Combining Bevacizumab with Temozolomide Increases the = Antitumor Efficacy of Temozolomide in a Human Glioblastoma Orthotopic = Xenograft Model

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Journal=20 List > Neoplasia=20 > v.1= 0(12);=20 Dec 2008

PubMed articles by:

Neoplasia. = 2008 December; = 10(12):=20 1383=E2=80=931392.

PMCID:=20 PMC2586689

Combining Bevacizumab with Temozolomide = Increases the=20 Antitumor Efficacy of Temozolomide in a Human Glioblastoma = Orthotopic=20 Xenograft Model 1

V=C3=A9ronique=20 Mathieu,^*² Nancy De = N=C3=A8ve,^=E2=80=A0 Marie Le=20 Mercier,^*² Janique = Dewelle,^=E2=80=A0=20 Jean-Fran=C3=A7ois Gaussin,^=E2=80=A0 Mischael = Dehoux,^=E2=80=A0 Robert=20 Kiss,^*² and Florence=20 Lefranc^*^=E2=80=A1²

^*Laborarory of Toxicology, = Institute of=20 Pharmacy, Free University of Brussels [ULB], Brussels, = Belgium

^=E2=80=A0Unibioscreen SA, = Brussels, Belgium

^=E2=80=A1Department of = Neurosurgery, Erasme=20 University Hospital, Brussels, Belgium

Address all correspondence to: Robert = Kiss, PhD,=20 Laboratory of Toxicology, Institute of Pharmacy, Free University = of=20 Brussels (ULB), Campus de la Plaine, Boulevard du Triomphe, 1050 = Brussels,=20 Belgium. E-mail: rkiss/at/ulb.ac.be

²F.L. is a Clinical = Research=20 Fellow and R.K. is a Director of Research with the Fonds = National de=20 la Recherche Scientifique (FNRS, Belgium); M.L.M. is a holder = of a=20 Grant FNRS-T=C3=A9l=C3=A9vie (FNRS, Belgium) and V.M. is a = Postdoctoral Researcher=20 supported by the Fonds Yvonne Bo=C3=ABl (Brussels, Belgium).

Received August 5, 2008; Revised September = 9, 2008;=20 Accepted September 12, 2008.

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Introduction

Materials=20 and Methods

Results

Discussion

References

Abstract

Purpose

The aims of = the present=20 work were to investigate the in vitro and in = vivo=20 antiangiogenic effects of chronic temozolomide treatment on = various glioma=20 models and to demonstrate whether bevacizumab (Avastin) increased = the=20 therapeutic benefits contributed by temozolomide in glioma.

Experimental = Design

The=20 expression levels of various antiangiogenic factors in four glioma = cell=20 lines were evaluated after chronic in vitro treatment = with=20 temozolomide by Western blot. Proliferation and migration assays = were=20 performed on human endothelial cells incubated with supernatants = of glioma=20 cells treated with and without temozolomide. Orthotopic glioma = models were=20 used to evaluate the antiangiogenic effects of temozolomide in = vivo and the therapeutic benefits of different temozolomide = treatment=20 schedules used alone or in combination with bevacizumab.

Results

Temozolomide, = a=20 proautophagic and proapoptotic drug, decreased the expression = levels of=20 HIF-1=CE=B1, ID-1, ID-2, and cMyc in the glioma models = investigated, all of=20 which playing major roles in angiogenesis and the switch to = hypoxic=20 metabolism. These changes could be, at least partly, responsible = for the=20 impairment of angiogenesis observed in vitro and in=20 vivo. Moreover, combining bevacizumab with temozolomide = increased the=20 survival of glioma-bearing mice in comparison to each compound=20 administered alone.

Conclusions

In = addition to the=20 numerous mechanisms of action already identified for temozolomide, = we=20 report here that it also exerts antitumor effects by impairing = angiogenic=20 processes. We further emphasize that bevacizumab, which is an=20 antiangiogenic drug with a different mechanism of action, could be = useful=20 in combination with temozolomide to increase the latter's = therapeutic=20 benefit in glioma patients.

