Pharmacodynamic effects of high dose lovastatin in subjects with advanced malignancies

Sarah A. Holstein, Howard R. Knapp, Gerald H. Clamon, Daryl J. Murry, Raymond Hohl

Research output: Contribution to journalArticle

62 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)155-164
Number of pages10
JournalCancer Chemotherapy and Pharmacology
Volume57
Issue number2
DOIs
StatePublished - Jan 1 2006

Fingerprint

Pharmacodynamics
Lovastatin
Bioactivity
Neoplasms
Cholesterol
Biosynthetic Pathways
Coenzyme A
Creatine Kinase
Transaminases
Cell culture
Toxicity
Oxidoreductases
Animals
Animal Models
Cell Culture Techniques
Plasmas
Liver
Enzymes
Serum

All Science Journal Classification (ASJC) codes

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

Holstein, Sarah A. ; Knapp, Howard R. ; Clamon, Gerald H. ; Murry, Daryl J. ; Hohl, Raymond. / Pharmacodynamic effects of high dose lovastatin in subjects with advanced malignancies. In: Cancer Chemotherapy and Pharmacology. 2006 ; Vol. 57, No. 2. pp. 155-164.
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Pharmacodynamic effects of high dose lovastatin in subjects with advanced malignancies. / Holstein, Sarah A.; Knapp, Howard R.; Clamon, Gerald H.; Murry, Daryl J.; Hohl, Raymond.

In: Cancer Chemotherapy and Pharmacology, Vol. 57, No. 2, 01.01.2006, p. 155-164.

Research output: Contribution to journalArticle

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