This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Crokart, N. Articles by Gallez, B. Search for Related Content PubMed PubMed Citation Articles by Crokart, N. Articles by Gallez, B. Related Collections Commentary

Glucocorticoids Modulate Tumor Radiation Response through a Decrease in Tumor Oxygen Consumption

Authors' Affiliations: Laboratories of ¹ Medicinal Chemistry and Radiopharmacy, ² Biomedical Magnetic Resonance, ³ Molecular Imaging and Experimental Radiotherapy, and ⁴ Pharmacology and Therapeutics, Université Catholique de Louvain, Brussels, Belgium

Requests for reprints: Bernard Gallez, CMFA/REMA, Avenue Mounier 73.40, B-1200 Brussels, Belgium. Phone: 32-2-764-7344; Fax: 32-2-764-7390; E-mail: Gallez{at}cmfa.ucl.ac.be.

	Abstract

Top Abstract Materials and Methods Results Discussion References

 
Purpose: We hypothesized that glucocorticoids may enhance tumor radiosensitivity by increasing tumor oxygenation (pO₂) through inhibition of mitochondrial respiration.

Experimental Design: The effect of three glucocorticoids (hydrocortisone, dexamethasone, and prednisolone) on pO₂ was studied in murine TLT liver tumors and FSaII fibrosarcomas. At the time of maximum pO₂ (t_max, 30 min after administration), perfusion, oxygen consumption, and radiation sensitivity were studied. Local pO₂ measurements were done using electron paramagnetic resonance. The oxygen consumption rate of tumor cells after in vivo glucocorticoid administration was measured using high-frequency electron paramagnetic resonance. Tumor perfusion and permeability measurements were assessed by dynamic contrast-enhanced magnetic resonance imaging.

Results: All glucocorticoids tested caused a rapid increase in pO₂. At t_max, tumor perfusion decreased, indicating that the increase in pO₂ was not caused by an increase in oxygen supply. Also at t_max, global oxygen consumption decreased. When irradiation (25 Gy) was applied at t_max, the tumor radiosensitivity was enhanced (regrowth delay increased by a factor of 1.7).

Conclusion: These results show the potential usefulness of the administration of glucocorticoids before irradiation.

Here, we hypothesized that glucocorticoids could be other important modulators of tumor oxygenation. The rationale for this hypothesis is that glucocorticoids are known to inhibit oxidative phosphorylation of the respiratory chain, with important effect on respiration rate of cells (15, 16). Using two different tumor models, we show that the administration of glucocorticoids (hydrocortisone, prednisolone, and dexamethasone) has a profound effect on tumor oxygenation. To identify the factors responsible for this tumor reoxygenation, we characterized changes in the tumor microenvironment: perfusion, permeability, and oxygen consumption. We also investigated the sensitivity of tumors to irradiation at the time of maximal reoxygenation.

	Materials and Methods

Top Abstract Materials and Methods Results Discussion References

 
Animal tumor models
Two different syngeneic tumor models were implanted in the gastrocnemius muscle in the rear leg of male mice (20-25 g; B&K, Hull, United Kingdom): the transplantable liver tumor TLT in NMRI mice and the FSaII tumor in C3H mice. All treatments were applied when the tumor reached 8.0 ± 0.5 mm. All experiments were conducted according to national animal care regulations.

Treatments
Anesthesia. Animals were anesthetized by inhalation of isoflurane mixed with 21% oxygen in a continuous flow (1.5 L/h) delivered by a nose cone. Induction of anesthesia was done using 3% isoflurane and stabilized at 1.2% for a minimum of 15 min before any measurement. The temperature of the animals was kept constant using an IR light, a homeothermic blanket control unit, or a flow of temperature-controlled warm air.

Glucocorticoids. All glucocorticoids were administered by 100-µL i.p. injection. Hydrocortisone was administered at 7.7 mg/kg (Solu-Cortef, Pharmacia, Pfizer, Brussels, Belgium; diluted in saline to 1.9 mg/mL), dexamethasone at 5 mg/kg (Aacidexam, Organon, Brussels, Belgium; diluted in saline to 1.25 mg/mL), and prednisolone at 75 mg/kg (Alexis Biochemicals, Zandhoven, Belgium; diluted in saline to 25 mg/mL).

