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Experimental Therapeutics |
Departments of Cancer and Infection Research [S. R. W., D. J. O., M. D., J. K., R. C., J. A. J., S. J. B., P. J. V., J. O. C., H. L. M., G. A. G., G. D. H., A. P. T., E. S. E. S., B. C.] and Safety Assessment [G. H. P. R., P. F. W., A. L. B.], AstraZeneca, Cheshire SK10 4TG, United Kingdom, and AstraZeneca Pharma, Centre de Recherches, 51689 Reims Cedex 2, France [L. F. H.]
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ABSTRACT |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Although a wide range of angiogenic stimulators and inhibitors have been identified (see Ref. 13 for review), inhibition of VEGF signal transduction alone may represent a particularly attractive therapeutic approach, given its pivotal role in pathological angiogenesis, including the sustained neovascularization required to support tumor growth and metastasis (14) . Such a strategy is reliant on low endothelial cell turnover in the adult, with angiogenesis being predominantly confined to ovarian endocrine function (15) and wound healing (16) . In the normal quiescent state, vessels are stabilized by periendothelial support and signaling from angiopoietin-1/Tie-2 (17) and potentially Ephrin B2/EphB4 (18) ligand/receptor complexes. In contrast, VEGFRs are up-regulated on endothelium at sites of active angiogenesis (19) , providing an opportunity for selective therapeutic intervention. Furthermore, VEGF overexpression by tumor cells occurs frequently in response to hypoxia (20 , 21) , loss of tumor suppressor gene function (22 , 23) , and oncogene activation (24 , 25) . The enhanced vascular permeability induced by VEGF in this setting may also increase tumor nutrient and catabolite exchange as well as facilitate the extravasation of macromolecular proteins (thereby promoting development of a tumor stroma) and intravasation of tumor cells. Consequently, it is hypothesized that inhibition of VEGF signaling will provide a means for stabilizing or slowing the progression of solid tumor disease.
There are three associated transmembrane receptors for vascular endothelial growth factor family ligands found on endothelium, Flt-1 (VEGFR1), KDR (VEGFR2), and Flt-4 (VEGFR3), which are related to the PDGFR family (26) . Each receptor possesses intrinsic tyrosine kinase activity that is stimulated after ligand binding and receptor dimerization and is mandatory for transmission of a cytoplasmic signaling response. Flt-1 and KDR have different binding specificities for the separate isoforms of VEGF (generated by alternative exon splicing) and for additional vascular endothelial growth factor family members (PlGF and VEGF-B, -C, and -D) that can also be subjected to alternative exon splicing or proteolytic processing (see Ref. 27 for review). Flt-4 only binds VEGF-C and -D and is largely located on lymphatic endothelium (28, 29, 30) . Clearly, there is a range of potential signaling responses that may be mediated through these receptors, particularly when one considers the potential for receptor homo- and heterodimerization (31) . In addition, some isoforms of VEGF have been shown recently to bind to neuropilin 1 and 2 coreceptors on endothelial and tumor cells, and these coreceptors were found to cooperate with Flt-1 and KDR, although the biological significance of these interactions remains to be fully resolved (32, 33, 34) . Despite the apparent complexity in VEGFR signaling, activation of KDR alone is sufficient to promote all of the major phenotypic responses to VEGF, including endothelial cell proliferation, migration, and survival, and the induction of vascular permeability (35, 36, 37) .