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Abstract

Materials=20 and Methods

Results

Discussion

References

Introduction

Glioblastoma (GBM) is the most frequent and most malignant = human brain=20 tumor [1,2].=20 Prognosis remains very poor because GBM cells dramatically invade = brain=20 parenchyma and they are naturally resistant to apoptosis and thus = to most=20 cytotoxic drugs and to radiotherapy [3,4].=20 The treatment of GBMs requires a multidisciplinary approach that = takes the=20 presently incurable nature of the disease into consideration and = normally=20 includes surgery, radiotherapy, and chemotherapy [5].=20 Although temozolomide (TMZ; Temodal) does not cure GBM patients, = it=20 significantly improves GBM patient survival and quality of life = [6]=20 even of patients harboring 9p or 10q chromosomal deletions which = are=20 associated with dismal prognosis [7].=20 Temozolomide exerts its antitumor effects through several distinct = mechanisms of action. Temozolomide increases GBM sensitivity to=20 radiotherapy [8]=20 most effectively in O⁶-methylguanine-DNA=20 methyltransferase (MGMT)-negative GBMs by increasing the degree of = radiation-induced double-strand DNA damage [9].=20 Part of TMZ's cytotoxicity toward GBM cells is exerted through=20 proautophagic [10]=20 and/or apoptotic [11]=20 processes. Hegi et al. [12]=20 showed that patients who had GBMs that contained a methylated MGMT = promoter benefited from TMZ, whereas those who did not were less=20 responsive. In addition to MGMT [12,13],=20 other determinants of sensitivity of gliomas to TMZ are p53 = status,=20 proliferation rate, and double-strand breaks (DSBs) repair [11,13].=20 The O⁶-methylguanine adducts formed by TMZ = also lead=20 to inhibition of the NF-=CE=BAB signaling pathway [14],=20 which is constitutively activated in GBMs and contributes to their = resistance to cytotoxic drugs and to radiotherapy [3].=20 The Akt signaling pathway is also directly involved in GBM cell = resistance=20 to apoptosis [3,15],=20 and Akt activation suppresses TMZ-induced Chk2 activation and=20 G₂ arrest, with the overriding effect being protection = from=20 TMZ-induced cytotoxicity [16].=20 It has also been suggested that TMZ-induced anti-GBM effects could = relate=20 to antiangiogenic effects [17=E2=80=9320].

Apart from all these detrimental effects of TMZ against GBM = cells=20 leading to beneficial therapeutic consequences for GBM patients, = the=20 compound can also be associated with positive effects on GBM = cells. By=20 impairing these TMZ-associated positive effects on GBM cells, at = least=20 partly, it would be possible to further increase the therapeutic = benefits=20 contributed by this drug to GBM patients. For example, TMZ can = induce an=20 autophagy-associated ATP surge that protects glioma cells and may=20 contribute to drug resistance [21].=20 Fisher et al. [22]=20 have shown that treatment of human GBM cells with TMZ activates = stress=20 mechanisms that include the angiogenesis-inducing proteins notably = hypoxia-inducible factors such as HIF-1=CE=B1 and vascular = endothelial growth=20 factor (VEGF), leading therefore to proangiogenic signals [22].=20 This is in contrast to previous antiangiogenic effects reported = for the=20 drug [17=E2=80=9320].=20 We recently demonstrated that TMZ increases galectin-1 expression = in GBM=20 cells both in vitro and in vivo [23,24].=20 Galectin-1 is a hypoxia-regulated protein [25]=20 that exerts potent proangiogenic effects [26]=20 and controls GBM cell migration [27].=20 However, reducing galectin-1 expression in these cells by siRNA = increases=20 the antitumor effects of various chemotherapeutic agents, in = particular,=20 TMZ, both in vitro and in vivo [23,24].=20 We have shown that decreasing galectin-1 expression in GBM [24]=20 models markedly impairs tumor neoangiogenesis through impairment = of ORP150=20 expression, which leads to defects in VEGF maturation (and thus = secretion)=20 and ultimately increases the therapeutic benefits contributed by = TMZ [24].=20 Taken together, these data strongly suggest that impairing VEGF = expression=20 in GBM would improve the therapeutic benefits of TMZ [24].

The aim of the present work was to investigate the in = vitro=20 and in vivo effects of chronic TMZ treatment on various = GBM=20 models and to identify those antiangiogenic pathways activated by = the=20 compound. Accordingly, the effects of TMZ on HIF-1=CE=B1, = inhibitor of=20 differentiation factors ID-1 and ID-2 and the oncogene = cMyc have=20 been investigated. Additionally, the studies reported here aimed = to=20 demonstrate whether bevacizumab (Avastin; a humanized monoclonal = antibody=20 against VEGF, which may have activity in recurrent malignant = gliomas [28])=20 increases the therapeutic benefits of TMZ in GBM = models.

Materials and Methods

Cell Cultures and = Compounds

The=20 Hs683 (ATCC code HTB-138), U87 (ATCC code HTB-14), U373 (ATCC code = HTB-17)=20 and T98G (ATCC code CRL-1690) human GBM cell lines were obtained = from the=20 American Type Culture Collection (ATCC; Manassas, VA) and = maintained in=20 our laboratory as detailed previously [23,24,27].

Primary human umbilical vein endothelium cells (HUVECs) were = obtained=20 from umbilical cords sampled at the Erasmus University Hospital, = Brussels,=20 Belgium. The cells were isolated by collagenase treatment and were = grown=20 in endothelial cell growth medium EGM-2 MV BulletKit from Lonza = (Verviers,=20 Belgium). Human umbilical vein endothelium cell cultures were used = between=20 passages 5 and 10. Two distinct batches of HUVECs designated CH14 = and=20 HTG06 were prepared.

