References of "Martinive, Philippe"
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See detailNew indications for radiotherapy: primary liver cancer and secondary liver oligometastases
JANVARY, Zsolt Levente ULg; JANSEN, Nicolas ULg; MARTINIVE, Philippe ULg et al

in Belgian Journal of Medical Oncology [=BJMO] (2011), 5(1), 8-13

Surgery is considered to be the standard treatment for intrahepatic malignancies, primary <br />cancers and metastatic lesions. However, a great many patients are not eligible for surgical <br ... [more ▼]

Surgery is considered to be the standard treatment for intrahepatic malignancies, primary <br />cancers and metastatic lesions. However, a great many patients are not eligible for surgical <br />intervention. Modern stereotactic radiotherapy has the potential to be an effective alternative <br />treatment modality with low toxicity for patients with primary hepatocellular carcinoma <br />and liver oligometastases. In this paper we intend to review the current status and published <br />experiences in the field of liver irradiation. [less ▲]

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See detailEVALUATION OF THE AUTOMATIC IMAGE REGISTRATION FEATURES OF A KV CONE-BEAM CT IMAGING SYSTEM
JANVARY, Zsolt Levente ULg; JANSEN, Nicolas ULg; MATHOT, Michel ULg et al

Poster (2010, September)

As a part of the clinical implementation of a kV cone-beam CT (CBCT) volumetric imaging system for new Elekta Synergy linear accelerators, the automatic image registration (IR) system of the XVI Software ... [more ▼]

As a part of the clinical implementation of a kV cone-beam CT (CBCT) volumetric imaging system for new Elekta Synergy linear accelerators, the automatic image registration (IR) system of the XVI Software was studied. We examined the effect of the variability of matching parameters of the software on the results of the patient position errors. [less ▲]

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See detail4DCT EVALUATION OF THE RESPIRATORY-RELATED MOVEMENT OF THE BREAST USING SURGICAL CLIPS AS FIDUCIALS
JANVARY, Zsolt Levente ULg; Broens, Audrey; MARTINIVE, Philippe ULg et al

Poster (2010, September)

To explore the respiratory-related displacement of the tumour bed in patients undergoing breast conserving <br />surgery followed by external-beam radiotherapy, by using respiratory correlated imaging and ... [more ▼]

To explore the respiratory-related displacement of the tumour bed in patients undergoing breast conserving <br />surgery followed by external-beam radiotherapy, by using respiratory correlated imaging and surgical clips as fiducials. [less ▲]

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See detailEVALUATION OF THE AUTOMATIC IMAGE REGISTRATION FEATURES OF A KV CONE-BEAM CT IMAGING SYSTEM
JANVARY, Zsolt Levente ULg; JANSEN, Nicolas ULg; MATHOT, Michel ULg et al

in Radiotherapy & Oncology (2010), 96(supp 1),

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See detailIdentification of cyclooxygenase-2 as a major actor of the transcriptomic adaptation of endothelial and tumor cells to cyclic hypoxia: effect on angiogenesis and metastases.
Daneau; Boidot; MARTINIVE, Philippe ULg et al

in Clinical Cancer Research : An Official Journal of the American Association for Cancer Research (2010), 16(2), 410-419

Purpose: Cyclic hypoxia in tumors originates from heterogeneities in RBC flux and influences not only tumor cells but also endothelial cells lining tumor blood vessels. Whether pO2 fluctuations ... [more ▼]