A variety of methodologies for inhibiting VEGF signal transduction are technically feasible. These include the use of antibodies for ligand sequestration or receptor antagonism, which are currently under clinical investigation (38
, 39)
. An alternative approach is to generate a low molecular weight inhibitor of the KDR tyrosine kinase domain, preferably as an oral therapy, suitable for chronic administration and continual restraint of angiogenesis. We have demonstrated previously that this is possible experimentally with the anilinoquinazoline ZD4190 (40)
. Subsequent development of ZD4190 revealed that this compound had variable and low oral bioavailability (<5%) in nonrodent species, which was attributed to its modest solubility (41)
. We now report another heteroaromatic-substituted anilinoquinazoline, ZD6474, which has significantly greater solubility (470-fold more soluble at pH 7.4) and improved oral bioavailability in nonrodent species (>50%), when compared with ZD4190 (41)
. ZD6474 is currently in Phase I evaluation for the treatment of cancer. Here we describe the ability of ZD6474 to inhibit VEGF signaling, tumor-induced neovascularization, and growth of human xenograft and syngeneic tumor models in vivo. The compound achieves greater activity in human tumor models than ZD4190, when examined at equivalent doses of 
50 mg/kg/day. In addition, the effect on well-established human tumor xenografts was examined, and ZD6474 was found to induce profound regression in PC-3 prostate tumors (0.9–1.4 cm3 pretreatment volume).
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MATERIALS AND METHODS |
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] was synthesized as described by Hennequin et al. (41)
. Flt-4 and c-kit tyrosine kinases were obtained from ProQuinase GmbH (Freiburg, Germany), and AKT and PDK1 serine-threonine kinases were obtained from Dundee University (Dundee, United Kingdom). All other receptor tyrosine kinases used in isolated enzyme assays were generated as insect cell lysates after cell infection with recombinant baculoviruses containing kinase domains. Human VEGF165 and bFGF were similarly prepared using Spodoptera frugipedera 21 insect cells and Escherichia coli strain BL21(DE3)pLysS respectively, and purified using a heparin-Sepharose column. EGF was obtained from R & D Systems (Abingdon, United Kingdom).
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-33P]ATP/reaction (Amersham Biosciences United Kingdom Ltd., Buckinghamshire, United Kingdom), 50 mM HEPES (pH 7.5), 1 mM DTT, 0.1 mM sodium orthovanadate, 0.1 mM sodium fluoride, 10 mM sodium glycerophosphate, 1 mg/ml BSA fraction V (Sigma-Aldrich, Dorset, United Kingdom), and a retinoblastoma substrate (part of the retinoblastoma gene, 792–928, expressed in a glutathione S-transferase expression system; 0.22 µM final concentration). Reactions were allowed to proceed at room temperature for 60 min before quenching for 2 h with 150 µl of a solution containing EDTA (62 mM final concentration), 3 µg of a rabbit immunoglobulin anti-glutathione S-transferase antibody (Molecular Probes) and protein A SPA-polyvinyltoluene beads (0.8 mg/reaction; Amersham). Plates were then sealed, centrifuged (1200 x g for 5 min), and counted on a Topcount NXT Microplate scintillation counter (Packard Instrument Co.) for 30 s.
AKT and PDK1 assays were performed with a reaction buffer containing 50 mM Tris-HCl (pH 7.5), 15 mM magnesium acetate, 0.1 mM EGTA, 5 mM DTT, and 0.1 mg/ml BSA fraction V. In the AKT assay, ZD6474 in DMSO [1% (v/v) final assay concentration] was added to a reaction mixture containing buffer, 0.2 µg/ml AKT (delta PH domain previously phosphorylated on S473 by active MAPK-activated protein kinase-2 and T308 by PDK1), 14 µM ATP, 0.1 µCi of [-33P]ATP/reaction, and 6.5 µM of a biotinylated Crosstide substrate [Bachem (United Kingdom) Ltd., St Helens, United Kingdom]. Plates were sealed and incubated at 30°C for 75 min, and the reaction was stopped by the addition of a well-mixed suspension of streptavidin-SPA beads (0.8 mg/reaction, Amersham) and cesium chloride (1 M final assay concentration) in a 50 mM Tris-HCl (pH 7.5) buffer containing 0.05% (w/v) sodium azide. Plates were resealed, incubated at room temperature for 15 min, centrifuged (960 x g for 2 min), transferred to a Topcount, and counted for 30 s (after 15 min for dark adaptation).