Temozolomide was obtained from Schering-Plough (Brussels, = Belgium).=20 Bevacizumab was obtained from Roche (Brussels, Belgium).

In Vitro Overall = Growth=20 Determination

Overall cell growth was assessed using the=20 3-[4,5-dimethylthiazol-2yl]-diphenyltetrazolium bromide (MTT) = colorimetric=20 assay (Sigma, Bornem, Belgium), as detailed elsewhere [23,29].=20 All determinations were carried out in sextuplicate. Control = conditions=20 consisted of endothelial cells cultured with endothelial cell = growth=20 medium EGM-2 MV BulletKit. Treatments were as follows: conditioned = media=20 from U373 GBM cells left untreated or treated with 100 =C2=B0M TMZ = for 72 hours=20 were collected. The MTT test was performed on the two HUVEC = primary=20 cultures in the presence of these 100% conditioned media, a = mixture of=20 conditioned medium, and HUVEC EGM-2 MV BulletKit medium in various = proportions ranging from 90% U373 conditioned medium + 10% = endothelial=20 cell medium to 10% U373 conditioned medium + 90% endothelial cell = culture=20 medium. As U373 cells are cultured in minimum essential medium=20 supplemented with 5% FCS, minimum essential medium + 5% = FCS-treated cells=20 were included as an internal control.

The IC₅₀ value, defined as the concentration that = reduces=20 the global cell growth of 50%, was calculated with the following = formula:=20 IC₅₀ =3D (X₂ - = X₁) x (50=20 - Y₁) / (Y₂ x=20 Y₁)) + X₁, where=20 X₁ and X₂ are the higher = and lower=20 used concentrations, respectively, that borders the concentration = that=20 reduces the global cell growth of 50% and Y₁ = and=20 Y₂ are the mean percentages of viable cells at = the=20 X₁ and X₂ concentrations,=20 respectively.

In Vivo Orthotopic=20 Xenografts

In vivo orthotopic xenografts of human = Hs683 and=20 U373 GBM cells in nude mice were obtained as described previously = [23,24,30,31].=20 Briefly, 50 =C2=B5l of serum-free culture medium containing = 100,000 GBM cells=20 were stereotactically injected into the brain of nude mice. All = mice=20 (6-week-old female nu/nu mice; 21 to 23 g; Iffa Credo, = Charles=20 Rivers, Arbresle, France) of a given experiment have Hs683 or U373 = GBM=20 cells stereotactically implanted into the brain on the same day. = Each=20 experimental group contained 11 mice. All the in vivo = experiments=20 described in the present study were performed based on = Authorization=20 #LA1230509 of the Animal Ethics Committee of the Federal = Department of=20 Health, Nutritional Safety, and the Environment (Belgium).

In Vivo Determination = of Tumor=20 Neoangiogenesis

Each mouse receiving a GBM orthotopic = xenograft=20 underwent euthanasia (in a CO₂ atmosphere during 5 min) = for=20 ethical reasons when it had lost 20% of its body weight compared = to the=20 day of tumor grafting. The brain was removed from the skull, fixed = in=20 buffered formalin for 5 days, embedded in paraffin, and then cut = into=20 5-=C2=B5m-thick sections. Resulting histology slides were stained = with=20 hematoxylin and eosin for blood vessel counts. To quantify the = level of=20 angiogenesis, a grid was used to determine the surface area of = blood=20 vessels in brain sections as reported previously [31,32].=20 Antiangiogenic effects were analyzed in two distinct GBM models = U373 (Figure=20 1C) and Hs683 (Figure=20 1D) with and without treatment with TMZ. The types of = blood=20 vessels taken into account are illustrated in Figure=20 2A. A minimum of five fields at a Gx400 magnification = were=20 analyzed per histologic slide and two slides were analyzed per = tumor.=20 Thus, a minimum total of 10 histologic fields per tumor were = analyzed.

Figure=20 1

TMZ in = GBM models=20 in vivo. (A) Intravenous TMZ treatment of = immunocompromised=20 mice bearing orthotopic xenografts of human U373 cells. The = black=20 symbols illustrate the survival of control (untreated) = groups,=20 whereas the open symbols show the groups treated=20 (more ...)

Figure=20 2

Impact of = TMZ=20 administration on angiogenesis in GBMs. (A) Aa shows the = typical=20 morphologic and infiltrative characteristics of the Hs683 = tumor (T)=20 in the excised brains of mice (HE indicates Gx40;=20 NB, normal brain tissue). Ab illustrates blood=20 vessels=20 (more ...)

