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Pharmacokinetics and pharmacodynamics of 17-demethoxy 17-[[(2-dimethylamino)ethyl]amino]geldanamycin (17DMAG, NSC 707545) in C.B-17 SCID mice bearing MDA-MB-231 human breast cancer xenografts

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Abstract

Purpose

17-demethoxy 17-[[(2-dimethylamino)ethyl]amino]geldanamycin (17DMAG, NSC 707545) is a water-soluble analogue of 17-(allylamino)-17-demethoxygeldanamycin (17AAG), a compound currently in clinical trials. These preclinical studies: (1) characterized 17DMAG concentrations in plasma, normal tissues, and tumor after i.v. delivery to mice; and (2) correlated tumor and normal tissue 17DMAG concentrations with alterations in heat shock protein 90 (HSP90) and selected HSP90-chaperoned proteins.

Methods

At specified times after i.v. administration of 75 mg/kg 17DMAG, SCID mice bearing s.c. MDA-MB-231 human breast xenografts were killed and plasma and tissues were retained. 17DMAG concentrations were determined by HPLC. Raf-1, heat shock protein 70 (HSP70), and HSP90 in tissues were determined by Western blotting.

Results

Peak plasma 17DMAG concentration was 15.4±1.4 μg/ml. The area under the plasma 17DMAG concentration versus time curve was 1072 μg/ml min, corresponding to a total body clearance of 70 ml/kg/min. Peak 17DMAG concentrations in liver (118.8±5.7 μg/g), kidney (122.9±10.6 μg/g), heart (81.3±8.1 μg/g), and lung (110.6±25.4 μg/g) occurred at 5–10 min, while peak concentrations in spleen (70.6±9.6 μg/g) and tumor (9.0±1.0 μg/g) occurred at 30–45 min. At 48 h, 17DMAG was detectable in tumor but not in any normal tissue. Raf-1 in tumors of 17DMAG-treated mice killed at 4, 7, 24 and 48 h was about 20% lower than in tumors from vehicle-treated mice. HSP90 and HSP70 in tumors of 17DMAG-treated animals were significantly lower than in tumors of control animals at 4, 7, and 24 h. Hepatic Raf-1 was decreased by more than 60% at all times after 17DMAG treatment; however, hepatic HSP90 was not affected. HSP70 was undetectable in livers of vehicle-treated mice or mice killed at 2 or 4 h after 17DMAG treatment, but was detected in livers at 7, 24 and 48 h. 17DMAG did not affect renal Raf-1. In contrast, renal HSP70 and HSP90 were decreased by more than 50% at 2 and 4 h after 17DMAG treatment. Renal HSP70 increased approximately twofold above that in kidneys from vehicle-treated control mice at 7 and 24 h, while HSP90 relative protein concentration was no different from that in controls.

Conclusions

Plasma pharmacokinetics of 17DMAG in tumor-bearing mice were similar to those previously reported in nontumor-bearing mice. 17DMAG was distributed widely to tissues but was retained for longer in tumors than normal tissues. Raf-1, HSP90, and HSP70 were altered to different degrees in tumors, livers, and kidneys of 17DMAG-treated animals. These data illustrate the complex nature of the biological responses to 17DMAG.

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Acknowledgements

We thank Diane Mazzei and her colleagues in the University of Pittsburgh Animal Facility; without their expert assistance, these studies would not have been possible. We also thank Mr Ezekiel Woods for excellent secretarial assistance and the UPCI Hematology/Oncology Writing Group for constructive suggestions regarding the manuscript.

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Authors and Affiliations

  1. Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA

    Julie L. Eiseman, Jing Lan & Merrill J. Egorin

  2. Molecular Therapeutics/Drug Discovery Program, University of Pittsburgh Cancer Institute, G27b Hillman Research Pavilion, 5117 Centre Ave., Pittsburgh, PA 15213, USA

    Julie L. Eiseman, Jing Lan, Theodore F. Lagattuta, Deborah R. Hamburger, Erin Joseph & Merrill J. Egorin

  3. Toxicology and Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD 20892, USA

    Joseph M. Covey

  4. Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA

    Merrill J. Egorin

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  1. Julie L. Eiseman
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Correspondence to Julie L. Eiseman.

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This work was supported by contract NO1-CM07106 and Grant 2P30 CA47904, awarded by the National Cancer Institute.

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Eiseman, J.L., Lan, J., Lagattuta, T.F. et al. Pharmacokinetics and pharmacodynamics of 17-demethoxy 17-[[(2-dimethylamino)ethyl]amino]geldanamycin (17DMAG, NSC 707545) in C.B-17 SCID mice bearing MDA-MB-231 human breast cancer xenografts. Cancer Chemother Pharmacol 55, 21–32 (2005). https://doi.org/10.1007/s00280-004-0865-3

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