A Phase I-II Trial of Lovastatin for Anaplastic Astrocytoma and Glioblastoma Multiforme

Abstract

Malignant gliomas are thought to be highly dependent on the mevalonate pathway for cell growth. Lovastatin, a cholesterol-lowering drug, inhibits not only the rate-limiting step in the mevalonate pathway (hepatic hydroxymethyl glutaryl coenzyme A reductase), but also the prenylation of several key regulatory proteins including ras and the small guanosine triphosphate binding proteins. Therefore, from August 1994 through March 1996, 18 patients with either anaplastic glioma or glioblastoma multiforme were entered into a trial testing the safety of high-dose lovastatin with or without radiation. Although the response data is too premature to evaluate activity, the fact that high doses of lovastatin are well tolerated with concurrent radiation suggests that central nervous system toxicity will not be a significant limiting toxicity as more selective farnesyltransferase inhibitors are brought into the clinic as radiation sensitizers.

The association between 3‐hydroxy‐3‐methylglutaryl conenzyme A inhibitor use and breast carcinoma risk among postmenopausal women

“…25 Small clinical trials have evaluated the dosing and scheduling of statins as adjuncts to chemotherapeutic agents. 20,[41][42][43][44] The trials have found dosing to be significant, and dose-related toxicity to be minimal, but there has been only slight tumor response. One trial of longer duration (54 days) found a more favorable response among patients with leukemia.…”

Lovastatin potentiates antitumor activity of doxorubicin in murine melanoma via an apoptosis‐dependent mechanism

“…Serial dilutions of lovastatin (100 l, final concentrations 1-4 M) were added and supplemented with culture medium to a final volume of 200 l. Different incubation period for doxorubicin and lovastatin were used in order to gain comparable inhibition of cell proliferation in all experiments and these concentrations correspond to those that were observed in tumor treated patients. 22,23 After an incubation period of 48 hr a standard MTT assay was performed. Briefly, 25 l 3-(45-dimethylthiazol-2-yl)-diphenyltetrazolium bromide (MTT) (Sigma Chemical Co., St. Louis, MO) solution was added to each well.…”

“…However, the use of the statins in monotherapy in the treatment of cancers, particularly solid tumors, has not been feasible because the doses calculated as required to produce a clinically desirable inhibition of proliferation and an increase in apoptosis is associated with significant toxicity. 22,23 Some recent observations suggest that lovastatin may increase vulnerability of tumor cells to the action of other chemotherapeutic agents by targeting specifically multidrug-resistant, P-glycoprotein-expressing tumor cells. 9,28,29 This observation may be considered as a possible explanation of the augmentation of doxorubicininduced apoptosis in combination with lovastatin in our study, although other mechanisms cannot be ruled out.…”

Pravastatin Reduces Radiation-Induced Damage to Normal Tissues

“…Because the main aim of the present study was to assess the potential negative effect of pravastatin on tumor response to radiotherapy, only a small number of animals were treated with pravastatin alone (sham-irradiated). Statins have been reported to have anti-tumor effects and some clinical data have supported their potential use against tumors (26)(27)(28)(29)(30)(31)(32). However, there has only been one randomized clinical trial studying this, which showed that the addition of pravastatin did not improve outcomes in patients with advanced gastric cancer (32).…”