Tumor Radiosensitization by Antiinflammatory Drugs: Evidence for a New Mechanism Involving the Oxygen Effect

Crokart, Nathalie; Radermacher, Kim A.; Jordan, Bénédicte F.; Baudelet, Christine; Cron, Greg O.; Grégoire, Vincent; Beghein, Nelson; Bouzin, Caroline; Feron, Olivier; Gallez, Bernard

doi:10.1158/0008-5472.can-05-1288

Cited by 77 publications

(56 citation statements)

References 34 publications

(50 reference statements)

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“…The decrease in perfusion is likely due to a vascular steal effect with a redistribution of the blood flow that feeds the tumor and the muscle. More recently, we observed that NS-398, an antiinflammatory agent, induced a similar effect in the same tumor model (15).…”

Section: Discussionsupporting

confidence: 52%

“…2), showing that the perfusion is significantly reduced by NS-398. The value of Vp (plasmatic volume fraction) was unchanged, and the permeability (K trans and K ep ) was significantly decreased in this case (15).…”

Section: Discussionmentioning

confidence: 65%

“…Theoretical modeling studies by Secomb et al (14) showed that hypoxia was more efficiently reduced by a reduction in the oxygen consumption rate than by an increase in the oxygen sup-ply. NS-398, a nonsteroidal antiinflammatory drug (NSAID), was also shown to increase the radiosensitivity of tumors by increasing tumor oxygenation via the same mechanism as insulin (15).…”

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confidence: 99%

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Complex relationship between changes in oxygenation status and changes in R: The case of insulin and NS‐398, two inhibitors of oxygen consumption

Jordan¹,

Crokart²,

Baudelet³

et al. 2006

Magnetic Resonance in Med

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Insulin and NS-398 have been reported to inhibit oxygen consumption in experimental tumor models, thereby increasing oxygenation and radiosensitization. The aim of this work was to use MRI to study changes in murine FSaII tumor hemodynamics after administration of those oxygen consumption inhibitors. A multiple-echo gradient-echo (GRE) MRI sequence (4.7 T) was used to map changes in three factors: the GRE signal (at TE ‫؍‬ 20 ms), the parameter S 0 (theoretical signal at TE ‫؍‬ 0 ms), and the relaxation rate R* 2 . Perfusion maps were obtained by dynamic contrast-enhanced (DCE) MRI. Insulin caused a significant decrease in the tumor blood oxygen level-dependent (BOLD) signal over time. factor This was likely the result of decreased blood flow, since both S 0 and the percentage of perfused tumor decreased as well. Tumor R* 2 did not change significantly in response to the treatments, which is surprising considering that other non-MRI techniques (electron paramagnetic resonance (EPR) oximetry and fiber-optic probes) have shown that tumor oxygenation increases after treatment. This suggests that metabolic changes associated with vasoactive challenges may have an unpredictable influence on blood saturation and R* 2 . In conclusion, this study further emphasizes the fact that changes in BOLD signal and R* 2 in tumors do not depend uniquely on changes in oxygenation status. Magn Reson Med 56:637-643, 2006.

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Section: Discussionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 65%

mentioning

confidence: 99%

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Complex relationship between changes in oxygenation status and changes in R: The case of insulin and NS‐398, two inhibitors of oxygen consumption

Jordan¹,

Crokart²,

Baudelet³

et al. 2006

Magnetic Resonance in Med

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“…Diclofenac is also widely used to treat pain associated with cancer, and treatment combinations of diclofenac with chemotherapeutic drugs are common. In addition, preclinical evidence is accumulating that NSAIDs, including diclofenac, have beneficial effects as adjuvant therapy in treatment of some types of cancer (Crokart et al, 2005;Johnsen et al, 2005). Due to this widespread co-use of drugs, interactions of NSAIDs with chemotherapeutic drugs can result in unexpected toxicities or failure of chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

Transport of Diclofenac by Breast Cancer Resistance Protein (ABCG2) and Stimulation of Multidrug Resistance Protein 2 (ABCC2)-Mediated Drug Transport by Diclofenac and Benzbromarone

