The pharmacokinetics of single high doses of dexamethasone in cancer patients

Brady, Michael Emmett; Sartiano, George P.; Rosenblum, Sidney; Zaglama, N E; Bauguess, Carl T.

doi:10.1007/bf02455994

Cited by 56 publications

(41 citation statements)

References 13 publications

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“…Zibera et al 26 made obvious that DEX inhibited the growth of GR-positive and -negative cells only at high doses (5 to 125 mM). On the contrary, lower DEX concentrations (1.6 to 1000 nM), resembling more plasma levels of patients receiving antiemetic GC therapy, 27 increased the proliferation of GR-positive but not of -negative cells. 28 Langeveld et al 29 investigated the effect of DEX on the proliferation of seven human glioma cell lines.…”

Section: The Effect Of Gcs Is Dependent On Gr Levelsmentioning

confidence: 95%

Cell Cycle Arrest by Glucocorticoids May Protect Normal Tissue and Solid Tumors from Cancer Therapy

Mattern¹,

Büchler²,

Herr³

2007

Cancer Biology & Therapy

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ABBrevIAtIons DEX ABstrActGlucocorticoids have been widely used as cotreatment for patients with cancer due to potent pro-apoptotic properties in lymphoid cells, reduction of nausea and diminishing acute toxicity on normal tissue. There are now data from preclinical and, to some extent, clinical studies, demonstrating that these medicaments are highly suspicious to induce therapy resistance in the majority of malignant solid tumors-irrespective of tumor origin and the nature of specific anticancer drugs or irradiation used for treatment. Despite these huge amounts of data, the underlying mechanisms of cell type-specific signaling by these steroid hormones are just beginning to be described. This review summarizes our present understanding of a relationship between glucocorticoid-induced reversible cell cycle arrest and therapy resistance in solid tumors. We give a summary of our current knowledge of decreased proliferation rates in response to glucocorticoid pre and combination treatment which are suspicious to be involved not only in protection of normal tissues, but also in protection of solid tumors from cytotoxic effects of anticancer agents. The inhibition of cell cycle progression by pretreatment with GCs may be crucially involved in switching the balance of several interacting pathways to survival upon treatment with GCs.

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Section: The Effect Of Gcs Is Dependent On Gr Levelsmentioning

confidence: 95%

Cell Cycle Arrest by Glucocorticoids May Protect Normal Tissue and Solid Tumors from Cancer Therapy

Mattern¹,

Büchler²,

Herr³

2007

Cancer Biology & Therapy

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“…Cells were seeded in 96-multiwell plates (1x100,000 cells/well), and after incubation for 24 h, the cells were treated with cetuximab alone or in combination with dexamethasone for 24, 48 or 76 h, respectively. In all experiments described in this publication, cetuximab was used in two different concentrations (0.5 and 5.0 μmol/l), while dexamethasone was used at four increasing concentrations ranging from 1 to 10 μmol/l; these concentrations are comparable with the clinically achievable tissue concentrations of the drug (16). The number of cells was determined in a Rosenthal chamber after 24, 48 and 72 h of treatment.…”

Section: Methodsmentioning

confidence: 99%

Does dexamethasone inhibit anticancer activity of cetuximab in squamous cell carcinoma cell lines of the head and neck?

Wagenblast

Baghi²,

Mörtel³

et al. 2009

Oncol Rep

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Abstract. Glucocorticoids such as dexamethasone are widely used as comedication in the treatment of head and neck cancer, e.g., to improve appetite and decrease weight loss and fatigue in patients with advanced disease or as antiallergic and antiemetic prophylaxis during anti-EGFR therapy. However, the literature suggests that dexamethasone induces resistance to antineoplastic agents in many solid tumor models in vitro and in vivo. Since this phenomenon has never been investigated in head and neck cancer, the present study was conducted to investigate the effect of dexamethasone on the antiproliferative activity of cetuximab in vitro in squamous cell carcinoma of the head and neck (SCCHN) cell lines. The antiproliferative effect of the anti-EGFR agent cetuximab alone and in combination with increasing concentrations of dexamethasone was examined in eight SCCHN cell lines at three different time-points (24, 48 and 72 h). Cell growth inhibition and viability were measured quantitatively using WST and LDH assays. Absolute tumor cell numbers were determined by cell counting in a Rosenthal chamber. Cetuximab alone inhibited the growth of all eight SCCHN cell lines significantly (p=0.008). In some cases the addition of dexamethasone reduced the antiproliferative activity of cetuximab (p≤0.038) but remained significant in all of the eight SCCHN cell lines compared with untreated controls (p≤0.028) at each drug concentration and each time-point. In contrast to the results reported for other tumor models, in our study dexamethasone showed in the majority of the evaluated dexamethasone drug concentrations and timepoints no inhibition of the cytotoxic activity of cetuximab. The reasons for these discrepant findings are unclear but may be related to the degree of tumor cell differentiation or proliferation rate. Thus, further studies are required to elucidate the molecular mechanisms underlying the interaction between dexamethasone and cetuximab in different tumors.