Purpose: Cyclic hypoxia in tumors originates from heterogeneities in RBC flux and influences not only tumor cells but also endothelial cells lining tumor blood vessels. Whether pO2 fluctuations, particularly transient reoxygenation periods, alter the well-known hypoxia-inducible factor (HIF)–dependent gene program is largely unknown. Experimental Design: We compared the transcriptomic profiles of endothelial and tumor cells exposed to cyclic hypoxia versus continuous hypoxia to uncover a possible differential effect on angiogenesis and metastases. Results: Microarray analyses identified early genes that were selectively induced by cyclic hypoxia in endothelial cells. Among them, we focused on PTGS2 because the observed increase in mRNA expression led to a significant increase in the expression and activity of cyclooxygenase-2 (COX-2; the protein product of PTGS2). HIF-1α was shown to be stabilized by cyclic hypoxia (despite reoxygenation periods) and to favor COX-2 induction as validated by the use of echinomycin and HIF-1α targeting small interfering RNA. Using a specific COX-2 inhibitor and a dedicated COX-2 targeting small interfering RNA, we documented that COX-2 accounted for the higher endothelial cell survival and angiogenic potential conferred by cyclic hypoxia. Cyclic hypoxia also led to a preferential COX-2 induction in tumor cells and, contrary to continuous hypoxia, fostered a higher metastatic take of prechallenged tumor cells. Conclusions: Our study documents that PTGS2/COX-2 is part of a cyclic hypoxia gene signature and largely accounts for the unique phenotype of endothelial and tumor cells exposed to fluctuations in pO2, thereby offering new perspectives for the clustering of tumors expressing COX-2 together with other cyclic hypoxia-responsive genes. Clin Cancer Res; 16(2); 410–9 [less ▲]

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See detailLa vascularisation tumorale en tant que source de résistance aux traitements de radiothérapie et chimiothérapie
MARTINIVE, Philippe ULg; COUCKE, Philippe ULg

in Revue Médicale de Liège (2010), 65(3), 133-139

Angiogenesis is a hallmark of tumours. The newly formed tumour vessels are structurally and functionally abnormal leading to tumour perfusion heterogeneities and subsequently to the development of hypoxic ... [more ▼]

Angiogenesis is a hallmark of tumours. The newly formed tumour vessels are structurally and functionally abnormal leading to tumour perfusion heterogeneities and subsequently to the development of hypoxic areas. Generally, tumour hypoxia refers to an increasing distance between vasculature and tumour cells (i.e. chronic hypoxia). Chronic hypoxia promotes tumour resistance to treatments and metastasis. The temporal aspect of hypoxia is completely neglected in chronic hypoxia. Intermittent hypoxia (HI) takes the transient and temporal aspect of hypoxia into account. HI is defined as pO2 fluctuations in tumour vessels secondary to transient arrest of tumour blood flow. IH extends the concept of tumour hypoxia to tumour vessels and vascular cells. Transient arrest of tumour blood flow promotes tumour resistance to radio- and chemotherapy treatments and favours metastasis. Moreover, IH protects tumour vessels and endothelial cells against pro-apoptotic stresses and promotes angiogenesis. A comprehensive dissection of the mechanisms leading to IH allows the development and establishment of new therapeutic approaches. [less ▲]

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See detailImpact of cyclic hypoxia on HIF-1a regulation in endothelial cells: new insights for anti-tumor treatments
Martinive, Philippe ULg

in FEBS Journal (2008)

Impact of cyclic hypoxia on HIF-1alpha regulation in endothelial cells - new insights for anti-tumor treatments.Martinive P, Defresne F, Quaghebeur E, Daneau G, Crokart N, Grégoire V, Gallez B, Dessy C ... [more ▼]

Impact of cyclic hypoxia on HIF-1alpha regulation in endothelial cells - new insights for anti-tumor treatments.Martinive P, Defresne F, Quaghebeur E, Daneau G, Crokart N, Grégoire V, Gallez B, Dessy C, Feron O. Unit of Pharmacology and Therapeutics, Université catholique de Louvain, Brussels, Belgium. Heterogeneities in tumor blood flow are associated with cyclic changes in pO(2) or cyclic hypoxia. A major difference from O(2) diffusion-limited or chronic hypoxia is that the tumor vasculature itself may be directly influenced by the fluctuating hypoxic environment, and the reoxygenation phases complicate the usual hypoxia-induced phenotypic pattern. Here, we determined the cyclic hypoxia-driven pathways that modulate hypoxia inducible factor (HIF)-1alpha abundance in endothelial cells to identify possible therapeutic targets. We found that exposure of endothelial cells to cycles of hypoxia/reoxygenation led to accumulation of HIF-1alpha during the hypoxic periods and the phosphorylation of protein kinase B (Akt), extracellular regulated kinase (ERK) and endothelial nitric oxide synthase (eNOS) during the reoxygenation phases. We identified stimulation of mitochondrial respiration and activation of the phosphoinositide-3 kinase (PI3K)/Akt pathway during intervening reoxygenation periods as major triggers of the stabilization of HIF-1alpha. We also found that the NOS inhibitor nitro-l-arginine methyl ester further stimulated the cyclic hypoxia-driven HIF-1alpha accumulation and the associated gain in endothelial cell survival, thereby mirroring the effects of a PI3K/Akt inhibitor. However, combination of both drugs resulted in a net reduction in HIF-1alpha and a dramatic in decrease in endothelial cell survival. In conclusion, this study identified cyclic hypoxia, as reported in many tumor types, as a unique biological challenge for endothelial cells that promotes their survival in a HIF-1alpha-dependent manner through phenotypic alterations occurring during the reoxygenation periods. These observations also indicate the potential of combining Akt-targeting drugs with anti-angiogenic drugs, in particular those interfering with the NO pathway. PMID: 19077164 [PubMed - as supplied by publisher [less ▲]

