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.
ABSTRACT Squamous cell carcinomas of the head and neck (HNSCC) and of the cervix (CC) are particularly sensitive to the apoptotic effects of lovastatin in vitro. In this Phase I study, the safety and maximum related dose (MTD) of lovastatin was evaluated in these specific clinical settings. This was a Phase I open-label study to determine the recommended Phase II dose (RPTD) of lovastatin in advanced HNSCC or CC. This study involved a dose and duration escalation of lovastatin starting at 5/mg/kg/day x 2 weeks, every 21 days, until the MTD was reached. Plasma samples were collected for pharmacokinetic analysis. All 26 patients enrolled were evaluable. Dose-limiting toxicity (DLT) consisting of reversible muscle toxicity was seen at 10 mg/kg/day x 14 days. Toxicity may be related to relative renal insufficiency. The MTD was determined to be 7.5 mg/kg/day x 21 days, every 28 days. The low lipid levels experienced on study did not translate into adverse events. Biologically relevant plasma lovastatin levels were obtained. No objective responses were seen but the median survival of patients on study was 7.5 months (mean 9.2 +/- 1.5 months). Stable disease (SD) for more than 3 months was seen in 23% of patients. One patient achieved SD and clinical benefit for 14 months on study and a further 23 months off treatment. The disease stabilisation rate of 23% seen in these end-stage patients is encouraging. We conclude that the administration of lovastatin at 7.5 mg/kg/day for 21 consecutive days on a 28-day schedule is well tolerated in patients with good renal function and warrants further clinical evaluation.
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ABSTRACT: Radiotherapy delivered with the antibody cetuximab is a standard treatment option for locally advanced head and neck cancer. Cetuximab acts by blocking epidermal growth factor receptor (EGFR) signaling to inhibit cancer progression. However, a significant percentage of patients will not respond satisfactorily to radiotherapy and cetuximab. Statins reduce the synthesis rate of cholesterol and isoprenoid derivates that may be required for an efficient cell signaling mediated by EGFR. We pre-clinically assessed whether the statin simvastatin could improve this combined therapy. In vitro, simvastatin enhanced the effects of radiotherapy alone and in combination with cetuximab in wound healing, cell proliferation, and clonogenic assays in FaDu cells. These results were reflected in xenoimplanted tumors growing into subcutaneous tissue of athymic mice where concomitant treatment with simvastatin decreased tumor growth. Consistently, lower levels of the phosphorylated ERK1/2, AKT and STAT3 oncoproteins, and higher levels of caspase-3 and apoptosis in cell cultures and xenografts were observed. The EGFR overexpressing A431 cell line was used to reproduce these antitumor effects of simvastatin. Our findings suggest that simvastatin may improve the efficiency of concomitant radiotherapy and cetuximab. Further investigation in the treatment of locally advanced tumors such as head and neck cancer is warranted.Translational oncology 01/2014; · 3.40 Impact Factor
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ABSTRACT: Despite significant, frequently very strong, antiproliferative and tumoricidal effects of statins demonstrated in vitro, their antitumor effects in animal models are modest, and their efficacy in clinical trials has not been proven. As such, statins seem unlikely to be ever regarded as antitumor agents. However, statins are regularly taken by many elderly cancer patients for the prevention of cardiovascular events. Owing to their pleiotropic effects in normal and tumor cells, statins interact in various ways with many antitumor treatment modalities, either potentiating or diminishing their effectiveness. Elucidation of these interactions might affect the choice of treatment to be planned in cancer patients as some combinations might be contraindicated, whereas others might elicit potentiated antitumor effects but at a cost of increased general toxicity. Some other combinations might induce either comparable or even stronger antitumor effects, but with a beneficial concomitant reduction of specific side effects. Most of the studies reviewed in this article have been carried in vitro or in experimental tumor models, but clinical relevance of the findings is also discussed.Medicinal Research Reviews 07/2009; 30(1):102-35. · 9.58 Impact Factor
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ABSTRACT: We have previously demonstrated the ability of lovastatin, a potent inhibitor of mevalonate synthesis, to induce tumour specific apoptosis. The apoptotic effects of lovastatin were regulated in part by the Integrated Stress Response (ISR) that regulates cellular responses to a wide variety of stress inducers. A key regulator of the ISR apoptotic response is activating transcription factor 3 (ATF3) and its target gene CHOP/GADD153. In this study, we demonstrate that in multiple lovastatin resistant clones of the squamous cell carcinoma (SCC) cell line SCC9, lovastatin treatment (1-25μM, 24hrs) in contrast to the parental line, failed to significantly induce ATF3 expression. Furthermore, the SCC derived cell lines SCC25 and HeLa that are sensitive to lovastatin-induced apoptosis also preferentially induce ATF3 expression compared to resistant breast (MCF-7) and prostate carcinoma (PC3) derived cell lines. In HeLa cells shRNA targeting ATF3 expression as well as in ATF3 deficient murine embryonic fibroblasts (MEFs), lovastatin-induced cytotoxicity and apoptosis were attenuated. In ex-vivo HNSCC tumours, lovastatin also induced ATF3 mRNA expression in 2/4 tumours evaluated. Salubrinal, an agent that can sustain the activity of a key regulator of the ISR eIF2α, further increased the expression of ATF3 and demonstrated synergistic cytotoxicity in combination with lovastatin in SCC cells. Taken together, our results demonstrate preferential induction of ATF3 in lovastatin sensitive tumour derived cell lines that regulates lovastatin-induced apoptosis. Importantly, combining lovastatin with salubrinal enhanced ATF3 expression and induced synergistic cytotoxicity in SCC cells. © 2013 Wiley Periodicals, Inc.International Journal of Cancer 07/2013; · 6.20 Impact Factor