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“…Final concentrations of the solvents in medium were 0.01% or less. We used DEX in concentrations between 0.1 and 10 mM since these amounts are comparable with the clinical setting where one dose of 12 mg DEX (about 0.15 mg kg À1 ) resulted in plasma concentrations of 0.25 -0.5 mM with a half-life of several hours (Brady et al, 1987). We employed cisplatin in concentrations of 7 -34 mM, which are within the range found in tumours and plasma of patients treated with a single dose of 150 mg m À2 cisplatin (Tegeder et al, 2003).…”

Section: Drugsmentioning

confidence: 99%

Dexamethasone-induced cisplatin and gemcitabine resistance in lung carcinoma samples treated ex vivo

et al. 2005

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Chemotherapy for lung cancer not only has severe side effects but frequently also exhibits limited, if any clinical effectiveness. Dexamethasone (DEX) and similar glucocorticoids (GCs) such as prednisone are often used in the clinical setting, for example, as cotreatment to prevent nausea and other symptoms. Clinical trials evaluating the impact of GCs on tumour control and patient survival of lung carcinoma have never been performed. Therefore, we isolated cancer cells from resected lung tumour specimens and treated them with cisplatin in the presence or absence of DEX. Cell number of viable and dead cells was evaluated by trypan blue exclusion and viability was measured by the MTT-assay. We found that DEX induced resistance toward cisplatin in all of 10 examined tumour samples. Similar results were found using gemcitabine as cytotoxic drug. Survival of drug-treated lung carcinoma cells in the presence of DEX was longlasting as examined 2 and 3 weeks after cisplatin treatment of a lung carcinoma cell line. These data corroborate recent in vitro and in vivo xenograft findings and rise additional concerns about the widespread combined use of DEX with antineoplastic drugs in the clinical management of patients with lung cancer. British Journal of Cancer (2005) The incidence of lung cancer has increased considerably over the past 50 years and lung carcinoma has become the leading cause of death by cancer in both men and women (Levi et al, 2004). The prognosis is still poor and about 80% of patients die within 1 year of diagnosis (Office for National Statistics, 1997). Despite some advances in surgical procedures, chemotherapy and radiotherapy made over the past two decades, long-term survival in, for example, non-small-cell lung cancer (NSCLC) patients at stage 3 and 4 is obtained in only 5 -10% of cases (Cancer Research UK, 2004). The development of drug resistance in patients receiving chemotherapy or a combination therapy including ionizing radiation represents a major problem in cancer treatment. The present paper aims at addressing one aspect of this complex problem. Dexamethasone (DEX) and similar glucocorticoids (GCs) were first introduced to tumour therapy on the basis of proapoptotic effects in lymphoid cells and on their effectiveness in treating tumour-related oedema, inflammation, pain and electrolyte imbalance as well as stimulating appetite, and most importantly, preventing nausea and emesis caused by cytotoxic drugs (Aapro, 1991;Cheng et al, 1997;Kirkbride et al, 2000; The Italian Group of Anticancer Research, 1995, 2000. However, prospective randomised trials evaluating a potential impact on tumour control and patient survival have never been performed. Induction of apoptosis resistance toward chemotherapy by DEX was recently described in a cervical and a lung carcinoma cell line (Herr et al, 2003) as well as in a breast cancer cell line (Wu et al, 2004). In vivo, a xenografted and cisplatin-treated lung tumour cell line grew faster in the presence of DEX (Herr et al, 2003). These results and earl...

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The pharmacokinetics of single high doses of dexamethasone in cancer patients

Cited by 56 publications

References 13 publications

Cell Cycle Arrest by Glucocorticoids May Protect Normal Tissue and Solid Tumors from Cancer Therapy

Cell Cycle Arrest by Glucocorticoids May Protect Normal Tissue and Solid Tumors from Cancer Therapy

Does dexamethasone inhibit anticancer activity of cetuximab in squamous cell carcinoma cell lines of the head and neck?

Dexamethasone-induced cisplatin and gemcitabine resistance in lung carcinoma samples treated ex vivo

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