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Research ArticleCHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Dose Optimization of a Doxorubicin Prodrug (HMR 1826) in Isolated Perfused Human Lungs: Low Tumor pH Promotes Prodrug Activation by β-Glucuronidase

Thomas E. Mürdter, Godehard Friedel, Janne T. Backman, Monika McClellan, Monika Schick, Manfred Gerken, Klaus Bosslet, Peter Fritz, Heikki Toomes, Heyo K. Kroemer and Bernhard Sperker
Journal of Pharmacology and Experimental Therapeutics April 2002, 301 (1) 223-228; DOI: https://doi.org/10.1124/jpet.301.1.223
Thomas E. Mürdter
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Godehard Friedel
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Janne T. Backman
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Monika McClellan
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Monika Schick
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Manfred Gerken
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Klaus Bosslet
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Peter Fritz
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Heikki Toomes
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Heyo K. Kroemer
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Bernhard Sperker
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Abstract

HMR 1826 (N-[4-β-Glucuronyl-3-nitrobenzyl-oxycarbonyl]doxorubicin) is a nontoxic glucuronide prodrug from which active doxorubicin is released by β-glucuronidase. Preclinical studies aimed at dose optimization of HMR 1826, based on intratumoral pharmacokinetics, are important to design clinical studies. Using an isolated perfused human lung model, the uptake of doxorubicin into normal tissue and tumors after perfusion with 133 μg/ml (n = 6), 400 μg/ml (n = 10), and 1200 μg/ml (n = 6) HMR 1826 was compared. Extracellular tissue pH was measured, and enzyme kinetic studies were performed in vitro to investigate the effect of pH on the formation of doxorubicin. Extracellular pH was lower in tumors than in healthy tissue (6.46 ± 0.35, n = 8 versus 7.30 ± 0.33,n = 10; p < 0.001). In vitro, β-glucuronidase activity was 10 times higher at pH 6.0 than at neutral pH. After perfusion with HMR 1826, there was a linear relationship between HMR 1826 concentrations in perfusate and normal lung tissue. After perfusion with 133, 400, and 1200 μg/ml HMR 1826, the final doxorubicin concentrations in normal and tumor tissue were 2.7 ± 0.9, 11.1 ± 5.4, and 21.8 ± 8.4 μg/g (p < 0.05 for all comparisons), and 0.7 ± 0.3, 8.6 ± 2.0 μg/g (p < 0.01 versus 133 μg/g), and 8.7 ± 4.9 μg/g, respectively. This agrees with the enzyme kinetic observations of saturation of β-glucuronidase at 400 μg/ml HMR 1826 in the acidic environment of the tumor. Therefore, the escalation of the HMR 1826 dose most likely results in higher circulating concentrations than 400 μg/ml but does not increase the uptake of doxorubicin into tumors and, subsequently, antitumor efficacy. The isolated perfused human lung is an excellent model for preclinical investigations aimed at optimization of tissue pharmacokinetics of tumor-selective prodrugs.

Footnotes

  • ↵1 Present address: Department of Clinical Pharmacology, University of Helsinki, Haartmaninkatu 4, FIN-00290 Helsinki, Finland.

  • ↵2 Present address: Aventis Pharma Deutschland GmbH, D-65926 Frankfurt/Main, Germany.

  • ↵3 Present address: Schering AG, D-13342 Berlin, Germany.

  • This work was supported by the Robert Bosch Foundation, Stuttgart, the Mildred Scheel Foundation, Bonn (W 7/91/TO1), the Deutsche Forschungsgemeinschaft, Bonn (Kr 945/4-3), and the Landesversicherungsanstalt Württemberg.

  • Abbreviations:
    HMR 1826
    N-[4-β-glucuronyl-3-nitrobenzyl-oxycarbonyl]doxorubicin
    HPLC
    high pressure liquid chromatography
    • Received June 29, 2001.
    • Accepted January 4, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 301 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 301, Issue 1
1 Apr 2002
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Research ArticleCHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Dose Optimization of a Doxorubicin Prodrug (HMR 1826) in Isolated Perfused Human Lungs: Low Tumor pH Promotes Prodrug Activation by β-Glucuronidase

Thomas E. Mürdter, Godehard Friedel, Janne T. Backman, Monika McClellan, Monika Schick, Manfred Gerken, Klaus Bosslet, Peter Fritz, Heikki Toomes, Heyo K. Kroemer and Bernhard Sperker
Journal of Pharmacology and Experimental Therapeutics April 1, 2002, 301 (1) 223-228; DOI: https://doi.org/10.1124/jpet.301.1.223

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Research ArticleCHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Dose Optimization of a Doxorubicin Prodrug (HMR 1826) in Isolated Perfused Human Lungs: Low Tumor pH Promotes Prodrug Activation by β-Glucuronidase

Thomas E. Mürdter, Godehard Friedel, Janne T. Backman, Monika McClellan, Monika Schick, Manfred Gerken, Klaus Bosslet, Peter Fritz, Heikki Toomes, Heyo K. Kroemer and Bernhard Sperker
Journal of Pharmacology and Experimental Therapeutics April 1, 2002, 301 (1) 223-228; DOI: https://doi.org/10.1124/jpet.301.1.223
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