Oxygen measurements
Electron paramagnetic resonance (EPR) oximetry (using charcoal as the oxygen sensitive probe) was used to evaluate tumor oxygenation changes as previously described (6, 17). EPR spectra were recorded using a 1.2-GHz EPR spectrometer (Magnettech, Berlin, Germany) before and after administration of glucocorticoids. Two days before EPR analysis, mice were injected in the center of the tumor using the suspension of charcoal (100 mg/mL, 50 µL injected; particle size, <25 µm). These localized EPR measurements record the average pO₂ in a volume of 10 mm³ (6). Hydrocortisone was administered in FSaII tumor– and TLT tumor–bearing mice (n = 5 per group). Prednisolone and dexamethasone were administered in FSaII tumor–bearing mice (n = 4 per group). Saline was administered for both tumor types (n = 4 per group).

Oxygen consumption rate evaluation
The preparation of the tumor cells was as follows. FSaII tumors were dissected in sterile environment and gently pieced in McCoy's medium. The cell suspension was filtered (100 µm pore size nylon filter; Millipore, Brussels, Belgium), centrifuged (5 min, 450 x g, 4°C), and cells were set in culture in DMEM containing 10% fetal bovine serum. Confluent cells were suspended in medium without serum 2 h before treatment with hydrocortisone (5.2 µmol/L) or saline. Thirty minutes after treatment, they were trypsinized and cell viability was determined by trypan blue exclusion. An EPR method was used, which has previously been described (12). Briefly, the spectra were recorded on a Bruker EMX EPR spectrometer operating at 9 GHz. Cells (2 x 10⁷/mL) were suspended in 10% dextran in complete medium. A neutral nitroxide, ¹⁵N 4-oxo-2,2,6,6-tetramethylpiperidine-d₁₆-15N-1-oxyl at 0.2 mmol/L (CDN Isotopes, Pointe-Claire, Quebec, Canada), was added to 100-µL aliquots of tumor cells that were then drawn into glass capillary tubes. The probe was previously calibrated so that the line width measurements could be related to O₂ (12). The sealed tubes were placed into quartz EPR tubes and the samples were maintained at 37°C. Because the resulting line width reports on pO₂, it was possible to calculate oxygen consumption rates by measuring the pO₂ in the closed tube as a function of time and subsequently compute the slope of the resulting plot.

Perfusion measurements
Patent Blue staining. Patent Blue (Sigma-Aldrich, Bornem, Belgium) was used to obtain a rough estimate of the FSaII tumor perfusion (18) 30 min after administration of hydrocortisone (n = 7) or saline (n = 5). This technique involves the injection of 200 µL of Patent Blue solution (1.25%) into the tail vein of the mice. After 1 min, a uniform distribution of the staining throughout the body was obtained and mice were sacrificed. Tumors were carefully excised and cut in two size-matched halves. Pictures of each tumor cross section were taken with a digital camera. To compare the stained versus unstained area, an in-house program running on IDL (Interactive Data Language, RSI, Boulder, CO) was developed. For each tumor, a region of interest (stained area) was defined on the two pictures and the percentage of stained area of the whole cross section was determined (19). The mean of the percentage of the two pictures was then calculated and used as an indicator of tumor perfusion.