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See detail(19) F NMR in vivo spectroscopy reflects the effectiveness of perfusion - enhancing vascular modifiers for improving gemcitabine chemotheraypy
Cron, Greg O.; Ansiaux; MARTINIVE, Philippe ULg et al

in Magnetic Resonance in Medicine : Official Journal of the Society of Magnetic Resonance in Medicine (2008)

Laboratory of Biomedical Magnetic Resonance and Laboratory of Medicinal Chemistry and Radiopharmacy, Université Catholique de Louvain, UCL, Brussels, Belgium. Nuclear magnetic resonance spectroscopy of ... [more ▼]

Laboratory of Biomedical Magnetic Resonance and Laboratory of Medicinal Chemistry and Radiopharmacy, Université Catholique de Louvain, UCL, Brussels, Belgium. Nuclear magnetic resonance spectroscopy of fluorine-19 ((19)F NMR) has proven useful for evaluating kinetics of fluorinated chemotherapy drugs in tumors in vivo. This work investigated how three perfusion-enhancing vascular modifiers (BQ123, thalidomide, and Botulinum neurotoxin type A [BoNT-A]) would affect the chemotherapeutic efficacy of gemcitabine, a fluorinated drug widely used in human cancer treatment. Murine tumor growth experiments demonstrated that only BoNT-A showed a strong trend to enhance tumor growth inhibition by gemcitabine (1.7 days growth delay, P = 0.052, Student t-test). In accord with these results, (19)F NMR experiments showed that only BoNT-A increased significantly the uptake of gemcitabine in tumors (50% increase, P = 0.0008, Student t-test). Further experiments on gemcitabine kinetics (NMR vs time) and distribution ((19)F MRI) confirmed the uptake-enhancing properties of BoNT-A. The results of this study demonstrate that (19)F NMR can monitor modulation of the pharmacokinetics of fluorinated chemotherapy drugs in tumors. The results also show that (19)F NMR data can give a strong indication of the effectiveness of perfusion-enhancing vascular modifiers for improving gemcitabine chemotherapy in murine tumors. (19)F NMR is a promising tool for preclinical evaluation of such vascular modifiers and may ultimately be used in the clinic to monitor how these modifiers affect chemotherapy. 2007 Wiley-Liss, Inc PMID: 18050344 [PubMed - indexed for MEDLINE] [less ▲]

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See detailPreconditioning of the tumor vasculature and tumor cells by intermittent hypoxia: implications for anti-cancer therapies
Martinive, Philippe ULg

Poster (2007, January)

Hypoxia is a common feature in tumors associated with an increased resistance of tumor cells to therapies. In addition to O(2) diffusion-limited hypoxia, another form of tumor hypoxia characterized by ... [more ▼]