In Vitro Determination = of HUVEC=20 Capillary Networking

When cultured on Matrigel, HUVECs form=20 capillary-like networks [31].=20 An amount of 800 =C2=B5l of cold Matrigel was allowed to set at = 37=C2=B0C for 10=20 minutes in a 3-cm Petri dish. The HUVECs growing as primocultures = in=20 25-mm² flasks (Nunc, VWR, Leuven, Belgium) were = trypsinized,=20 counted, and resuspended in the following culture media: control = medium=20 was composed of 90% untreated U373 conditioned medium mixed with = 10% EGM=20 medium; treated medium was composed of 90% conditioned medium of=20 TMZ-treated U373 cells mixed with 10% EGM medium. U373 conditioned = media=20 were prepared as detailed above. A total of 250,000 HUVECs were = seeded=20 onto the matrix for each experiment conducted in duplicate. = Formation of=20 capillary networks was observed during 24 hours by means of a=20 computer-assisted stereomicroscope (Olympus SZ-40; Omnilabo SA, = Antwerp,=20 Belgium).

Protein Expression=20 Measurements

Western blot analyses were performed as detailed = previously [29,33].=20 Briefly, 40 =C2=B5g of denaturated protein extracts was loaded in = a=20 polyacrylamide gel. After electrophoresis, proteins were = transferred onto=20 a polyvinylidene fluoride membrane. To avoid aspecific binding of = the=20 antibodies, membranes were first blocked in a 5% milk or BSA = buffer for 1=20 hour. The proteins were then detected by overnight incubation at = 4=C2=B0C with=20 the following primary antibodies: anti-HIF-1=CE=B1 (dilution of = 1:200; Abcam,=20 Cambridge, UK), anti-ID-1 and -ID-2 (both at a dilution of 1:400; = Santa=20 Cruz, Heidelberg, Germany), anti-cMyc (dilution of 1:400; Santa = Cruz), and=20 antitubulin (dilution of 1:10,000; Abcam). Secondary antibodies = were=20 purchased from Pierce (PerbioScience, Erembodegem, Belgium). = Control=20 experiments included the omission of the incubation step with the = primary=20 antibodies (negative control). Tubulin immunoblot analysis was = then=20 performed on each membrane to assess the integrity and quantity of = the=20 extracts. Western blots were developed using the Pierce = Supersignal=20 Chemiluminescence system.

Statistical = Analyses

Survival=20 analyses were carried out by means of Kaplan-Meier curves and = Gehan's=20 generalized Wilcoxon test. Statistical comparisons between control = and=20 treated groups were established by carrying out the Kruskal-Wallis = test (a=20 nonparametric one-way analysis of variance) or the Mann-Whitney = test (in=20 the case of two groups). All statistical analyses were undertaken = using=20 Statistica (Statsoft, Tulsa, OK).

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Abstract

Introduction

Materials=20 and Methods

Discussion

References

Results

Investigation of the Duration = of TMZ=20 Treatment on the Survival of U373 and Hs683 Human GBM Orthotopic=20 Xenograft-Bearing Immunodeficient Mice

The U373 model is of=20 astroglial origin and displays weak if any sensitivity to = proapoptotic=20 cytotoxic drugs [30],=20 whereas the Hs683 model is of oligodendroglial origin [30]=20 and is sensitive to proapoptotic drugs [30].=20 Both dramatically invade the brain parenchyma, and surgery has = been=20 demonstrated to be of limited therapeutic benefit in the U373 GBM = model=20 [34].

At a dosage of 40 mg/kg i.v. three times a week (Monday, = Wednesday, and=20 Friday) for three consecutive weeks which displayed no toxicity to = mice=20 (data not shown), TMZ (open symbols) did not = significantly=20 increase (P > .05) the survival of U373-bearing mice = compared=20 to controls (Figure=20 1A, black filled symbols). The two pairs of = symbols:=20 circles versus squares represent two independent = experiments=20 performed 6 months apart. Increasing the length of TMZ treatment = (40 mg/kg=20 i.v.) to three times a week for 4 weeks resulted in a weak but=20 statistically significant increase in survival time (P = < .05;=20 Figure=20 1B, open circles). However, increasing = further the=20 length of TMZ treatment (40 mg/kg i.v.) to three times a week for = 5 weeks=20 markedly and significantly increased survival times in = U373-bearing mice=20 (P < .01; Figure=20 1B, open squares). Therapeutic benefits were = also=20 seen in the U373 GBM model when TMZ was administered orally at 80 = mg/kg=20 three times a week for five consecutive weeks, with marked = improvements in=20 survival time when the compound was administered for the first = time on the=20 14th as opposed to the 56th day after tumor graft (Figure=20 1C).

The higher sensitivity of Hs683 to cytotoxic drugs compared to = the U373=20 GBM model [30]=20 was also observed here with respect to TMZ, as evidenced by a = comparison=20 of the data presented in Figure=20 1, D (Hs683) and A (U373). Mice bearing = Hs683=20 xenografts were also treated with 40 mg/kg i.v. three times a week = for 3=20 weeks.