Magnetic resonance imaging measurements. The FSaII tumor perfusion was monitored 30 min after injection of hydrocortisone (n = 6) or saline (n = 6) via single-slice dynamic contrast-enhanced magnetic resonance imaging (MRI) at 4.7 T using the rapid-clearance blood pool agent P792 (Vistarem, Guerbet, Roissy, France; ref. 20). High-resolution multislice T₂-weighted spin-echo anatomic imaging was done just before dynamic contrast-enhanced T₁-weighted gradient-recalled echo imaging. T₁-weighted gradient-recalled echo images were obtained using the following variables: repetition time, 40 ms; echo time, 4.9 ms; slice thickness, 1.6 mm; flip angle, 90 degrees; matrix, 64 x 64; field of view, 4 cm; acquisition time, 2.56 s per scan. Pixel-by-pixel values for K_trans (influx volume transfer constant, from plasma into the interstitial space, units of min^–1), V_p (blood plasma volume per unit volume of tissue, unitless), and k_ep (fractional rate of efflux from the interstitial space back to blood, units of min^–1) in tumor were calculated via tracer kinetic modeling of the dynamic contrast-enhanced data, and the resulting parametric maps for K_trans, V_p, and k_ep were generated. Statistical significance for V_p or K_trans identified "perfused" pixels (i.e., pixels to which the contrast agent P792 had access; refs. 20, 21).

Tumor regrowth delay assay. The FSaII was locally irradiated with a 250-kV X-ray irradiator (RT 250, Philips Medical system; 1.2 Gy/min, 25 Gy). The tumor was centered in a 3-cm-diameter circular irradiation field. After treatment, tumor diameter was measured every day using a digital caliper until the diameter reached 16 mm, at which time the mice were sacrificed. A linear fit was done for diameters ranging from 8 to 16 mm, allowing determination of the time to reach a particular size for each mouse. Four groups of FSaII tumor–bearing mice were used for this study: saline (n = 7), hydrocortisone (n = 7), saline 30 min before irradiation (n = 6), and hydrocortisone 30 min before irradiation (n = 5).

Clonogenic cell survival assay
FSaII tumors were dissected in sterile environment and gently pieced in McCoy's medium. The cell suspension was filtered (100 µm pore size nylon filter; Millipore), centrifuged (5 min, 450 x g, 4°C), and cells were set in culture in DMEM containing 10% fetal bovine serum. Confluent cells were treated with hydrocortisone (5.24 µmol/L) or saline 30 min before irradiation (2, 5, 8, or 12 Gy). The cells were washed and reincubated in the conditioned medium without drug 1 h after irradiation. After 7 days of incubation in a humidified 5% CO₂ atmosphere at 37°C, the dishes were stained with crystal violet. All colonies formed by >50 cells were counted.

Statistical analysis
The change in pO₂ was assessed by Wilcoxon signed-rank test. The oxygen consumption slopes were compared by a Wilcoxon rank-sum test. The dynamic contrast-enhanced MRI variables and the Patent Blue results were compared by Wilcoxon rank-sum test. For the regrowth delay study, a one-way ANOVA Tukey's multiple comparison test was applied, and for clonogenic cell survival assay, a two-way ANOVA test was applied.

	Results

Top Abstract Materials and Methods Results Discussion References

 
Effect of hydrocortisone on the tumor oxygenation. Hydrocortisone, dexamethasone, and prednisolone were tested for their possible effect on tumor oxygenation. After administration of hydrocortisone, we observed a rapid increase in pO₂ in both TLT and FSaII tumor models (Fig. 1A and B ) that was not observed for saline groups. The same kind of kinetics was observed after administration of dexamethasone and prednisolone in FSaII tumors (Fig. 1C and D). The maximal pO₂ was reached 30 min after treatment. This value was significantly higher than that before treatment (P < 0.05) for all the drugs tested. The tumor pO₂ remained elevated until at least 1 h after administration.

View larger version (19K): [in this window] [in a new window]   Fig. 1. Tumor pO2 measured by EPR oximetry as a function of time in TLT tumors treated with hydrocortisone (n = 5; A); FSaII tumors treated with hydrocortisone (n = 5; B); FSaII tumors treated with dexamethasone (n = 4; C); and FSaII tumors treated with prednisolone (n = 4; D). Arrows, injection time of the drug.

View larger version (7K): [in this window] [in a new window]   Fig. 2. Effect of hydrocortisone administration on tumor oxygen consumption rate in FSaII cells. Hydrocortisone-pretreated cells consumed oxygen significantly more slowly than cells treated with saline alone. , saline (n = 5); , hydrocortisone (n = 5). P < 0.01, Wilcoxon rank-sum test.