In PDK1 assays, ZD6474 was added to an equivalent volume of buffer (10 µl) containing AktSer473 substrate (3 µg/ml final concentration) and cold ATP (7.5 µM). PDK1 (4 ng in 10 µl of buffer) was then added to each well, and the plates were sealed, agitated, and left at room temperature for 2 h. Next, a mixture (10 µl) of biotinylated Crosstide (5 µM final concentration) and 0.1 µCi of [-33P]ATP/reaction was added, and plates were reagitated and incubated at room temperature for 1 h. Reactions were stopped and counted as described in the AKT assay.
The dual specificity kinase MEK was also examined using a [-33P]ATP-based assay, but with a MAPK substrate and myelin basic protein (Sigma) to capture radioactivity onto filters. The compound was added to a MEK/MAPK premix containing 100 mM EGTA, 1 mg/ml BSA, 1 mM sodium orthovanadate, 14 mM ß-mercaptoethanol, and 0.03% polyoxyethylene 23 lauryl ether (Brij-35; Sigma Diagnostics), with 35 µg/ml c-raf-activated MEK and 1.3 µg/ml MAPK. The reaction was started by the addition of ATP and magnesium acetate to a final concentration of 10 µM and 10 mM, respectively. After 1 h at room temperature, [-33P]ATP and myelin basic protein were added to a final concentration of 5.5 µCi and 275 µg/ml, respectively. The reaction was stopped after 10 min at room temperature by the addition of phosphoric acid (12.5% final concentration). The product of the reaction was harvested by paper capture and analyzed by scintillation counting.
Inhibition of Growth Factor-mediated Endothelial Cell Proliferation.
HUVEC proliferation in the presence and absence of growth factors was evaluated using [3H]thymidine incorporation (42)
. Briefly, HUVECs isolated from umbilical cords were plated (at passage 2–8) in 96-well plates (1000 cells/well) and dosed with ZD6474 ± VEGF or EGF (3 ng/ml) or bFGF (0.3 ng/ml). The cultures were incubated for 4 days (37°C; 7.5% CO2) and then pulsed with 1 µCi/well [3H]thymidine (Amersham) and reincubated for 4 h. Cells were harvested and assayed for the incorporation of tritium using a beta counter. IC50 data were interpolated as described above.
Inhibition of an Acute VEGF-induced Hypotension in Rat.
Methodology to enable blood pressure measurement in anesthetized rats was as described previously (43)
. Briefly, anesthesia was induced in male Alderley Park rats (Wistar derived, 230–280 g in weight) using 
-chloralose (Sigma, Dorset, United Kingdom) by the i.v. route and then maintained with thiopentone (Intraval; May & Baker) via the i.p. route. Once surgical anesthesia was established, the carotid artery was cannulated to enable blood pressure recording using a pressure transducer (Bell and Howell Ltd., Basingstoke, United Kingdom) and a Lectromed MT8P amplifier (Lectromed United Kingdom Ltd., Letchworth, United Kingdom). The jugular vein was cannulated to allow growth factor administration. Body temperature was maintained with a thermostatically controlled heated blanket coupled to a rectal thermometer (Harvard Apparatus Ltd., Edenbridge, United Kingdom). Human VEGF165 (32 µg/kg) or bFGF (40 µg/kg) was administered as a bolus injection [0.1 ml/250 g body weight in 0.85% (w/v) sodium chloride], and a maximal blood pressure drop was recorded within 2 min (typically 26–30 mm Hg). These changes were sustainable for more than 20 min in control experiments. ZD6474 (2.5 mg/kg) or vehicle alone [25% (w/v) hydroxypropyl-ß-cyclodextrin in Sorensons phosphate buffer (pH 5.5)] was administered i.v., and blood pressure was recorded 5 min later to determine the effect on growth factor-induced hypotension.