Characterization of the In = Vivo=20 TMZ-Induced Effects on Angiogenesis in U373 and Hs683 Human GBM = Orthotopic=20 Xenografts

The levels of angiogenesis were evaluated by = determining=20 blood vessel surface area per field on histologic slides as = detailed=20 previously [31]=20 and as illustrated in Figure=20 2Ab in the case of Hs683 GBM. For this analysis, = brain=20 samples were taken from animals implanted with U373 or Hs683 GBM = and=20 treated, respectively, as detailed in Figure=20 1, C (control versus TMZ 80 mg/kg p.o., 3i x = 5w from=20 14 to 56 days after graft) and D (control versus = TMZ 40=20 mg/kg i.v., 3i x 5w from 7 days after graft). A significant = decrease in=20 angiogenesis was found in U373 tumor samples when the TMZ = treatment=20 started on day 56 (Figure=20 2Ac) after tumor graft, whereas this was not the case = if the=20 treatment began earlier (data not shown). By contrast, clinical = outcome=20 (in survival) has been shown to be more improved when TMZ = treatment=20 started earlier (Figure=20 1C). This apparent discrepancy between the = therapeutic=20 benefits and the antiangiogenic effects of TMZ treatment could, = however,=20 be explained, at least partly, by the shorter time lapse between = the end=20 of TMZ treatment and the time of euthanasia for analysis when = treatment=20 started on day 56 (median time, ~50 days) than the time lapse of = the other=20 groups (median time for the group beginning treatment on day 14, = ~170=20 days). For those later, angiogenesis could have reincreased after = TMZ=20 treatment. This hypothesis was further re-enforced with the = significant=20 decrease in angiogenesis obtained in the case of the more = aggressive and=20 shorter-lived Hs683 mouse model (Figure=20 2Ac) for which the delay between the last TMZ = administration=20 and euthanasia is quite short (median time, 12 days). Taken = together,=20 these data suggest that TMZ could act as an antiangiogenic = compound in=20 vivo.

Effects of TMZ on the Growth=20 Characteristics of Human U87, T98G, U373, and Hs683 GBM Cell Lines = In=20 Vitro

In vitro IC₅₀ inhibitory = growth values=20 for TMZ after 3 days of culture were 472 =C2=B1 14 =C2=B5M for = U87, 118 =C2=B1 3 =C2=B5M for=20 U373, 634 =C2=B1 23 =C2=B5M for T98G, and 719 =C2=B1 12 =C2=B5M = for Hs683 GBM cells. These=20 data are in accordance with those reported by Fisher et al. [22]=20 who observed that a TMZ dose-related decrease in U251 and U87 GBM = cell=20 numbers was evident at a TMZ concentration of 200 =C2=B5M, which = became evident=20 on day 6 and peaked after 8 days with a 3.5-fold reduction in cell = viability.

U87, U373, T98G, and Hs683 GBM cells were treated in = vitro in=20 a chronic manner with 100 =C2=B5M TMZ. The drug was added to the = culture media=20 each day for 7 hours (after that, the media were replaced with = fresh=20 medium without drug for 17 hours) for five consecutive days, and = protein=20 analyses were performed on the 3rd, 5th, and 7th days that = followed the=20 5th TMZ administration to the GBM culture media (Figures=20 3 and 4).=20 The morphologic illustrations in Figure=20 2B show that a treatment of 5 x 100 =C2=B5M TMZ (with = an=20 observation 7 days after the 5th TMZ administration) did not = impair T98G=20 cell population growth, slightly impaired U87 (data not shown) and = Hs683=20 cell population growth, and moderately impaired U373 cell = population=20 growth. These data are in accordance with those reported by = Kanzawa et al.=20 [10]=20 who observed that 100 =C2=B5M TMZ impaired cell growth and caused = cell cycle=20 arrest in the G₂/M phase in U373 GBM cells but not in = T98G=20 cells. Thus, the in vitro 5 x 100 =C2=B5M treatment = adopted here for=20 four distinct human GBM cel lines slightly, if any, impaired their = growth=20 characteristics. This protocol was then used to investigate = whether TMZ=20 was able to modify the expression levels of various key factors = implicated=20 in tumor angiogenesis as detailed below.

Figure=20 3

Western = blot=20 analyses of the expression levels of HIF-1=CE=B1 and ID2 in = Hs683, U373,=20 T98G, and U87 GBM cell lines. Cells were treated for 7 hours = for=20 five consecutive days with 100 =C2=B5M TMZ or left = untreated.=20 Protein extracts were collected=20 (more ...)

Figure=20 4

Western = blot=20 analyses of the expression levels of ID-1 and c-Myc in = Hs683, U373,=20 T98G, and U87 GBM cell lines. Temozolomide treatment, sample = processings, and legends are similar to those of Figure=20 3.