View larger version (24K): [in this window] [in a new window]   Fig. 3. Perfusion and permeability were assessed in FSaII tumors by dynamic contrast-enhanced MRI with P792 as the contrast agent in FSaII tumor–bearing mice 30 min after saline (n = 6) or hydrocortisone (n = 6) treatment. A, typical MRI images of FSaII tumors showing the perfused pixels 30 min after treatment. B, columns, mean percentage of perfused pixels for treated and control groups; bars, SE. **, P < 0.01, Wilcoxon rank-sum test. C, distribution of pharmacokinetics variables in tumors treated with saline or hydrocortisone. D, columns, overall estimation of pharmacokinetic variables in tumors; bars, SE. Statistical analysis done with Wilcoxon rank-sum test; NS, nonsignificant.

View larger version (11K): [in this window] [in a new window]   Fig. 4. Effect of hydrocortisone on the regrowth delay of four groups of FSaII tumors: control group only injected once with saline (, n = 7); second group injected once with hydrocortisone (, n = 7); third group treated with saline 30 min before 25 Gy irradiation (, n = 6); and fourth group treated with hydrocortisone 30 min before 25 Gy irradiation (, n = 5).

View larger version (8K): [in this window] [in a new window]   Fig. 5. A clonogenic cell survival assay was done on FSaII cells to discriminate between an oxygen effect and a direct radiosensitization effect. Compared with control cells, hydrocortisone did not exert any sensitizing effect. For all doses, irradiation led to a significant decrease (P < 0.001, two-way ANOVA). These observations show that hydrocortisone radiosensitizes tumors through changes in the tumor microenvironment rather than by a direct sensitizing effect. Columns, mean; bars, SE.

	Discussion

Top Abstract Materials and Methods Results Discussion References

For the first time, we report that glucocorticoids induce a significant increase in tumor oxygenation in two different tumor models (Fig. 1). This phenomenon occurs rapidly, within 30 min after administration (t_max). At t_max, multiple modalities were applied to determine the mechanisms responsible for this effect. Because a change in oxygenation could result from an increase in oxygen blood supply or a change in consumption rate, we investigated both variables. Our results show that the reoxygenation of the tumors is linked to an effect on oxygen consumption. This was determined by measuring the oxygen consumption rate by tumor cells (Fig. 2): we found that oxygen consumption was significantly reduced after in vivo administration of hydrocortisone. This decrease in oxygen consumption could be explained by the capacity of glucocorticoids to inhibit cytochrome c oxidase (complex IV) of the mitochondrial respiratory chain (15, 16). At this point, we may also note the remarkable similarity of this effect between nonsteroidal anti-inflammatory drugs (14) and glucocorticoids (the present study). Both classes of drugs inhibit the prostaglandin cascade at two different levels (inhibition of cyclooxygenase and inhibition of phospholipase A2). Although some studies have described a direct effect of these drugs with specific complexes of the mitochondrial respiratory chain, it is likely that unspecific effects may occur with most drugs that interfere with the prostaglandin cascade. Indeed, prostaglandins are known to play a major role in the mitochondrial respiration (22–25), and the inhibition of their production should lead to a similar decrease in oxygen consumption and tumor reoxygenation. Moreover, the results obtained from dynamic contrast-enhanced MRI (Fig. 3) and by the Patent Blue assay preclude the possibility that the increase in tumor oxygenation may also result from an increase in perfusion. This decrease in perfusion is not surprising because the anti-inflammatory effects of glucocorticoids are known to be associated with a reduction in the vascular tone (or with vasoconstriction). This phenomenon was already observed in the same tumor model using anti–cyclooxygenase-2 drugs (14). It is interesting to note that for both glucocorticoids and cyclooxygenase-2 inhibitors (14), the decrease in oxygen consumption was sufficient to counteract the decrease in perfusion, and that the balance was in favor of an increase in tumor oxygenation. Finally, we cannot exclude that glucocorticoids may also increase tumor oxygenation by additional mechanisms. For example, it is well known that chronic treatments using glucocorticoids could lead to hyperglycemia in some patients. The so-called "Crabtree effect" results in a reduction of oxygen consumption via respiration in favor of glycolysis. In chronic treatments using glucocorticoids, this effect could be additive to the effect on the tumor mitochondrial respiratory chain to explain an increase in tumor oxygenation. The effect of glucocorticoids on the response to irradiation has been a matter of debate in the literature. Some reports in the literature have suggested an increased radioresistance induced by some glucocorticoids (26–30). The mechanisms proposed for increased radioresistance include an effect on the cell cycle (26), a decrease in radio-induced apoptosis (27, 28), and metabolic changes (29). However, this radioprotective effect was observed in few cell lines (31, 32) and not in some others (32–34). Here, we did not find any direct radiosensitization effect in vitro when the tumor cells were incubated in the presence of glucocorticoids (Fig. 5). On the contrary, we observed an important radiosensitization in vivo (Fig. 4), indicating that this effect is clearly linked to an effect on the tumor microenvironment. To our knowledge, this radiosensitization effect induced by the glucocorticoids is described here for the first time. Moreover, the demonstration that the enhanced radiosensitivity is mediated by an oxygen effect predicts that the radiosensitization of normal tissue is unlikely. This radiosensitization will more than likely be higher for hypoxic tumor regions than for well-oxygenated tissues. Further preclinical studies should confirm these assumptions. For this purpose, several normal tissue models can be used to determine whether glucocorticoids are responsible for toxicity on early-responding tissues (e.g., intestinal regenerated crypt assay) or late-responding tissues (e.g., leg contracture assay).