Epiphyseal Growth Plate Hypertrophy in Rat.
For all additional in vivo work, ZD6474 was suspended in a 1% (v/v) solution of polyoxyethylene (20)
sorbitan mono-oleate in deionized water and administered by oral gavage. Young female Alderley Park rats (Wistar derived, 150 g in weight, 4–8 weeks of age) were dosed daily for 14 days with ZD6474 (at 0.25 ml/100 g body weight) or vehicle. Morphometric image analysis of femoro-tibial sections was performed as described previously (40)
. Growth plate areas from the femur and tibia in each joint were combined for an analysis of the effect of compound treatment.
Tumor Cell Lines.
Seven human tumor cell lines were used [PC-3 (prostate adenocarcinoma), Calu-6 and A549 (lung carcinoma), MDA-MB-231 (mammary gland adenocarcinoma), SKOV-3 (ovarian adenocarcinoma), A431 (vulval carcinoma), and SW620 (colorectal carcinoma)], each of which was obtained from the American Type Culture Collection (Manassas, VA). Two murine tumor cell lines, Lewis Lung and B16-F10, were also obtained from the American Type Culture Collection, and a syngeneic subclone of B16-F10 [B16-F10(AP3)] was generated by three rounds of serial in vivo passage (i.e., i.v. inoculation of 1 x 105 B16-F10 cells in AP C57/BL6 mice and recovery of tumor cells from a tumor deposit in the lungs). Each cell line was maintained as an exponentially growing monolayer, and all cell culture reagents, where not specified, were obtained from Life Technologies, Inc. (Paisley, United Kingdom). Culture conditions for PC-3, Calu-6, MDA-MB-231, and SKOV-3 cells were as described previously (40)
. A431, A549, Lewis Lung, and B16-F10(AP3) cells were cultured in DMEM with 2 mM L-glutamine (Sigma, Poole, United Kingdom) and 5% (A431) or 10% FCS (Labtech International, Ringmer, United Kingdom). Media for A431 were supplemented with 1% nonessential amino acids (Life Technologies, Inc.). This supplement was also used in media for B16-F10(AP3) cells, with the further addition of 1% MEM vitamins (Life Technologies, Inc.) and 1% pyruvate (1 mM final concentration;Sigma). SW620 cells were grown in L15 (non-CO2-equilibrated) media (Life Technologies, Inc.) containing 10% FCS and 2 mM glutamine. All cell lines were maintained at 37°C with 7.5% CO2, except for SW620 cells, for which CO2 was excluded. Cell lines were periodically screened for the presence of Mycoplasma in culture and analyzed for 15 types of virus in a mouse antibody production test (Syngenta, Alderley Park, United Kingdom) before routine use in vivo.
Tumor Cell Cytotoxicity Assay.
Tumor cells were plated in their respective media at predetermined densities that were known to enable logarithmic cell growth during the period of assay (PC-3, 500 cells/well; all others, 1000 cells/well). Plates were incubated for 24 h (37°C with CO2 as described) before the addition of ZD6474 (0.1–100 µM) or vehicle (0.1% DMSO in medium). Plates were reincubated for an additional 72 h before assessing cell proliferation by [3H]thymidine incorporation as described in HUVEC experiments.
In Vivo Tumor Models.
Tumor implantation procedures were performed on mice of at least 8 weeks of age. All mice were bred and maintained at Alderley Park, provided with sterilized food and water ad libitum, and housed in a barrier facility with 12-h light/dark cycles. Human tumor xenografts were grown in female athymic (nu/nu genotype) Swiss mice housed in negative pressure isolators (PFI Systems Ltd., Oxford, United Kingdom), and syngeneic tumors were grown in C57/BL6 mice.
Intradermal Tumor Angiogenesis.