Characterization of TMZ-Induced = Antiangiogenic Effects in Human U87, T98G, U373, and Hs683 GBM = Cell=20 Lines

When treating U87 and U251 GBM cells for 4 days with = 100 =C2=B5M=20 TMZ, Fisher et al. [22]=20 observed a common up-regulation of 61 genes in these two cell = lines, with=20 14 of these genes being known to be up-regulated by the = transcription=20 factor HIF-1=CE=B1. Analyzing the data provided by Fisher et al. = [22]=20 and our own previous results [23,24]=20 of the potential relationship between endoplasmic reticulum = stress,=20 angiogenesis, and TMZ treatment in experimental GBMs and the data=20 emphasizing the antiangiogenic effects of TMZ in various GBM = models [18,19]=20 or in GBM patients [17],=20 we decided to investigate the effects of TMZ on hypoxia-related = and=20 proangiogenic factors, i.e., HIF-1=CE=B1, ID-1, ID-2, and c-Myc. = Cell lines=20 were treated for 7 hours/day for 5 days with 100 =C2=B5M TMZ or = vehicle alone=20 (controls) as indicated above, and samples were analyzed 3, 5, and = 7 days=20 after the last TMZ treatment.

Temozolomide produced a marked and sustained decrease in = HIF-1=CE=B1=20 expression in the four GBM cell lines investigated (Figure=20 3A). Positive controls obtained by treating cells = with 100 =C2=B5M=20 CoCl₂ for 4 hours showed a marked increase in = HIF-1=CE=B1 expression=20 level.

ID factors, a family of four proteins interfering with = transcription=20 factors and preventing their activities, are implicated in the = control of=20 differentiation and cell cycle progression during embryogenesis = and=20 tumorigenesis but have also been shown to be major players in = angiogenesis=20 control [35].=20 ID-1 and ID-3 are required for endothelial cell proliferation, = networking=20 processes, and for endothelial precursor recruitment [35,36].=20 ID-2 is an HIF-1=CE=B1-inducible protein [37]=20 that exerts a major role in angiogenesis [35]=20 as it functions as a master regulator of VEGF expression [38].=20 Temozolomide treatment of the four GBM cell lines led to a = generally=20 marked and sustained decrease in ID-1 and ID-2 expressions (Figures=20 3B and 4A).

The c-Myc oncogene has been shown to be involved in = the=20 angiogenic switch of tumors. This activity relates to modification = in pro-=20 versus antiangiogenic factor expression [39,40]=20 and to a deep involvement in metabolic adaptation to hypoxia [41,42].=20 Although the proto-oncoprotein c-Myc seems to be the diametric = opposite of=20 HIF-1=CE=B1 in most processes, recent studies indicate that c-Myc = is an=20 integral part of the HIFs/c-Myc molecular pathway in the hypoxic = response.=20 It has been shown that HIFs engage with c-Myc by various = mechanisms to=20 achieve oxygen homeostasis for cell survival [42].=20 Temozolomide, which is a proautophagic agent, induced a = significant and=20 sustained decrease in the expression of c-Myc (up to 7 days after = final=20 drug treatment) in the four GBM cell lines (Figure=20 4B).

Characterization of TMZ-Induced = Effects=20 on Antiangiogenic Factors in HUVEC Endothelial Cell = Lines

When TMZ is=20 provided to GBM patients, it will target not only GBM cells but = also a=20 large set of cell types implicated in tumor angiogenesis, = including=20 endothelial cells. As shown above, TMZ modifies the expression = levels of=20 various angiogenic factors in GBM cells. These changes could lead = to=20 modifications to the microenvironment of tumor endothelial cells = and thus=20 to tumor angiogenesis. This hypothesis was evaluated in = vitro by=20 analyzing the effects of GBM cell culture supernatants on the = global=20 growth level of HUVEC cell lines. U373 GBM cells were treated for = 72 hours=20 with 100 =C2=B5M TMZ or left untreated. The collected supernatants = either neat=20 or diluted with fresh HUVEC culture medium in different = proportions were=20 incubated with HUVEC endothelial cells and viability/proliferation = assessed using the colorimetric MTT assay. Conditioned media from=20 untreated U373 GBM cells induced a significant increase in the = global=20 growth of the two different primary HUVEC cell lines CH14 and = HTG06=20 compared to endothelial growth medium (Figure=20 5A). By contrast, conditioned media from TMZ-treated = U373=20 cells induced a significant decrease in the overall growth of = these two=20 primary HUVEC cell lines when compared to either endothelial cell = culture=20 medium (reported as 100% global growth in Figure=20 5A) or to conditioned media from untreated U373 = cells. These=20 results seem to indicate that TMZ exerts a marked indirect = antiangiogenic=20 effect in vitro, which may relate to the compound's = effects on=20 the expression of the proangiogenic factors studied above. Indeed, = when=20 TMZ is added alone into the endothelial culture medium, no effects = are=20 observed either on global growth or on capillary networking (data = not=20 shown).

Figure=20 5

Temozolomide=20 effects on HUVECs in vitro and in combination with=20 bevacizumab in vivo in GBM models. (A) Graphical=20 representation of the effects of GBM conditioned media, = either from=20 U373 GBM cells treated with TMZ or left untreated, on the = global=20 growth=20 (more ...)