Finally, the demonstration of an oxygen effect gives unique insights for treatment combinations in the clinic. Because glucocorticoids are commonly used during several cancer therapies (e.g., to treat edema associated with malignant glioma; refs. 35, 36), our study suggests a potential therapy benefit if those glucocorticoids were to be given just before the irradiation.

	Acknowledgments

 
We thank Guerbet Laboratories (Roissy, France) for providing P792.

	Footnotes

 
Grant support: Belgian National Fund for Scientific Research (FNRS), Télévie, Fonds Joseph Maisin, and "Actions de Recherches Concertées-Communauté Française de Belgique-ARC 04/09-317."

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: C. Baudelet and B. Jordan are Research Fellows of the FNRS. O. Feron is a Research Associate of the FNRS.

Received 4/ 3/06; revised 8/25/06; accepted 10/11/06.

	References

Top Abstract Materials and Methods Results Discussion References

 

1. Kaanders JH, Bussink J, van der Kogel AJ. Clinical studies of hypoxia modification in radiotherapy. Semin Radiat Oncol 2004;14:233–40.[CrossRef][Medline]
2. Nordsmark M, Bentzen SM, Rudat V, et al. Prognostic value of tumor oxygenation in 397 head and neck tumors after primary radiation therapy. An international multi-center study. Radiother Oncol 2005;77:18–24.[CrossRef][Medline]
3. Brown JM, Wilson WR. Exploiting tumour hypoxia in cancer treatment. Nat Rev Cancer 2004;4:437–47.[CrossRef][Medline]
4. Ansiaux R, Baudelet C, Cron GO, et al. Botulinum toxin potentiates cancer radiotherapy and chemotherapy. Clin Cancer Res 2006;12:1276–83.[Abstract/Free Full Text]
5. Bussink J, Kaanders JH, van der Kogel AJ. Clinical outcome and tumour microenvironmental effects of accelerated radiotherapy with carbogen and nicotinamide. Acta Oncol 1999;38:875–82.[CrossRef][Medline]
6. Gallez B, Jordan BF, Baudelet C, Misson PD. Pharmacological modifications of the partial pressure of oxygen in murine tumors: evaluation using in vivo EPR oximetry. Magn Reson Med 1999;42:627–30.[CrossRef][Medline]
7. Song CW, Park H, Griffin RJ. Improvement of tumor oxygenation by mild hyperthermia. Radiat Res 2001;155:515–28.[CrossRef][Medline]
8. Kleinberg L, Grossman SA, Carson K, et al. Survival of patients with newly diagnosed glioblastoma multiforme treated with RSR13 and radiotherapy: results of a phase II new approaches to brain tumor therapy CNS consortium safety and efficacy study. J Clin Oncol 2002;20:3149–55.[Abstract/Free Full Text]
9. Hou H, Khan N, O'Hara JA, et al. Increased oxygenation of intracranial tumors by efaproxyn (efaproxiral), an allosteric hemoglobin modifier: in vivo EPR oximetry study. Int J Radiat Oncol Biol Phys 2005;61:1503–9.[CrossRef][Medline]
10. Secomb TW, Hsu R, Ong ET, Gross JF, Dewhirst MW. Analysis of the effects of oxygen supply and demand on hypoxic fraction in tumors. Acta Oncol 1995;34:313–6.[Medline]