To visualize the induction of angiogenesis by a tumor in vivo, an intradermal tumor model was used. In this model, neovasculature, observed predominantly at the tumor periphery, can be quantified by vessel counting (44
, 45)
. Male nude mice were anesthetized (inhalant 4% Halothane-vet; Merial Animal Health Ltd., Essex, United Kingdom), and 107 A549 human lung tumor cells in 50 µl of PBS (Dulbecco’s pH 7.4, without calcium chloride and magnesium chloride; Sigma) were implanted intradermally at two sites in the abdominal region. Two additional injections of PBS (50 µl) were performed on each mouse as a control. All implant sites were marked with indelible ink to aid identification at the end of the experiment. Mice were allowed to recover fully from anesthesia before being dosed p.o. with ZD6474 (50 or 100 mg/kg/day) or vehicle (4 mice/group). Daily dosing was continued for a total period of 5 days. Each mouse was humanely culled 24 h after the last dose of ZD6474 or vehicle, and a section of the abdominal wall skin encompassing all implant sites was removed and spread onto filter paper. Sections were examined by light microscopy (x10 magnification), and the total number of blood vessels (major vessels and branching points) was determined within a 1-cm2 area around each implant site. Vessel counts from implants of PBS were consistent irrespective of treatment; the mean value (27 ± 1.2; mean ± SE) was therefore subtracted from control and ZD6474-treated vessel counts to give a more accurate indication of tumor-induced blood vessel formation and to ascertain the effect of treatment.
s.c. Tumor Models.
Protocols for establishing s.c. PC-3, Calu-6, SKOV-3, and MDA-MB-231 tumors were as described previously (40)
. SW620 and A549 tumors were established by s.c. injection of 1 x 106 and 5 x 106 cells, respectively, in 100 µl of serum-free media containing 50% Matrigel (Fred Baker, Liverpool, United Kingdom), into the hind flank of mice. A431 tumors were also initially established in the same way but were used (10–14 days after inoculation) to generate cubic tumor fragments of 0.5–1 mm3 in diameter, which were implanted for therapy experiments. Mice were randomized into groups of 10 before treatment at a point when tumors reached a volume of 0.15–0.47 cm3. Mice then received (p.o.) either ZD6474 (12.5–100 mg/kg/day) or vehicle, administered once daily at 0.1 ml/10 g body weight. Subsequent experiments also examined treatment of much larger tumors (up to 1.4 cm3 in volume). For studies examining rodent tumors, B16-F10(AP3) cells (1 x 105 cells in 100 µl) or a suspension of disaggregated Lewis Lung tumor cells (recovered from established tumors; 50-µl volume), in PBS without calcium chloride or magnesium chloride (Life Technologies, Inc.), was implanted s.c. Because these syngeneic models have aggressive growth characteristics, ZD6474 (25–100 mg/kg/day) or vehicle was dosed p.o. from the day of tumor implantation. Tumor volumes were assessed at least twice weekly by bilateral Vernier caliper measurement and calculated (taking length to be the longest diameter across the tumor and width to be the corresponding perpendicular diameter) using the formula (length xwidth) x 
(length x width) x (
/6). Growth inhibition from the start of treatment was assessed by comparison of the differences in tumor volume between control and treated groups. Because the variance in mean tumor volume data increases proportionally with volume (and is therefore disproportionate between groups), data were log-transformed to remove any size dependency before statistical evaluation. Statistical significance was evaluated using a one-tailed two-sample t test.
Histological Analysis of Calu-6 Tumors.