As a further evaluation, the effects of the GBM conditioned = medium on=20 the tubulogenesis of HUVECs were determined. Human umbilical vein=20 endothelium cells were first treated for 24 hours with the GBM = conditioned=20 media detailed previously and then evaluated for capillary-like = structure=20 formation when seeded on a Matrigel matrix in the same conditioned = culture=20 medium. Figure=20 5Ba illustrates the tubular network formed by HUVECs = cultured=20 with a mixture of 90% untreated U373 conditioned medium and 10%=20 endothelial culture medium. Using the U373 cells conditioned = medium=20 treated for 72 hours with 100 =C2=B5M TMZ led to impairment of the = tubular=20 networking abilities of HUVECs as illustrated in Figure=20 5Bb. The antiangiogenic effects of TMZ observed = in=20 vivo could therefore be related to modifications in = proangiogenic=20 factor expression evidenced above in GBM cells in = vitro.

Effects of Combining = Bevacizumab and TMZ=20 in Human GBM Orthotopic Xenograft Models

The Hs683 GBM = orthotopic=20 model was used to evaluate the potential of combining TMZ with=20 bevacizumab, an antiangiogenic antibody targeting VEGF approved = for the=20 treatment of specified cancer indications [43].

Temozolomide and bevacizumab were administered individually or = in=20 combination at 40 mg/kg p.o. (suboptimal doses) and 10 mg/kg i.v., = respectively, three times per week for three consecutive weeks. = Drug=20 administration began 5 days after GBM cell grafting. Temozolomide = alone=20 significantly improved animal survival times in Hs683 model = (P =3D=20 .002; Figure=20 5C). Hs683 was also responsive to bevacizumab, which = had a=20 more marked effect on animal survival times than TMZ (P = <=20 .0006 compared to the control group). However, the combination of=20 bevacizumab with TMZ improved significantly the therapeutic = benefits of=20 TMZ or bevacizumab alone in this GBM model (P =3D .0008 = and=20 P =3D .02, respectively; Figure=20 5C). Similar experiment has been conducted in a human = primary=20 culture-derived orthotopic GBM model. Whereas this latter was = highly=20 responsive to temozolomide but did not respond to bevacizumab = alone,=20 combination of both treatment significantly (P < .001) = improved the therapeutic benefits of temozolomide (data not = shown).

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Abstract

Introduction

Materials=20 and Methods

Results

References

Discussion

In addition to the large set of mechanisms of action already = identified=20 for TMZ's antitumor activities, the present study emphasizes that = the=20 compound also exerts its effects by impairing angiogenic = processes.=20 Indeed, it has been demonstrated in vitro in this study = that the=20 overall growth of HUVEC endothelial cell was decreased and = capillary=20 network formation impaired when these cells were treated with = conditioned=20 culture media from GBM cells treated with TMZ (Figure=20 5, A and B). Similar features have been = recently=20 observed with the cdk inhibitor SNS-032 [44].=20 The effects observed with TMZ could occur, at least partly, = through a=20 TMZ-induced decrease in the expression levels of several = proangiogenic=20 factors as indicated in Figures=20 3 and 4.

Hypoxia plays a major role in the induction and stimulation of=20 angiogenesis through transcription factors like HIF family members = or=20 oncogenes like c-Myc. The present study shows that TMZ is = able to=20 inhibit HIF-1=CE=B1 expression in GBM cells. HIF-1=CE=B1 belongs = to a heterodimeric=20 transcription factor family composed of =CE=B1 and =CE=B2 subunits = [45].=20 In general, angiogenesis is dependent on the accumulation of HIFs = [45].=20 HIF-1 is among the primary genes involved in the = homeostatic=20 process, which can increase vascularization in hypoxic areas such = as=20 localized ischemia and tumors [45].=20 Moreover, the hypoxia-induced metabolic switch to the anaerobic = regimen of=20 cancer cells involves the activation and interplay of HIF and = c-Myc=20 transcription factors [41,42].=20 The proangiogenic activities of the latter relate to induced = expression=20 and release of interleukin 1=CE=B2 [39],=20 which acts as proangiogenic factor, and decreasing = thrombospondin-1=20 expression, which itself acts as an antiangiogenic factor [40].=20 Figure=20 4 reveals that TMZ induces a marked decrease in c-Myc = expression in=20 GBM cells. Given the important role of c-Myc in the hypoxic = metabolism=20 switch, it remains possible that the decrease in its expression = induced by=20 TMZ treatment could impair cell survival in an adverse hypoxic = environment=20 and induce autophagic processes which have been well documented by = Kanzawa=20 et al. [10]=20 in the case of TMZ treatment of glioma.