11. Biaglow JE, Manevich Y, Leeper D, et al. MIBG inhibits respiration: potential for radio- and hyperthermic sensitization. Int J Radiat Oncol Biol Phys 1998;42:871–6.[CrossRef][Medline]
12. Jordan BF, Gregoire V, Demeure RJ, et al. Insulin increases the sensitivity of tumors to irradiation: involvement of an increase in tumor oxygenation mediated by a nitric oxide-dependent decrease of the tumor cells oxygen consumption. Cancer Res 2002;62:3555–61.[Abstract/Free Full Text]
13. Jordan BF, Sonveaux P, Feron O, et al. Nitric oxide as a radiosensitizer: evidence for an intrinsic role in addition to its effect on oxygen delivery and consumption. Int J Cancer 2004;109:768–73.[CrossRef][Medline]
14. Crokart N, Radermacher K, Jordan BF, et al. Tumor radiosensitization by antiinflammatory drugs: evidence for a new mechanism involving the oxygen effect. Cancer Res 2005;65:7911–6.[Abstract/Free Full Text]
15. Morin C, Zini R, Simon N, Charbonnier P, Tillement JP, Le Louet H. Low glucocorticoid concentrations decrease oxidative phosphorylation of isolated rat brain mitochondria: an additional effect of dexamethasone. Fundam Clin Pharmacol 2000;14:493–500.[Medline]
16. Simon N, Jolliet P, Morin C, Zini P, Urien S, Tillement JP. Glucocorticoids decrease cytochrome c oxidase activity of isolated rat kidney mitochondria. FEBS Lett 1998;435:25–8.[CrossRef][Medline]
17. Gallez B, Baudelet C, Jordan BF. Assessment of tumor oxygenation by electron paramagnetic resonance: principles and applications. NMR Biomed 2004;17:240–62.[CrossRef][Medline]
18. Sersa G, Cemazar M, Miklavcic D, Chaplin DJ. Tumor blood flow modifying effect of electrochemotherapy with bleomycin. Anticancer Res 1999;19:4017–22.[Medline]
19. Ansiaux R, Baudelet C, Jordan BF, et al. Thalidomide radiosensitizes tumors through early changes in the tumor microenvironment. Clin Cancer Res 2005;11:743–50.[Abstract/Free Full Text]
20. Baudelet C, Ansiaux R, Jordan BF, Havaux X, Macq B, Gallez B. Physiological noise in murine solid tumours using T2*-weighted gradient-echo imaging: a marker of tumour acute hypoxia? Phys Med Biol 2004;49:3389–411.[CrossRef][Medline]
21. Cron GO, Beghein N, Crokart N, et al. Changes in the tumor microenvironment during low-dose-rate permanent seed implantation iodine-125 brachytherapy. Int J Radiat Oncol Biol Phys 2005;63:1245–51.[CrossRef][Medline]
22. Dlugosz JW, Korsten MA, Lieber CS. The effect of the prostaglandin analogue-misoprostol on rat liver mitochondria after chronic alcohol feeding. Life Sci 1991;49:969–78.[CrossRef][Medline]
23. Karmazyn M. Prostaglandins stimulate calcium-linked changes in heart mitochondrial respiration. Am J Physiol 1986;251:H141–7.
24. Okabe K, Malchesky PS, Nose Y. Protective effect of prostaglandin I2 on hepatic mitochondrial function of the preserved rat liver. Tohoku J Exp Med 1986;150:373–9.[Medline]
25. Wimhurst JM, Harris EJ. Prostaglandin induction of mitochondrial respiration and adaptive changes of enzymes in the perfused rat liver. Eur J Biochem 1974;42:33–43.[Medline]
