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Interactions of Everolimus and Sorafenib in Whole Blood Lymphocyte Proliferation

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ABSTRACT

Purpose

Everolimus is an immunosuppressant that blocks growth factor-mediated proliferation of hematopoietic cells by targeting the mammalian target of rapamycin (mTOR). Sorafenib is a multikinase inhibitor that inhibits cell proliferation by arresting cells in the G0-G1 phase of the cell cycle. These agents are under investigation as combination therapy for various cancers. Because the two drugs individually inhibit lymphocyte proliferation, this study examined the effects of everolimus and sorafenib on lymphocyte proliferation in order to anticipate possible immunosuppression.

Methods

Inhibition of lymphocyte proliferation was evaluated ex vivo over a range of concentrations of these drugs, alone and in combination. Data analysis, using a population approach to characterize interactions, employed the Ariens noncompetitive interaction model, which was modified to accommodate interactions of the two drugs.

Results

Everolimus alone caused partial inhibition of lymphocyte proliferation, with a mean IC50 of 4.5 nM for females and 10.5 nM in males. Sorafenib alone caused complete inhibition, with a mean IC50 of 11.4 μM and no difference between genders.

Conclusion

The population estimate for the interaction term was greater than 1, suggesting that the two drugs exert slight antagonism in terms of inhibition of lymphocyte proliferation.

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ACKNOWLEDGMENTS AND DISCLOSURES

This work was support by a grant from the UB Center for Translational Research and NIH Grant No. GM57980.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, New York, 14214, USA

    Dipti K. Pawaskar, Robert M. Straubinger & William J. Jusko

  2. Department of Cancer Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York, 14263, USA

    Robert M. Straubinger

  3. Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York, 14263, USA

    Gerald J. Fetterly & Wen W. Ma

Authors
  1. Dipti K. Pawaskar
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  2. Robert M. Straubinger
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  3. Gerald J. Fetterly
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  4. Wen W. Ma
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  5. William J. Jusko
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Correspondence to William J. Jusko.

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Pawaskar, D.K., Straubinger, R.M., Fetterly, G.J. et al. Interactions of Everolimus and Sorafenib in Whole Blood Lymphocyte Proliferation. Pharm Res 30, 707–713 (2013). https://doi.org/10.1007/s11095-012-0909-z

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  • DOI: https://doi.org/10.1007/s11095-012-0909-z

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