Hypoxia is a common feature in tumors associated with an increased resistance of tumor cells to therapies. In addition to O(2) diffusion-limited hypoxia, another form of tumor hypoxia characterized by fluctuating changes in pO(2) within the disorganized tumor vascular network is described. Here, we postulated that this form of intermittent hypoxia promotes endothelial cell survival, thereby extending the concept of hypoxia-driven resistance to the tumor vasculature. We found that endothelial cell exposure to cycles of hypoxia reoxygenation not only rendered them resistant to proapoptotic stresses, including serum deprivation and radiotherapy, but also increased their capacity to migrate and organize in tubes. By contrast, prolonged hypoxia failed to exert protective effects and even seemed deleterious when combined with radiotherapy. The use of hypoxia-inducible factor-1alpha (HIF-1alpha)-targeting small interfering RNA led us to document that the accumulation of HIF-1alpha during intermittent hypoxia accounted for the higher resistance of endothelial cells. We also used an in vivo approach to enforce intermittent hypoxia in tumor-bearing mice and found that it was associated with less radiation-induced apoptosis within both the vascular and the tumor cell compartments (versus normoxia or prolonged hypoxia). Radioresistance was further ascertained by an increased rate of tumor regrowth in irradiated mice preexposed to intermittent hypoxia and confirmed in vitro using distinctly radiosensitive tumor cell lines. In conclusion, we have documented that intermittent hypoxia may condition endothelial cells and tumor cells in such a way that they are more resistant to apoptosis and more prone to participate in tumor progression. Our observations also underscore the potential of drugs targeting HIF-1alpha to resensitize the tumor vasculature to anticancer treatments. PMID: 17178869 [PubMed - indexed for MEDLINE] [less ▲]

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See detailGlucocorticoids Modulate Tumor Radiation Response through a Decrease in Tumor Oxygen Consumption
Crokart, Nathalie; JORDAN, Bénédicte; BAUDELET, Christine et al

in Clinical Cancer Research : An Official Journal of the American Association for Cancer Research (2007), 15(13), 6305

Purpose: We hypothesized that glucocorticoids may enhance tumor radiosensitivity by increasing tumor oxygenation (pO2) through inhibition of mitochondrial respiration. <br /> <br />Experimental Design ... [more ▼]

Purpose: We hypothesized that glucocorticoids may enhance tumor radiosensitivity by increasing tumor oxygenation (pO2) through inhibition of mitochondrial respiration. <br /> <br />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 (tmax, 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. <br /> <br />Results: All glucocorticoids tested caused a rapid increase in pO2. At tmax, tumor perfusion decreased, indicating that the increase in pO2 was not caused by an increase in oxygen supply. Also at tmax, global oxygen consumption decreased. When irradiation (25 Gy) was applied at tmax, the tumor radiosensitivity was enhanced (regrowth delay increased by a factor of 1.7). <br /> <br />Conclusion: These results show the potential usefulness of the administration of glucocorticoids before irradiation. [less ▲]

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See detailPreconditioning of the Tumor Vasculature and Tumor Cells by Intermittent Hypoxia: Implications for Anticancer Therapies
Martinive, Philippe ULg; DEFRESNE, Florence; BOUZIN, Caroline et al

in Cancer Research (2006), 66(24), 11736-44

Hypoxia is a common feature in tumors associated with an increased resistance of tumor cells to therapies. In addition to O2 diffusion–limited hypoxia, another form of tumor hypoxia characterized by ... [more ▼]

Hypoxia is a common feature in tumors associated with an increased resistance of tumor cells to therapies. In addition to O2 diffusion–limited hypoxia, another form of tumor hypoxia characterized by fluctuating changes in pO2 within the disorganized tumor vascular network is described. Here, we postulated that this form of intermittent hypoxia promotes endothelial cell survival, thereby extending the concept of hypoxia-driven resistance to the tumor vasculature. We found that endothelial cell exposure to cycles of hypoxia reoxygenation not only rendered them resistant to proapoptotic stresses, including serum deprivation and radiotherapy, but also increased their capacity to migrate and organize in tubes. By contrast, prolonged hypoxia failed to exert protective effects and even seemed deleterious when combined with radiotherapy. The use of hypoxia-inducible factor-1α (HIF-1α)–targeting small interfering RNA led us to document that the accumulation of HIF-1α during intermittent hypoxia accounted for the higher resistance of endothelial cells. We also used an in vivo approach to enforce intermittent hypoxia in tumor-bearing mice and found that it was associated with less radiation-induced apoptosis within both the vascular and the tumor cell compartments (versus normoxia or prolonged hypoxia). Radioresistance was further ascertained by an increased rate of tumor regrowth in irradiated mice preexposed to intermittent hypoxia and confirmed in vitro using distinctly radiosensitive tumor cell lines. In conclusion, we have documented that intermittent hypoxia may condition endothelial cells and tumor cells in such a way that they are more resistant to apoptosis and more prone to participate in tumor progression. Our observations also underscore the potential of drugs targeting HIF-1α to resensitize the tumor vasculature to anticancer treatments. (Cancer Res 2006; 66(24): 11736-44) [less ▲]