It has been previously shown that TMZ increases the expression = levels=20 of galectin-1 in gliomas [23,24].=20 Galectin-1 is a potent proangiogenic factor [26]=20 involved in the endoplasmic reticulum stress response [24].=20 In fact, regulation of angiogenesis results from the fine tuning = of the=20 balance between pro- and antiangiogenic factors [45].=20 Here, we have shown that TMZ induced a marked decrease in the = expression=20 of a number of proangiogenic factors leading to antiangiogenic = effects,=20 not only in vitro but also in vivo, as revealed = in Figure=20 2, A and B. Our results therefore support = previous=20 publications demonstrating that conventional and metronomic TMZ = treatments=20 have antiangiogenic properties [17=E2=80=9320].=20 However, it still remains possible to increase the therapeutic = benefit of=20 TMZ with antiangiogenic approaches/compounds having different = targets.=20 This was previously evidenced by decreasing galectin-1 expression = [24],=20 which impaired VEGF maturation and secretion [23]=20 and by knocking down HIF-1=CE=B1 (Table=20 1) [46].

Table=20 1

Review of = the=20 Studies Combining Antiangiogenic Approaches With TMZ = Treatment in=20 GBM = Models.

The present study shows that administering in combination TMZ = and=20 bevacizumab to Hs683 orthotopic GBM-bearing mice markedly delayed = death in=20 these animals compared to when each drug was administered alone = (Figure=20 4). All in vivo studies conducted to date with TMZ in = combination with antiangiogenic approaches for the experimental = treatment=20 of glioma models are summarized in Table=20 1. Therapeutic approaches combining antiangiogenic drugs such = as=20 bevacizumab with cytotoxics have recently entered routine practice = for=20 cancers in general [43,52].=20 For example, in the case of breast cancer, bevacizumab exerts = potent=20 antiangiogeneic activities [53]=20 and potentiates paclitaxel antitumor effects [54].=20 The success of such combinations could result from at least three=20 different mechanisms of action as emphasized by Kerbel [55]:=20 1) preventing nutrient supply for tumor cell repopulation, 2)=20 normalization of tumor vasculature leading to improved cytotoxic = drug=20 delivery inside the tumor, and 3) increasing the antiangiogenic = effects of=20 the chemotherapeutic agents themselves.

Owing to well-known abnormalities, tumor blood vessel walls are = leaky,=20 leading to an increase in interstitial pressure, which in turn = interferes=20 with the diffusion of therapeutic agents into the tumor. = Therefore, blood=20 vessel normalization obtained with antiangiogenic compounds could = be=20 associated with higher drug tumor/plasma ratios as shown by Ma et = al. [49]=20 (Table=20 1) and recently by Zhou et al. [51]=20 (Table=20 1) in the case of TMZ in glioma model treatment. However, in = the case=20 of brain tumors, blood vessel normalization could be linked to the = restoration of the blood-brain barrier (BBB) which could hinder = the=20 transendothelial diffusion of anticancer agents like TMZ. This = process has=20 been evidenced in a human orthotopic glioma model (Table=20 1) [50].=20 A better understanding of the resulting effects of such = combinations might=20 be achieved when taking into account the tumor models (s.c.=20 versus orthotopic implantation) and/or the antiangiogenic = compounds used, which are characterized by different mechanisms of = action=20 leading to either synergistic or negative effects. Combination = therapy of=20 bevacizumab and a cytotoxic seems well tolerated and active = against=20 recurrent malignant gliomas [28,43].=20 Bevacizumab may alter the recurrence pattern of malignant gliomas = by=20 suppressing enhancing tumor recurrence more effectively than it = suppresses=20 nonenhancing infiltrative tumor growth [28].=20 However, Chamberlain [56]=20 raises the point why the use of irinotecan in combination with = bevacizumab=20 in a phase 2 study [43]=20 despite consideration of the extremely limited single-agent = activity of=20 irinotecan in recurrent GBM.

Antiangiogenic compounds also seem to be promising in = increasing the=20 therapeutic benefits of radiotherapy [57].=20 A phase 2 pilot study of bevacizumab in combination with TMZ and = regional=20 radiotherapy for the treatment of patients with newly diagnosed = GBM=20 recently reported that toxicities were acceptable to continue = enrollment=20 and a preliminary analysis of efficacy showed encouraging mean=20 progression-free survival [58].=20 =E2=80=9CPure=E2=80=9D antiangiogenic drugs, such as bevacizumab, = should reenforce the=20 antiangiogenic effects of certain cytotoxics. For TMZ in = particular, we=20 have demonstrated in the present study its antiangiogenic = properties=20 in vitro and in vivo when used alone. Using the = Web site=20 developed by the National Library of Medicine for the US National=20 Institutes of Health, the authors obtained information on eight = clinical=20 trials being conducted with bevacizumab in combination with TMZ, = which are=20 recruiting patients with GBMs including those newly diagnosed. Our = present=20 study further validates these approaches.

Footnotes

¹This work has been = supported=20 partly by grants awarded by the Fonds Yvonne Bo=C3=ABl = (Brussels,=20 Belgium) and by the FNRS (Brussels, = Belgium).

Top

Abstract

Introduction

Materials=20 and Methods

Results

Discussion

References

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Articles=20 from Neoplasia (New = York,=20 N.Y.) are provided here courtesy of
Neoplasia=20 Press

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