Lagas

Kruijssen²,

Wetering³

et al. 2008

Drug Metab Dispos

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ABSTRACT:Diclofenac is an important analgesic and anti-inflammatory drug, widely used for treatment of postoperative pain, rheumatoid arthritis, and chronic pain associated with cancer. Consequently, diclofenac is often used in combination regimens and undesirable drug-drug interactions may occur. Because many drug-drug interactions may occur at the level of drug transporting proteins, we studied interactions of diclofenac with apical ATP-binding cassette (ABC) multidrug efflux transporters. Using Madin-Darby canine kidney (MDCK)-II cells transfected with human P-glycoprotein (P-gp; MDR1/ABCB1), multidrug resistance protein 2 (MRP2/ABCC2), and breast cancer resistance protein (BCRP/ABCG2) and murine Bcrp1, we found that diclofenac was efficiently transported by murine Bcrp1 and moderately by human BCRP but not by P-gp or MRP2. Furthermore, in Sf9-BCRP membrane vesicles diclofenac inhibited transport of methotrexate in a concentration-dependent manner. We next used MDCK-II-MRP2 cells to study interactions of diclofenac with MRP2-mediated drug transport. Diclofenac stimulated paclitaxel, docetaxel, and saquinavir transport at only 50 M. We further found that the uricosuric drug benzbromarone stimulated MRP2 at an even lower concentration, having maximal stimulatory activity at only 2 M. Diclofenac and benzbromarone stimulated MRP2-mediated transport of amphipathic lipophilic drugs at 10-and 250-fold lower concentrations, respectively, than reported for other MRP2 stimulators. Because these concentrations are readily achieved in patients, adverse drug-drug interactions may occur, for example, during cancer therapy, in which drug concentrations are often critical and stimulation of elimination via MRP2 may result in suboptimal chemotherapeutic drug concentrations. Moreover, stimulation of MRP2 activity in tumors may lead to increased efflux of chemotherapeutic drugs and thereby drug resistance.Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits potent analgesic and anti-inflammatory properties and is extensively used to treat postoperative pain, rheumatoid arthritis, osteoarthritis, and acute gouty arthritis (Davies and Anderson, 1997). Diclofenac is also widely used to treat pain associated with cancer, and treatment combinations of diclofenac with chemotherapeutic drugs are common. In addition, preclinical evidence is accumulating that NSAIDs, including diclofenac, have beneficial effects as adjuvant therapy in treatment of some types of cancer (Crokart et al., 2005;Johnsen et al., 2005). Due to this widespread co-use of drugs, interactions of NSAIDs with chemotherapeutic drugs can result in unexpected toxicities or failure of chemotherapy. For example, NSAIDs are known to restrict plasma clearance of methotrexate (MTX). When MTX is used at high-dose regimens for cancer treatment, interactions with NSAIDs can result in severe toxicity, with sometimes fatal outcome (Thyss et al., 1986). In a recent study, using human kidney slides, it was demonstrated that diclofenac and its acyl-glucuronide c...

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“…It has been predicted that modification of oxygen consumption is much more efficient at alleviating hypoxia than modification of oxygen delivery (10). Several drugs that inhibit mitochondrial respiration, such as metaiodobenzylguanidine (11), insulin (12,13), and cyclooxygenase-2 inhibitors (14), have been characterized for their potential to increase tumor oxygenation and thereby enhance radiosensitivity.…”

mentioning

confidence: 99%

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

Crokart¹,

Jordan²,

Baudelet³

et al. 2007

Clinical Cancer Research

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Purpose: We hypothesized that glucocorticoids may enhance tumor radiosensitivity by increasing tumor oxygenation (pO 2 ) through inhibition of mitochondrial respiration. Experimental Design: The effect of three glucocorticoids (hydrocortisone, dexamethasone, and prednisolone) on pO 2 was studied in murine TLT liver tumors and FSaII fibrosarcomas. At the time of maximum pO 2 (t max , 30 min after administration), perfusion, oxygen consumption, and radiation sensitivity were studied. Local pO 2 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 pO 2 . At t max , tumor perfusion decreased, indicating that the increase in pO 2 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.Tumor hypoxia is a critical determinant of resistance to radiotherapy and chemotherapy (1, 2). To target this resistance, prodrugs have been developed that are activated in hypoxic regions (3). In addition to this approach, we may also consider that a transient increase in tumor oxygenation may be beneficial if combined with radiotherapy. Indeed, a number of tumor oxygenating treatments have been developed to improve the therapeutic outcome. Mechanistically, tumor hypoxia results from an imbalance between oxygen delivery and oxygen consumption, either of which may be potentially targeted by therapeutic interventions. On one hand, oxygen delivery may be increased by increasing tumor perfusion (4 -7) or by changing the hemoglobin saturation curve (8, 9). On the other hand, tumor hypoxia can be alleviated by decreasing the oxygen consumption. It has been predicted that modification of oxygen consumption is much more efficient at alleviating hypoxia than modification of oxygen delivery (10). Several drugs that inhibit mitochondrial respiration, such as metaiodobenzylguanidine (11), insulin (12, 13), and cyclooxygenase-2 inhibitors (14), have been characterized for their potential to increase tumor oxygenation and thereby enhance radiosensitivity.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....

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Tumor Radiosensitization by Antiinflammatory Drugs: Evidence for a New Mechanism Involving the Oxygen Effect

Cited by 77 publications

References 34 publications

Complex relationship between changes in oxygenation status and changes in R: The case of insulin and NS‐398, two inhibitors of oxygen consumption

Complex relationship between changes in oxygenation status and changes in R: The case of insulin and NS‐398, two inhibitors of oxygen consumption

Transport of Diclofenac by Breast Cancer Resistance Protein (ABCG2) and Stimulation of Multidrug Resistance Protein 2 (ABCC2)-Mediated Drug Transport by Diclofenac and Benzbromarone

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

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