26. Brock WA, Williams M, McNaney D, Milas L, Peters LJ, Weichselbaum RR. Modification by dexamethasone of radiation response of in vitro cultured cells. Int J Radiat Oncol Biol Phys 1984;10:2113–7.[Medline]
27. Kamradt MC, Mohideen N, Krueger E, Walter S, Vaughan AT. Inhibition of radiation-induced apoptosis by dexamethasone in cervical carcinoma cell lines depends upon increased HPV E6/E7. Br J Cancer 2000;82:1709–16.[CrossRef][Medline]
28. Kamradt MC, Mohideen N, Vaughan AT. RU486 increases radiosensitivity and restores apoptosis through modulation of HPV E6/E7 in dexamethasone-treated cervical carcinoma cells. Gynecol Oncol 2000;77:177–82.[CrossRef][Medline]
29. Millar BC, Jinks S. The effect of dexamethasone on the radiation survival response and misonidazole-induced hypoxic-cell cytotoxicity in Chinese hamster cells V-79-753B in vitro. Br J Radiol 1981;54:505–11.[Abstract]
30. Millar BC, Jenkins TC, Fielden EM, Jinks S. Polyfunctional Radiosensitizers. VI. Dexamethasone inhibits shoulder modification by uncharged nitroxyl biradicals in mammalian cells irradiated in vitro. Radiat Res 1983;96:160–72.[CrossRef][Medline]
31. Kondziolka D, Somaza S, Martinez AJ, et al. Radioprotective effects of the 21-aminosteroid U-74389G for stereotactic radiosurgery. Neurosurgery 1997;41:203–8.[CrossRef][Medline]
32. Mariotta M, Perewusnyk G, Koechli OR, et al. Dexamethasone-induced enhancement of resistance to ionizing radiation and chemotherapeutic agents in human tumor cells. Strahlenther Onkol 1999;175:392–6.[CrossRef][Medline]
33. Lordo CD, Stroude EC, Delmaestro RF. The effects of dexamethasone on C6 astrocytoma radiosensitivity. J Neurosurg 1989;70:767–73.[Medline]
34. Benediktsson G, Blomquist E, Carlsson J. Failure of betamethasone to alter the radiation response of two cultured human glioma cell-lines. J Neurooncol 1990;8:47–53.[CrossRef][Medline]
35. Gomes JA, Stevens RD, Lewin JJ, Mirski MA, Bhardwaj A. Glucocorticoid therapy in neurologic critical care. Crit Care Med 2005;33:1214–24.[CrossRef][Medline]
36. Kaal EC, Vecht CJ. The management of brain edema in brain tumors. Curr Opin Oncol 2004;16:593–600.[CrossRef][Medline]

This article has been cited by other articles:

				J. DeWever, F. Frerart, C. Bouzin, C. Baudelet, R. Ansiaux, P. Sonveaux, B. Gallez, C. Dessy, and O. Feron Caveolin-1 Is Critical for the Maturation of Tumor Blood Vessels through the Regulation of Both Endothelial Tube Formation and Mural Cell Recruitment Am. J. Pathol., November 1, 2007; 171(5): 1619 - 1628. [Abstract] [Full Text] [PDF]

				M. W. Dewhirst, I. C. Navia, D. M. Brizel, C. Willett, and T. W. Secomb Multiple Etiologies of Tumor Hypoxia Require Multifaceted Solutions Clin. Cancer Res., January 15, 2007; 13(2): 375 - 377. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Crokart, N. Articles by Gallez, B. Search for Related Content PubMed PubMed Citation Articles by Crokart, N. Articles by Gallez, B. Related Collections Commentary