A Phase I trial of prolonged administration of lovastatin in patients with recurrent or metastatic squamous cell carcinoma of the head and neck or of the cervix☆
Introduction
The statin family of drugs block hepatic synthesis of cholesterol, predominantly lowering the low-density serum lipoproteins (LDLs) and hence improve the cholesterol profile [1], [2], [3], [4]. Large clinical trials established their ability to safely reduce cardiovascular events, as well as all-cause mortality [3], [4], [5], [6]. Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme of the mevalonate pathway, a complex pathway yielding vital products for a variety of key cellular functions, including membrane integrity, cell signalling, protein synthesis and cell cycle progression (Fig. 1) [7]. Furthermore, retinoids, which induce cellular differentiation and growth inhibitory responses, are also end-products of the mevalonate pathway in plants. The activity of HMG-CoA reductase is closely regulated by feedback mechanisms [7].
There is growing experimental evidence indicating that statins have anticancer effects ranging from antiproliferative, pro-apoptotic, differentiating, anti-invasive and radiosensitising properties, depending on the particular cell type and circumstances under which they are studied [8], [9], [10], [11]. (For recent reviews see Refs. [6], [12]). In addition, a retrospective analysis of the large, safety and efficacy trials of statins in coronary artery disease suggested an oncoprotective effect of these agents as the incidence of common cancers appeared to be reduced [4]. Subsequent large and well-designed observational studies conducted on Canadian, Dutch and Israeli populations more strongly support a decrease in the risk of incident cancer following chronic use of statins [13], [14], [15]. All of these findings together suggest that inhibition of the mevalonate pathway may offer a novel approach to the treatment of cancer. Direct evidence for statins as cancer agents in patients has not yet been established.
Lovastatin, a fungal antibiotic, is a specific and non-reversible competitive inhibitor of HMG-CoA reductase. It is one of the first-generation statins and therefore has a large body of safety and pharmacokinetic data from clinical trials and general use for hyperlipidaemia [1], [2]. It is metabolised in the liver by the cytochrome P450 isoenzyme, CYP3A4, with less than 10% being excreted renally [6]. Its role as a cytostatic agent in malignant cells has been appreciated for some time [11]. In addition, via its inhibitory action in the mevalonate pathway, lovastatin appears to be a promising pro-apoptotic and differentiating agent, and there is strong evidence for a cytotoxic effect in a number of transformed cell lines including solid tumour lines from squamous cell cancer of the head and neck (HNSCC) and cervical cancer (CC) [8], [10]. However, other dividing cells such as normal bone marrow progenitors are not affected by lovastatin [9]. The apoptotic response observed in susceptible cell lines is in part due to the depletion of the downstream product geranylgeranyl pyrophosphate, but not farnesyl pyrophosphate or other products of the mevalonate pathway, including cholesterol or ubiquinone [16]. One pro-apoptotic consequence of lovastatin exposure is downregulation of bcl-2 mRNA and protein, although the mechanism of this downregulation is not known [8], [17].
In a Phase I clinical trial of lovastatin given as a single oral agent [18], 88 patients with solid tumours were treated with repeated courses consisting of 7 days of consecutive dosing, followed by 3 weeks of rest, every 4 weeks. Doses ranging from 2 to 45 mg/kg/day were tested, and the maximum tolerated dose (MTD) was determined to be 25 mg/kg/day. This dose is approximately 25 times the usual upper limit used to lower LDLs. This study showed peak plasma lovastatin concentration of 0.10–3.92 μM were achieved, with trough levels at the MTD averaging 0.28 μM, which corresponded with in vitro levels that can trigger apoptosis in sensitive cell lines [10]. Dose-limiting toxicity (DLT) was myopathy that appeared to be associated with low levels of ubiquinone in patients, another end-product of the mevalonate pathway. Only one minor response was documented in a patient with recurrent high-grade glioma. Two small Phase II trials have been reported using a similar dose and schedule which did not show promising activity [19], [20]. Interestingly, a randomised Phase II trial in 83 unresectable hepatocellular carcinoma (HCC) suggested a survival advantage when patients were randomised to receive continuous daily pravastatin (another lipid-lowering agent from the statin family) versus no pravastatin following treatment with arterial emobilisation and oral 5-fluorouracil (5-FU) chemotherapy (median survival 18 months vs. 9 months, P = 0.006) [21]. While survival differences in this small study could be due to an imbalance of prognostic features in the HCC patients between the two treatment arms, the role of statins in HCC warrants further study.
