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Dexamethasone as a chemoprotectant in cancer chemotherapy: hematoprotective effects and altered pharmacokinetics and tissue distribution of carboplatin and gemcitabine

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Abstract

Purpose

Hematoprotective strategies may offer new approaches to prevent chemotherapy-induced hematotoxicity. The present study was undertaken to investigate the chemoprotective effects of dexamethasone and its optimal dose and the underlying mechanisms.

Methods

Lethal toxicity and hematotoxicity of carboplatin were compared in CD-1 mice with or without dexamethasone pretreatment. Plasma and tissue pharmacokinetics of carboplatin were determined in CD-1 mice. Carboplatin was quantified by HPLC. Gemcitabine was analyzed by radioactivity counting.

Results

Pretreatment with dexamethasone prevented lethal toxicity of carboplatin in a dose- and schedule-dependent manner. The best protective effects of dexamethasone pretreatment as measured by survival were observed at the dose level of 0.1 mg/mouse per day for 5 days (80% vs 10% in controls). In contrast, posttreatment with dexamethasone had no protective effects. Pretreatment with dexamethasone significantly prevented the decrease in granulocyte counts. To elucidate the mechanisms by which dexamethasone pretreatment reduces hematotoxicity, we examined the effects of dexamethasone pretreatment on the pharmacokinetics of carboplatin and gemcitabine in CD-1 mice. No significant differences in plasma pharmacokinetics of carboplatin or gemcitabine were observed between control and mice pretreated with dexamethasone. However, dexamethasone pretreatment significantly decreased carboplatin and gemcitabine uptake in spleen and bone marrow with significant decreases in AUC, T1/2, and Cmax, and an increase in CL.

Conclusions

To our knowledge, this is the first time that dexamethasone has been shown to significantly decrease host tissue uptake of chemotherapeutic agents, suggesting a mechanism responsible for the chemoprotective effects of dexamethasone. This study provides a basis for future study to evaluate dexamethasone as a chemoprotectant in cancer patients.

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Acknowledgements

We would like to thank Jie Hang, Zhuo Zhang, Gautam Prasad, Zhenqi Shi, Bing Pang, and Lin Lin for their excellent technical assistance. We also thank Dr. Al LoBuglio and Dr. Donald L. Hill for helpful discussions.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Division of Clinical Pharmacology, Comprehensive Cancer Center, University of Alabama, Birmingham, AL 35294, USA

    Hui Wang, Mao Li & Ruiwen Zhang

  2. Division of Hematology and Oncology, Department of Medicine, Comprehensive Cancer Center, University of Alabama, Birmingham, AL 35294, USA

    John J. Rinehart

Authors
  1. Hui Wang
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  2. Mao Li
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  3. John J. Rinehart
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  4. Ruiwen Zhang
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Corresponding author

Correspondence to Ruiwen Zhang.

Additional information

This study was partly supported by funds for the Cancer Pharmacology Laboratory from UAB Comprehensive Cancer Center.

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Wang, H., Li, M., Rinehart, J.J. et al. Dexamethasone as a chemoprotectant in cancer chemotherapy: hematoprotective effects and altered pharmacokinetics and tissue distribution of carboplatin and gemcitabine. Cancer Chemother Pharmacol 53, 459–467 (2004). https://doi.org/10.1007/s00280-003-0759-9

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  • DOI: https://doi.org/10.1007/s00280-003-0759-9

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