Phase I study of lovastatin, an inhibitor of the mevalonate pathway, in patients with cancer

Alain Thibault, Dvorit Samid, Anne C. Tompkins, William D. Figg, Michael R. Cooper, Raymond Hohl, Jane Trepel, Bertrand Liang, Nicholas Patronas, David J. Venzon, Eddie Reed, Charles E. Myers

Research output: Contribution to journalArticle

332 Citations (Scopus)

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 μM 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.

Original languageEnglish (US)
Pages (from-to)483-491
Number of pages9
JournalClinical Cancer Research
Volume2
Issue number3
StatePublished - Mar 1 1996

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Lovastatin
Mevalonic Acid
Ubiquinone
Neoplasms
Muscular Diseases
Cholesterol
Enzyme Inhibitors
Serum
Glioma
Biological Assay
Nausea
Fatigue
Diarrhea
Appointments and Schedules
Oxidoreductases
Theoretical Models

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Thibault, A., Samid, D., Tompkins, A. C., Figg, W. D., Cooper, M. R., Hohl, R., ... Myers, C. E. (1996). Phase I study of lovastatin, an inhibitor of the mevalonate pathway, in patients with cancer. Clinical Cancer Research, 2(3), 483-491.
Thibault, Alain ; Samid, Dvorit ; Tompkins, Anne C. ; Figg, William D. ; Cooper, Michael R. ; Hohl, Raymond ; Trepel, Jane ; Liang, Bertrand ; Patronas, Nicholas ; Venzon, David J. ; Reed, Eddie ; Myers, Charles E. / Phase I study of lovastatin, an inhibitor of the mevalonate pathway, in patients with cancer. In: Clinical Cancer Research. 1996 ; Vol. 2, No. 3. pp. 483-491.
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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 μM 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.",
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Thibault, A, Samid, D, Tompkins, AC, Figg, WD, Cooper, MR, Hohl, R, Trepel, J, Liang, B, Patronas, N, Venzon, DJ, Reed, E & Myers, CE 1996, 'Phase I study of lovastatin, an inhibitor of the mevalonate pathway, in patients with cancer', Clinical Cancer Research, vol. 2, no. 3, pp. 483-491.

Phase I study of lovastatin, an inhibitor of the mevalonate pathway, in patients with cancer. / Thibault, Alain; Samid, Dvorit; Tompkins, Anne C.; Figg, William D.; Cooper, Michael R.; Hohl, Raymond; Trepel, Jane; Liang, Bertrand; Patronas, Nicholas; Venzon, David J.; Reed, Eddie; Myers, Charles E.

In: Clinical Cancer Research, Vol. 2, No. 3, 01.03.1996, p. 483-491.

Research output: Contribution to journalArticle

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T1 - Phase I study of lovastatin, an inhibitor of the mevalonate pathway, in patients with cancer

AU - Thibault, Alain

AU - Samid, Dvorit

AU - Tompkins, Anne C.

AU - Figg, William D.

AU - Cooper, Michael R.

AU - Hohl, Raymond

AU - Trepel, Jane

AU - Liang, Bertrand

AU - Patronas, Nicholas

AU - Venzon, David J.

AU - Reed, Eddie

AU - Myers, Charles E.

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N2 - 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 μM 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.

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Thibault A, Samid D, Tompkins AC, Figg WD, Cooper MR, Hohl R et al. Phase I study of lovastatin, an inhibitor of the mevalonate pathway, in patients with cancer. Clinical Cancer Research. 1996 Mar 1;2(3):483-491.