Given the striking cytotoxicity of lovastatin against HNSCC and CC cell lines in vitro, we planned to assess its antitumour activity in these specific clinical settings. Both these tumour types in advanced stages are not cured by any conventional chemotherapy or radiation and median survival estimates are 6–9 months [22]. Novel anticancer agents, if selective against relevant molecular targets, may offer a better therapeutic index over conventional chemotherapy. Since the previous Phase I–II studies utilising the 1-week on, 3-weeks off schedule produced virtually no clinical efficacy, a prolonged oral administration of lovastatin, to provide a sustained exposure, is investigated in this study. In vitro, IC50s in the range of 0.5–5.0 μM in HNSCC and CC cell lines are sensitive to lovastatin’s apoptotic effects [10]. In fact, lower concentrations (0.1–1.0 μM) were quite sufficient to inhibit proliferation and induce apoptosis if these cells were exposed for a prolonged 5-day period (data not shown). We designed this study to involve a dose and duration escalation of lovastatin, until the recommended Phase II dose (RPTD) was reached aiming to achieve serum concentrations that could produce these anti-cancer effects in vitro. Pre- and post-treatment tumour biopsies were planned in consenting patients to evaluate any biological effects of lovastatin.
Section snippets
Patients and methods
This was a single-centre, Phase I open-label study to determine the RPTD of lovastatin in the treatment of patients with recurrent or metastatic HNSCC or cervical cancer. Cohorts to evaluate the escalating dose and duration of exposure of lovastatin were planned from 5 to 25 mg/kg/day given over 2–4 week periods. The characteristics of the enrolled patients and the actual dose escalation are summarised in Table 1, Table 2, respectively. Eligible patients had histologically proven HNSCC or CC,
Results
Twenty-six eligible patients were enrolled on the study. Four patients were not evaluable for response (one withdrew consent in the first week of treatment, three progressed clinically before completing 1 cycle of treatment). All 26 patients were evaluable for toxicity, but emphasis was placed on the 22 who completed at least one full cycle. Patients’ baseline characteristics are summarised in Table 1. All patients had been previously treated with either radiation and/or chemotherapy. The
Discussion
Inhibition of the mevalonate pathway has appeared a promising anticancer strategy based on pre-clinical studies showing numerous examples of the impact of statins on malignant cell differentiation, cycling and apoptosis [8], [9], [10], [11], [17], [25]. Potential cancer therapeutics capable of inhibiting the mevalonate pathway already exist and are widely used as safe and effective anti-cholesterol agents [6], [12]. In our own experience lovastatin appeared a potent cytostatic and pro-apoptotic
Conflict of interest statement
None declared.
Acknowledgements
We thank Apotex Canada for generously supplying the drug used in this study. This work was supported in part by the Cancer Impact Team Grant from the Princess Margaret Hospital Foundation. Dr. Knox was supported by a Cancer Care Ontario Research Fellowship in Oncology. The authors thank Dr. G. Lewis for helpful discussion.
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This manuscript contains original work. The work has been presented in part at the American Association for Cancer Research-National Cancer Institute-European Organisation for Research and Treatment of Cancer (AACR-NCI-EORTC): Molecular Targets and Cancer Therapeutics Meeting, Miami October 2001. A Phase I trial of prolonged administration of lovastatin in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (HNSCC) or of the cervix (CC). Abstract #347.