwest Oncology Group Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    K J Kopecky

  3. Department of Medicine, Loyola University Chicago, Maywood, IL, USA

    J Godwin

  4. Katmai Oncology Group, Anchorage, AK, USA

    J Anderson

  5. Department of Pathology, University of New Mexico, Albuquerque, NM, USA

    C L Willman

  6. Department of Cytogenetics, City of Hope National Medical Center, Duarte, CA, USA

    M L Slovak

  7. Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    A Hoque

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  1. J R Weiss
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Correspondence to C B Ambrosone.

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Weiss, J., Kopecky, K., Godwin, J. et al. Glutathione S-transferase (GSTM1, GSTT1 and GSTA1) polymorphisms and outcomes after treatment for acute myeloid leukemia: pharmacogenetics in Southwest Oncology Group (SWOG) clinical trials. Leukemia 20, 2169–2171 (2006). https://doi.org/10.1038/sj.leu.2404421

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