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Pharmacodynamic effects of high dose lovastatin in subjects with advanced malignancies

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Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

An Erratum to this article was published on 12 September 2006

Abstract

Lovastatin, an inhibitor of the rate-limiting enzyme in the cholesterol biosynthetic pathway, hydroxymethylglutaryl coenzyme A reductase, has shown interesting antiproliferative activities in cell culture and in animal models of cancer. The goal of the current study is to determine whether lovastatin bioactivity levels, in a range equivalent to those used in in vitro and preclinical studies, can be safely achieved in human subjects. Here we present the findings from a dose-escalating trial of lovastatin in subjects with advanced malignancies. Lovastatin was administered every 6 h for 96 h in 4-week cycles in doses ranging from 10 mg/m2 to 415 mg/m2. Peak plasma lovastatin bioactivity levels of 0.06–12.3 μM were achieved in a dose-independent manner. Cholesterol levels decreased during treatment and normalized during the rest period. A dose-limiting toxicity was not reached and there were no clinically significant increases in creatine phosphokinase or serum hepatic aminotransferases levels. No antitumor responses were observed. These results demonstrate that high doses of lovastatin, given every 4 h for 96 h, are well-tolerated and in select cases, bioactivity levels in the range necessary for antiproliferative activity were achieved.

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Acknowledgements

We thank Kriste A. Lewis and Deborah Kratz for their assistance with the plasma lovastatin bioactivity studies. There are no conflicts of interest for Sarah A. Holstein, Howard R. Knapp, Gerald H. Clamon, Daryl J. Murry, or Raymond J. Hohl. Supported by a grant M01-RR-59, National Center for Research Resources, General Clinical Research Centers Program, National Institutes of Health (NIH), Grant P20 CA103672 from the NIH-NCI and NIA, as well as the Roy J. Carver Charitable Trust as a Research Program of Excellence and the Roland W. Holden Family Program for Experimental Cancer Therapeutics.

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Authors and Affiliations

  1. Department of Internal Medicine, University of Iowa, Iowa City, IA, 52242, USA

    Sarah A. Holstein, Gerald H. Clamon & Raymond J. Hohl

  2. College of Pharmacy, University of Iowa, Iowa City, IA, 52242, USA

    Daryl J. Murry

  3. Research Division, Deaconess Billings Clinic, Billings, MT, 59101, USA

    Howard R. Knapp

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  1. Sarah A. Holstein
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  2. Howard R. Knapp
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  5. Raymond J. Hohl
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Correspondence to Raymond J. Hohl.

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An erratum to this article can be found at http://dx.doi.org/10.1007/s00280-006-0330-6

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Holstein, S.A., Knapp, H.R., Clamon, G.H. et al. Pharmacodynamic effects of high dose lovastatin in subjects with advanced malignancies. Cancer Chemother Pharmacol 57, 155–164 (2006). https://doi.org/10.1007/s00280-005-0013-8

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