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Cancer Chemother Pharmacol. 2006 Jan;57(2):155-64. Epub 2005 Aug 30.

Pharmacodynamic effects of high dose lovastatin in subjects with advanced malignancies.

Author information

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

Erratum in

  • Cancer Chemother Pharmacol. 2007 Mar;59(4):559.

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 microM 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.

PMID:
16133537
DOI:
10.1007/s00280-005-0013-8
[Indexed for MEDLINE]

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