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See detailPotentiation of cyclophosphamide chemotherapy using the anti-angiogenic drug thalidomide: Importance of optimal scheduling to exploit the ‘normalization’ window of the tumor vasculature
SEGERS, Jérôme; DI FAZIO, Vincent; ANSIAUX, Réginald et al

in Cancer Letters (2006), 244(1), 12935

The aim of this work was to study how administration schedule affects potentiation of cyclophosphamide, an alkylating agent, by thalidomide, an anti-angiogenic agent. Tumor oxygenation after thalidomide ... [more ▼]

The aim of this work was to study how administration schedule affects potentiation of cyclophosphamide, an alkylating agent, by thalidomide, an anti-angiogenic agent. Tumor oxygenation after thalidomide administration was determined over time by EPR oximetry. Such measurements provide a surrogate marker for determining the timing of ‘normalization’ of tumor vasculature. Re-growth delays were measured using different combinations and schedules of treatments. Additionally, the uptake of the metabolite of cyclophosphamide (hydroxycyclophosphamide or OH-CP) into tumors was determined by high performance liquid chromatography/tandem mass spectrometry (HPLC/MS/MS). A significant increase in pO2 was observed after 2 and 3 days of treatment before eventually declining on day 4. Thalidomide potentiated the effect of cyclophosphamide only when cyclophosphamide was administered after 2 days of treatment with thalidomide (no significant benefit using other schedules). In this time frame, the HPLC/MS/MS measurements showed that the quantity of OH-CP penetrating into the tumor was about twice in mice treated by thalidomide compared to controls. In conclusion, the present study demonstrates that the benefit of combined therapy using an anti-angiogenic agent with a cytotoxic agent requires knowledge of the time window during which the vessels initially become normalized. [less ▲]

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See detailMechanism of reoxygenation after antiangiogenic therapy using SU5416 and its importance for guiding combined antitumor therapy
ANSIAUX, Réginald; BAUDELET, Christine; JORDAN, Bénédicte et al

in Cancer Research (2006), 66(19), 9698704

Emerging preclinical studies support the concept of a transient "normalization" of tumor vasculature during the early stage of antiangiogenic treatment, with possible beneficial effects on associated ... [more ▼]

Emerging preclinical studies support the concept of a transient "normalization" of tumor vasculature during the early stage of antiangiogenic treatment, with possible beneficial effects on associated radiotherapy or chemotherapy. One key issue in this area of research is to determine whether this feature is common to all antiangiogenic drugs and whether the phenomenon occurs in all types of tumors. In the present study, we characterized the evolution of the tumor oxygenation (in transplantable liver tumor and FSAII tumor models) after administration of SU5416, an antagonist of the vascular endothelial growth factor receptor. SU5416 induced an early increase in tumor oxygenation [measured by electronic paramagnetic resonance (EPR)], which did not correlate with remodeling of the tumor vasculature (assessed by CD31 labeling using immunohistochemistry) or with tumor perfusion (measured by dynamic contrast enhanced-magnetic resonance imaging). Inhibition of mitochondrial respiration (measured by EPR) was responsible for this early reoxygenation. Consistent with these unique findings in the tumor microenvironment, we found that SU5416 potentiated tumor response to radiotherapy but not to chemotherapy. In addition to the fact that the characterization of the tumor oxygenation is essential to enable correct application of combined therapies, our results show that the long-term inhibition of oxygen consumption is a potential novel target in this class of compounds. [less ▲]

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See detailReversal of temporal and spatial heterogeneities in tumor perfusion identifies the tumor vascular tone as a tunable variable to improve drug delivery
Martinive, Philippe ULg; DE WEVER, Julie; BOUZIN, Caroline et al

in Molecular Cancer Therapeutics (2006), 5(6), 16207

Maturation of tumor vasculature involves the recruitment of pericytes that protect the endothelial tubes from a variety of stresses, including antiangiogenic drugs. Mural cells also provide mature tumor ... [more ▼]