Calu-6 tumors from a s.c. tumor xenograft experiment, treated with vehicle or ZD6474 (25–100 mg/kg/day) once daily for 24 days, were collected for histological analysis. Half of each tumor was fixed in 10% buffered formalin, and the other half was fixed in zinc fixative (BD PharMingen, Oxford, United Kingdom) for 24 h, before being processed to paraffin wax. Sections (3 µm) were produced by standard histological techniques. To visualize endothelial cells, CD31 was detected in zinc-fixed tissue using an avidin-biotin method. Briefly, endogenous peroxidase was blocked with 3% hydrogen peroxide (30 min), and nonspecific background staining was blocked with normal rabbit serum (1:20 dilution; Dako, Cambridgeshire, United Kingdom). Sections were incubated (1 h) with a monoclonal rat antimouse CD31 primary antibody (1:500 dilution; BD PharMingen), followed by a 30-min incubation with a mouse adsorbed biotinylated rabbit antirat immunoglobulin (1:200 dilution; Dako) and a further 30-min incubation with a StreptABComplex conjugated with horseradish peroxidase (Dako). Visualization was by a diaminobenzidine (Biogenex, Berkshire, United Kingdom) chromogen procedure. Sections were analyzed using a Zeiss KS400 (Version 3.0) image analyzer (Imaging Associates Ltd., Thame, United Kingdom), which counted up to six randomly selected fields of view at x1.6 objective lens magnification encompassing only viable tumor tissue (i.e., excluding areas of necrosis) to enable the determination of CD31 positive area/5000 µm2 viable tumor. To visualize necrosis, formalin-fixed, paraffin wax-embedded tissue sections were stained with H&E, and the relative area of necrotic tissue:total tumor area was determined visually, using interactive textual region detection morphometric image analysis of the whole tumor section. To visualize apoptosis, the Roche in situ cell death detection kit (Roche, Lewes, United Kingdom) was used, which incorporates the TUNEL technique. In brief, formalin-fixed, paraffin wax-embedded tissue sections were treated with proteinase K (2 min; Dako) and blocked for endogenous peroxidase using 3% hydrogen peroxide. Sections were then incubated for 1 h at 37°C in TUNEL reaction mixture, followed by a 30-min incubation with converter-Pod (peroxidase). Visualization was by a diaminobenzidine (Biogenex) chromogen procedure.
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RESULTS |
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). The compound has activity versus the kinase activity of the VEGF-C and -D receptor Flt-4 (IC50 = 108 nM) but has significantly less activity versus Flt-1 (IC50 = 1600 nM). Excellent selectivity for KDR was demonstrated versus additional tyrosine kinases (PDGFRß, Tie-2, FGFR1, c-Kit, erbB2, IGF-IR, and FAK), serine-threonine kinases (CDK2, AKT, and PDK1), and the dual specificity kinase MEK (Table 1)
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). No effect was observed on basal endothelial cell growth (2% serum) with a >50-fold concentration of ZD6474. The ZD6474 selectivity profile observed in the recombinant enzyme assay (i.e., inhibition of VEGF > EGF > bFGF) was also evident in this growth factor-stimulated HUVEC proliferation assay, with IC50 values of 170 and 800 nM for EGF- and bFGF-stimulated cell growth, respectively.
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Inhibition of VEGF Signaling Responses in Vivo.
For confirmation of inhibition of VEGF signaling and angiogenesis in vivo, two pharmacodynamic end points were examined in rat. Several growth factors (including VEGF) have been shown to induce a profound hypotension in anesthetized rats when administered as a large bolus dose. This effect is attributed to a specific signaling response through the growth factor’s cognate receptor to which tachyphylaxis can be demonstrated (46)
. ZD6474 (2.5 mg/kg, i.v.), reversed a VEGF-induced hypotension (by 63%;P < 0.001) but did not significantly affect a bFGF-induced hypotension (Fig. 3a)
. These data support inhibition of VEGF signaling in vivo by ZD6474, and the selectivity observed is consistent with that observed in tyrosine kinase and HUVEC proliferation assays. The effect of ZD6474 on growth plate morphology was also examined because angiogenesis is a prerequisite for ossification during long bone extension, and vascular invasion of the growth plate is dependent on VEGF secretion from hypertrophic chondrocytes (47)
. ZD6474 produced a dose-dependent hypertrophy of the femoro-tibial growth plates of young growing rats when administered once daily (p.o.) for 14 days (Fig. 3b)
. Doses of 50 and 100 mg/kg/day ZD6474 increased the combined growth plate area by 57% and 75%, respectively (P < 0.001, one-tailed two-sample t test).
