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Pharmacodynamic Modeling of Sequence-Dependent Antitumor Activity of Insulin-like Growth Factor Blockade and Gemcitabine

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Abstract

Agents that block insulin-like growth factor (IGF) signaling are under investigation in clinical trials. Antitumor effects are likely to be enhanced when combined with other agents, but administration sequence effects on activity are not well-described. Three breast cancer cell lines (MCF-7, MDA-MB-231, and Hs-578T) were treated with Gemcitabine and small molecule receptor tyrosine kinase inhibitor cis-3-[3-(4-methyl-piperazin-l-yl)-cyclobutyl]1-(2-phenyl-quinolin-7-yl)-imidazo [1,5-a]pyrazin-8-ylamine (PQIP) as single agents and then in combination in the forward (Gemcitabine followed by PQIP) and reverse (PQIP followed by Gemcitabine) sequences. Antitumor effects were assessed longitudinally by Bayesian analysis using WinBUGS. The pharmacodynamic model adequately predicted the observed data. The differences in the cell-kill rate constants for the forward vs. reverse sequence ranged from 0.11 to 0.64 (day−1), and statistical significance was generally dependent on cell line and PQIP concentration. These data indicate that treatment with Gemcitabine first, followed by PQIP is superior to the reverse sequence in vitro.

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Acknowledgments

The authors wish to thank Elizabeth Buck from OSI Pharmaceuticals for helpful suggestions and also to the Prospect Creek Foundation, which provided funding for these studies.

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Authors and Affiliations

  1. Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, 717 Delaware St S.E., Room 459, Minneapolis, MN, 55455, USA

    Amit Khatri, Richard C. Brundage, Jessica M. Hull, Brent W. Williams & Mark N. Kirstein

  2. Masonic Comprehensive Cancer Center, University of Minnesota, Minneapolis, MN, USA

    Douglas Yee & Mark N. Kirstein

  3. Department of Medicine and Pharmacology, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA

    Douglas Yee

Authors
  1. Amit Khatri
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  2. Richard C. Brundage
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  3. Jessica M. Hull
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  4. Brent W. Williams
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  5. Douglas Yee
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  6. Mark N. Kirstein
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Corresponding author

Correspondence to Mark N. Kirstein.

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Khatri, A., Brundage, R.C., Hull, J.M. et al. Pharmacodynamic Modeling of Sequence-Dependent Antitumor Activity of Insulin-like Growth Factor Blockade and Gemcitabine. AAPS J 14, 1–9 (2012). https://doi.org/10.1208/s12248-011-9308-3

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  • DOI: https://doi.org/10.1208/s12248-011-9308-3

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