Maturation of tumor vasculature involves the recruitment of pericytes that protect the endothelial tubes from a variety of stresses, including antiangiogenic drugs. Mural cells also provide mature tumor blood vessels with the ability to either relax or contract in response to substances present in the tumor microenvironment. The observed cyclic alterations in tumor blood flow and the associated deficit in chemotherapeutic drug delivery could in part arise from this vasomodulatory influence. To test this hypothesis, we focused on endothelin-1 (ET-1), which, besides its autocrine effects on tumor cell growth, is a powerful vasoconstrictor. We first document that an ETA receptor antagonist induced relaxation of microdissected tumor arterioles and selectively and quantitatively increased tumor blood flow in experimental tumor models. We then combined dye staining of functional vessels, fluorescent microsphere-based mapping, and magnetic resonance imaging to identify heterogeneities in tumor blood flow and to examine the reversibility of such phenomena. Data from all these techniques concurred to show that administration of an ETA receptor antagonist could reduce the extent of underperfused tumor areas, proving the key role of vessel tone variations in tumor blood flow heterogeneity. We also provide evidence that ETA antagonist administration could, despite an increase in tumor interstitial fluid pressure, improve access of cyclophosphamide to the tumor compartment and significantly influence tumor growth. In conclusion, tumor endogenous ET-1 production participates largely in the temporal and spatial variations in tumor blood flow. ETA antagonist administration may wipe out such heterogeneities, thus representing an adjuvant strategy that could improve the delivery of conventional chemotherapy to tumors. [Mol Cancer Ther 2006;5(6):1620–7] [less ▲]

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See detailCaveolin plays a central role in endothelial progenitor cell mobilization and homing in SDF-1-driven postischemic vasculogenesis.
SBAA, E; DE WEVER, J; MARTINIVE, Philippe ULg et al

in Circulation Research (2006), 98(9), 121927

When neovascularization is triggered in ischemic tissues, angiogenesis but also (postnatal) vasculogenesis is induced, the latter requiring the mobilization of endothelial progenitor cells (EPC) from the ... [more ▼]

When neovascularization is triggered in ischemic tissues, angiogenesis but also (postnatal) vasculogenesis is induced, the latter requiring the mobilization of endothelial progenitor cells (EPC) from the bone marrow. Caveolin, the structural protein of caveolae, was recently reported to directly influence the angiogenic process through the regulation of the vascular endothelial growth factor (VEGF)/nitric oxide pathway. In this study, using caveolin-1 null mice (Cav(-/-)), we examined whether caveolin was also involved in the EPC recruitment in a model of ischemic hindlimb. Intravenous infusion of Sca-1(+) Lin(-) progenitor cells, but not bone marrow transplantation, rescued the defective neovascularization in Cav(-/-) mice, suggesting a defect in progenitor mobilization. The adhesion of Cav(-/-) EPC to bone marrow stromal cells indeed appeared to be resistant to the otherwise mobilizing SDF-1 (Stromal cell-Derived Factor-1) exposure because of a defect in the internalization of the SDF-1 cognate receptor CXCR4. Symmetrically, the attachment of Cav(-/-) EPC to SDF-1-presenting endothelial cells was significantly increased. Finally, EPC transduction with caveolin small interfering RNA reproduced this advantage in vitro and, importantly, led to a more extensive rescue of the ischemic hindlimb after intravenous infusion (versus sham-transfected EPC). These results underline the critical role of caveolin in ensuring the caveolae-mediated endocytosis of CXCR4, regulating both the SDF-1-mediated mobilization and peripheral homing of progenitor cells in response to ischemia. In particular, a transient reduction in caveolin expression was shown to therapeutically increase the engraftment of progenitor cells. [less ▲]

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See detailBotulinum toxin potentiates cancer radiotherapy and chemotherapy
ANSIAUX, Reginald; BAUDELET, Christine; CRON, Greg et al

in Clinical Cancer Research : An Official Journal of the American Association for Cancer Research (2006), 12(4), 127683