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. Statistical significance was evident in each tumor xenograft model with administration of 25 mg/kg/day (P < 0.05 in SKOV-3 and P < 0.001 in all others). Of the seven human tumor xenografts studied, five were also significantly growth-inhibited by administration of 12.5 mg/kg/day ZD6474 (P < 0.01). Full growth inhibition profiles are shown for four of the xenograft models (Fig. 5)
. ZD6474 treatment was well tolerated, with only small effects on body weight (particularly at ZD6474 doses of 
50 mg/kg/day) and no adverse effects on clinical condition (even at 100 mg/kg/day for 5 weeks). When body weights of mice from all seven xenograft experiments were analyzed, treatment with 12.5, 25, 50, or 100 mg/kg/day ZD6474 for 3 weeks induced mean body weight losses of 0.3%, 2.2%, 3.8%, and 7.7%, respectively, when compared with pretreatment values, whereas vehicle-treated controls gained 1.8% body weight during this period. Similar effects on body weight were observed when ZD6474 was administered for a longer duration; in the PC-3 xenograft experiment, treatment with 12.5, 25, 50, or 100 mg/kg/day ZD6474 for a total of 5 weeks induced mean body weight losses of 1.4%, 1.0%, 2.6%, and 10%, respectively, whereas vehicle-treated controls remained at their starting (pretreatment) mean body weight. The activity of ZD4190, a predecessor of ZD6474, had been examined previously in Calu-6, MDA-MB-231, PC-3, and SKOV-3 tumors (40)
. ZD6474 consistently produced a greater inhibition of tumor growth than ZD4190 when compared at doses of 50 and 100 mg/kg/day in these models (Fig. 6)
, although this just failed to reach statistical significance at 50 mg/kg/day in PC-3 (P = 0.07). Whereas superior inhibition of tumor growth was not obtained with 100 mg/kg/day ZD6474 in SKOV-3, this was to be expected, given that ZD4190 inhibited the growth of this tumor completely (i.e., by 95 ± 6%) at this dose (Fig. 6)
. The effect of ZD6474 treatment on rapidly growing syngeneic tumors in immunocompetent mice was also examined because the tumor:host signaling responses may be reproduced more accurately in these models. ZD6474 also inhibited the growth of these tumors (Fig. 7)
, with highly significant activity evident at 25 mg/kg/day (Table 2)
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; n = 5 mice/group). These treatments were also found to increase the percentage of necrosis within Calu-6 tumors (by 2.7- and 3.2-fold with 50 and 100 mg/kg/day, respectively; Fig. 8c
). Statistically significant effects on CD31 staining or necrosis were not observed in Calu-6 tumors from mice treated with 25 mg/kg/day ZD6474, despite observing significant tumor growth inhibition. An examination of tumor cell apoptosis in nonnecrotic areas of tumor (using TUNEL) did not reveal differences in the extent or pattern of staining between vehicle-treated controls and any ZD6474-treated group (25–100 mg/kg/day; data not shown).
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. In contrast, ZD6474 induced regression in established PC-3 prostate tumors of varying sizes (Fig. 9b)
, with the most dramatic effects being produced in the largest tumors (1.4 cm3 tumors regressing to <0.2 cm3 after 3 weeks of treatment).
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In recombinant enzyme assays, ZD6474 is a potent inhibitor of KDR activity (VEGFR2; IC50 = 40 nM), with additional activity versus the tyrosine kinase of the VEGF-C and -D receptor Flt-4 (VEGFR3;IC50 = 110 nM) and comparatively less activity versus that of Flt-1 (VEGFR1; IC50 = 1600 nM).
