title: Phase I study of lovastatin, an inhibitor of the mevalonate pathway, in patients with cancer.
abstract: Lovastatin, an inhibitor of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (the major regulatory enzyme of the mevalonate pathway of cholesterol synthesis), displays antitumor activity in experimental models. We therefore conducted a Phase I trial to characterize the tolerability of lovastatin administered at progressively higher doses to cancer patients. From January 1992 to July 1994, 88 patients with solid tumors (median age, 57 +/- 14 years) were treated p.o. with 7-day courses of lovastatin given monthly at doses ranging from 2 to 45 mg/kg/day. The inhibitory effects of lovastatin were monitored through serum concentrations of cholesterol and ubiquinone, two end products of the mevalonate pathway. Concentrations of lovastatin and its active metabolites were also determined, by bioassay, in the serum of selected patients. Cyclical treatment with lovastatin markedly inhibited the mevalonate pathway, evidenced by reductions in both cholesterol and ubiquinone concentrations, by up to 43 and 49% of pretreatment values, respectively. The effect was transient, however, and its magnitude appeared to be dose independent. Drug concentrations reached up to 3.9 micrometer and were in the range associated with antiproliferative activity in vitro. Myopathy was the dose-limiting toxicity. Other toxicities included nausea, diarrhea, and fatigue. Treatment with ubiquinone was associated with reversal of lovastatin-induced myopathy, and its prophylactic administration prevented the development of this toxicity in a cohort of 56 patients. One minor response was documented in a patient with recurrent high-grade glioma. Lovastatin given p.o. at a dose of 25 mg/kg daily for 7 consecutive days is well tolerated. The occurrence of myopathy, the dose-limiting toxicity, can be prevented by ubiquinone supplementation. To improve on the transient inhibitory activity of this dosing regimen on the mevalonate pathway, alternative schedules based on uninterrupted administration of lovastatin should also be studied.
authors.affiliation: Clinical Pharmacology Branch and Biometrics Section, National Cancer Institute, Warren Magnussen Clinical Center, NIH, Bethesda, Maryland 20892-1576, USA.
authors.forename: A
authors.initials: A
authors.lastname: Thibault
authors.forename: D
authors.initials: D
authors.lastname: Samid
authors.forename: A C
authors.initials: AC
authors.lastname: Tompkins
authors.forename: W D
authors.initials: WD
authors.lastname: Figg
authors.forename: M R
authors.initials: MR
authors.lastname: Cooper
authors.forename: R J
authors.initials: RJ
authors.lastname: Hohl
authors.forename: J
authors.initials: J
authors.lastname: Trepel
authors.forename: B
authors.initials: B
authors.lastname: Liang
authors.forename: N
authors.initials: N
authors.lastname: Patronas
authors.forename: D J
authors.initials: DJ
authors.lastname: Venzon
authors.forename: E
authors.initials: E
authors.lastname: Reed
authors.forename: C E
authors.initials: CE
authors.lastname: Myers
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects*; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects*; D008148:Lovastatin / Q000009:adverse effects* / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D014451:Ubiquinone / Q000097:blood
chemical_list: D000970:Antineoplastic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D014451:Ubiquinone; D008148:Lovastatin