PURPOSE: Structural and functional abnormalities in the tumor vascular network are considered factors of resistance of solid tumors to cytotoxic treatments. To increase the efficacy of anticancer ... [more ▼]

PURPOSE: Structural and functional abnormalities in the tumor vascular network are considered factors of resistance of solid tumors to cytotoxic treatments. To increase the efficacy of anticancer treatments, efforts must be made to find new strategies for transiently opening the tumor vascular bed to alleviate tumor hypoxia (source of resistance to radiotherapy) and improve the delivery of chemotherapeutic agents. We hypothesized that Botulinum neurotoxin type A (BoNT-A) could interfere with neurotransmitter release at the perivascular sympathetic varicosities, leading to inhibition of the neurogenic contractions of tumor vessels and therefore improving tumor perfusion and oxygenation. <br /> <br />EXPERIMENTAL DESIGN: To test this hypothesis, BoNT-A was injected locally into mouse tumors (fibrosarcoma FSaII, hepatocarcinoma transplantable liver tumor), and electron paramagnetic resonance oximetry was used to monitor pO(2) in vivo repeatedly for 4 days. Additionally, contrast-enhanced magnetic resonance imaging was used to measure tumor perfusion in vivo. Finally, isolated arteries were mounted in wire myograph to monitor specifically the neurogenic tone developed by arterioles that were co-opted by the surrounding growing tumor cells. <br /> <br />RESULTS: Using these tumor models, we showed that local administration of BoNT-A (two sites; dose, 29 units/kg) substantially increases tumor oxygenation and perfusion, leading to a substantial improvement in the tumor response to radiotherapy (20 Gy of 250-kV radiation) and chemotherapy (cyclophosphamide, 50 mg/kg). This observed therapeutic gain results from an opening of the tumor vascular bed by BoNT-A because we showed that BoNT-A could inhibit neurogenic tone in the tumor vasculature. <br /> <br />CONCLUSIONS: The opening of the vascular bed induced by BoNT-A offers a way to significantly increase the response of tumors to radiotherapy and chemotherapy. [less ▲]

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See detailAnti-tumor effect of caveolin gene delivery are mediated through the inhibition of the pro-angiogenic and vasodilatating effect of nitric oxide
Brouet, A.; DeWever, Julie; MARTINIVE, Philippe ULg et al

in FASEB Journal (2005)

In tumors, caveolin-1, the structural protein of caveolae, constitutes a key switch through its function as a tumor suppressor and a promoter of metastases. In endothelial cells (EC), caveolin is also ... [more ▼]

In tumors, caveolin-1, the structural protein of caveolae, constitutes a key switch through its function as a tumor suppressor and a promoter of metastases. In endothelial cells (EC), caveolin is also known to directly interact with the endothelial nitric oxide synthase (eNOS) and thereby to modulate nitric oxide (NO)-mediated processes including vasodilation and angiogenesis. In this study, we examined whether the modulation of the stoichiometry of the caveolin/eNOS complex in EC lining tumor blood vessels could affect the tumor vasculature and consecutively tumor growth. For this purpose, we used cationic lipids, which are delivery systems effective at targeting tumor vs. normal vascular networks. We first documented that in vitro caveolin transfection led to the inhibition of both VEGF-induced EC migration and tube formation on Matrigel. The DNA-lipocomplex was then administered through the tail vein of tumor-bearing mice. The direct interaction between recombinant caveolin and native eNOS was validated in coimmunoprecipitation experiments from tumor extracts. A dramatic tumor growth delay was observed in mice transfected with caveolin- vs. sham-transfected animals. Using laser Doppler imaging and microprobes, we found that in the early time after lipofection (e.g., when macroscopic effects on the integrity of the tumor vasculature were not detectable), caveolin expression impaired NO-dependent tumor blood flow. At later stages post-transfection, a decrease in tumor microvessel density in the central core of caveolin-transfected tumors was also documented. In conclusion, our study reveals that by exploiting the exquisite regulatory interaction between eNOS and caveolin and the propensity of cationic lipids to target EC lining tumor blood vessels, caveolin plasmid delivery appears to be a safe and efficient way to block neoangiogenesis and vascular function in solid tumors, independently of any direct effects on tumor cells. [less ▲]

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