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Pharmacodynamic effects of high dose lovastatin in subjects with advanced malignancies
Sarah A Holstein1, Howard R Knapp, Gerald H Clamon
1Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA.
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.
Insights
High doses of lovastatin, an HMG-CoA reductase inhibitor, were safely achieved in cancer patients. These doses reached levels necessary for potential antiproliferative activity without dose-limiting toxicity.
Area of Science:
- Pharmacology
- Oncology
- Biochemistry
Background:
- Lovastatin inhibits HMG-CoA reductase, a key enzyme in cholesterol biosynthesis.
- Lovastatin exhibits antiproliferative effects in preclinical cancer models.
- Previous studies suggest potential anticancer applications for lovastatin.
Purpose of the Study:
- To determine if lovastatin bioactivity levels, effective in preclinical studies, can be safely achieved in humans.
- To evaluate the safety and tolerability of escalating lovastatin doses in advanced cancer patients.
Main Methods:
- A dose-escalating clinical trial was conducted in subjects with advanced malignancies.
- Lovastatin was administered every 6 hours for 96 hours in 4-week cycles.
- Doses ranged from 10 mg/m² to 415 mg/m², with safety and bioactivity monitored.
Main Results:
- Peak plasma lovastatin bioactivity levels (0.06-12.3 microM) were achieved dose-independently.
- Cholesterol levels decreased during treatment and normalized during rest periods.
- No dose-limiting toxicity was observed; creatine phosphokinase and liver enzymes remained stable.
Conclusions:
- High-dose lovastatin administered every 6 hours for 96 hours is well-tolerated in cancer patients.
- Achievable bioactivity levels in some patients are within the range required for antiproliferative effects.
- Further investigation into lovastatin's therapeutic potential in oncology is warranted.
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