Security and Maximal Tolerated Doses of Fluvastatin In Pediatric Cancer Patients

López-Aguilar, Enrique; Sepúlveda-Vildósola, Ana Carolina; Rivera-Márquez, Hugo; Cerecedo-Díaz, Fernando; Valdez-Sánchez, Martha; Villasís‐Keever, Miguel Angel

doi:10.1016/s0188-0128(98)00018-9

Cited by 30 publications

(19 citation statements)

References 18 publications

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“…Fluvastatin has the same toxicity profile as other HMG-CoA reductase inhibitors, while it has not been associated with rhabdomyolysis and myopathy (Scripture and Pieper, 2001). Furthermore, fluvastatin has been safely administered at high doses in paediatric patients with cancer (Lopez-Aguilar et al, 1999). Indeed, micromolar concentrations of gemcitabine and fluvastatin have been reached in human plasma in pharmacokinetic studies (Kroep et al, 1999;Kantola et al, 2000), and these plasma levels are in the range of the antiproliferative activity found in the present study.…”

Section: Discussionsupporting

confidence: 63%

Fluvastatin synergistically enhances the antiproliferative effect of gemcitabine in human pancreatic cancer MIAPaCa-2 cells

et al. 2005

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The new combination between the nucleoside analogue gemcitabine and the cholesterol-lowering drug fluvastatin was investigated in vitro and in vivo on the human pancreatic tumour cell line MIAPaCa-2. The present study demonstrates that fluvastatin inhibits proliferation, induces apoptosis in pancreatic cancer cells harbouring a p21ras mutation at codon 12 and synergistically potentiates the cytotoxic effect of gemcitabine. The pharmacologic activities of fluvastatin are prevented by administration of mevalonic acid, suggesting that the shown inhibition of geranyl-geranylation and farnesylation of cellular proteins, including p21rhoA and p21ras, plays a major role in its anticancer effect. Fluvastatin treatment also indirectly inhibits the phosphorylation of p42ERK2/mitogen-activated protein kinase, the cellular effector of ras and other signal transduction peptides. Moreover, fluvastatin administration significantly increases the expression of the deoxycytidine kinase, the enzyme required for the activation of gemcitabine, and simultaneously reduces the 5 0 -nucleotidase, responsible for deactivation of gemcitabine, suggesting a possible additional role of these enzymes in the enhanced cytotoxic activity of gemcitabine. Finally, a significant in vivo antitumour effect on MIAPaCa-2 xenografts was observed with the simultaneous combination of fluvastatin and gemcitabine, resulting in an almost complete suppression and a marked delay in relapse of tumour growth. In conclusion, the combination of fluvastatin and gemcitabine is an effective cytotoxic, proapoptotic treatment in vitro and in vivo against MIAPaCa-2 cells by a mechanism of action mediated, at least in part, by the inhibition of p21ras and rhoA prenylation. The obtained experimental findings might constitute the basis for a novel translational research in humans.

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Section: Discussionsupporting

confidence: 63%

Fluvastatin synergistically enhances the antiproliferative effect of gemcitabine in human pancreatic cancer MIAPaCa-2 cells

et al. 2005

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“…Beyond this, statins are tolerated at doses of up to 20 mg/kg/day in adults [57]. Thus, the statin concentrations applied in this study may well be given to patients.…”

Section: Discussionmentioning

confidence: 99%

Cell cycle arrest and apoptosis induction in hepatocellular carcinoma cells by HMG-CoA reductase inhibitors. Synergistic antiproliferative action with ligands of the peripheral benzodiazepine receptor

Sutter

Maaser

Höpfner

et al. 2005

Journal of Hepatology

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“…Pravastatin therapy as a treatment option for advanced hepatocellular carcinoma was not associated with a significantly better overall survival rate, although statin therapy seemed to be more beneficial than other new treatment options, including octreotide and gemcitabine therapy [121]. In a study using fluvastatin (8 mg/kg per day for 14 days every 4 weeks) in pediatric cancer patients, 10 of 12 patients died within 1-18 months because of their advanced disease stage, and laboratory assays demonstrated no significant changes during treatment [122]. Knox et al conducted a phase I trial of lovastatin administration (7.5 mg/kg per day for 21 consecutive days) in patients with recurrent or metastatic squamous cell carcinoma of the head and neck [43].…”

Section: Statins and Cancer Treatmentmentioning

confidence: 99%

The Role of Statins in Cancer Therapy

Cleeland²,

et al. 2006

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Learning ObjectivesAfter completing this course, the reader will be able to:1. Explain how statins, used in the treatment of hypercholesterolemia, may be applicable to cancer prevention.2. Discuss how statins potentially interfere with biologic processes relevant to cancer etiology. AbstractAdministration of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, to ambulatory patients is associated with a lower incidence of long-term adverse cardiovascular events, including death, myocardial infarction, stroke, atrial fibrillation, and renal dysfunction. However, increasing clinical evidence suggests that statins, independent of their effects on serum cholesterol levels, may also play a potential role in the prevention and treatment of cancer. Specifically, statins have been shown to exert several beneficial antineoplastic properties, including decreased tumor growth, angiogenesis, and metastasis. The feasibility and efficacy of statins for the prevention and treatment of cancer is reviewed. The Oncologist 2006;11:306-315

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Security and Maximal Tolerated Doses of Fluvastatin In Pediatric Cancer Patients

Cited by 30 publications

References 18 publications

Fluvastatin synergistically enhances the antiproliferative effect of gemcitabine in human pancreatic cancer MIAPaCa-2 cells

Fluvastatin synergistically enhances the antiproliferative effect of gemcitabine in human pancreatic cancer MIAPaCa-2 cells

Cell cycle arrest and apoptosis induction in hepatocellular carcinoma cells by HMG-CoA reductase inhibitors. Synergistic antiproliferative action with ligands of the peripheral benzodiazepine receptor

The Role of Statins in Cancer Therapy

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