Because KDR has the predominant role in mediating VEGF signal transduction in endothelial cells (35, 36, 37) , this profile is compatible with the aim of developing a VEGF signaling inhibitor. Although the quantitative relationship between enzyme and cell data was examined for KDR (i.e., by comparison with inhibition of VEGF-induced HUVEC proliferation), this relationship was not determined for Flt-1 and Flt-4. Flt-1 has the highest affinity for VEGF but yields a comparatively weak autophosphorylative response and does not induce mitogenesis in endothelial cells (31 , 48 , 49) . This receptor may act as a negative regulator of angiogenesis by sequestering VEGF (50) . Recent data suggest that Flt-1 signaling may be of consequence in pathological angiogenesis (51) but potentially only by virtue of its ability to transactivate KDR. Flt-4 was initially thought to be restricted to lymphatic endothelium (28) and therefore of less relevance to tumor angiogenesis. However, recent data suggest that Flt-4 can be elevated on tumor blood vessels during neovascularization (52 , 53) and that tumor VEGF-C expression can correlate with lymphatic invasion, increased metastasis, and a worse clinical prognosis (54 , 55) . Hence, if the inhibition of Flt-4 tyrosine kinase by ZD6474 translates into potent inhibition of Flt-4 signaling in cells, then this activity could potentially also impart a therapeutic benefit.
It is highly likely that ZD6474 adopts a kinase binding conformation, in which the adenine binding site of the kinase is occupied by the quinazoline ring, and the aniline of the molecule fits into a hydrophobic pocket that is structurally distinct between different kinases. By exploiting the nonconserved features of the KDR kinase domain, ZD6474 can achieve selectivity versus a range of tyrosine and serine-threonine kinases, including those of structurally related receptors (e.g., Flt-1, PDGFRß, and c-kit). However, although apparent selectivity for inhibition of KDR tyrosine kinase is evident versus many other kinases, ZD6474 was also found to elicit submicromolar activity versus that associated with EGFR. The activity of ZD6474 versus KDR tyrosine kinase translated into potent inhibition of VEGF signaling in human primary endothelial cells, with prevention of VEGF-induced proliferation (IC50 = 60 nM). Notably, the inhibition of VEGF signaling by ZD6474 occurs at concentrations well below those that show significant direct effects on the normal growth of endothelial (>3 µM) or tumor cells (2.7–13.5 µM).
Large i.v. doses of VEGF (10 µg/kg) have been shown to induce an acute hypotensive effect in anesthetized rats. This effect is thought to depend on VEGF receptor signaling because VEGF induces a rapid desensitization to itself (tachyphylaxis) but does not produce desensitization to hypotension induced by other growth factors, such as bFGF (43)
. Both VEGF- and bFGF-induced hypotension are dependent on production of nitric oxide because either response can be abolished with the nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester (56
, 57) . The observation that ZD6474 was able to reverse a VEGF-induced hypotension in rat but did not significantly affect that induced by bFGF is concordant with selective inhibition of VEGF signaling in vivo. ZD6474 also produced a dose-dependent hypertrophy of the femoro-tibial growth plates of young growing rats when administered p.o. for 14 days, which is to be expected, given the role of VEGF in bone morphogenesis (58)
. VEGF expression by hypertrophic chondrocytes is thought to drive the angiogenesis needed for endochondral ossification. Similar effects on long bone growth plates have been reported previously with a VEGF antibody (59)
and a soluble VEGFR construct (47)
that selectively sequester VEGF. Increased hypertrophic chondrocyte numbers have also been induced in the long bones of mice after Cre-lox-mediated VEGF deletion in cartilage using the collagen 2a1 promoter (60)
. Collectively, these data in rat indicate that ZD6474 inhibits VEGF signaling and angiogenesis in vivo.
Chronic once-daily oral administration of ZD6474 (12.5–100 mg/kg/day) produced a dose-dependent inhibition of tumor growth in a panel of human tumor xenograft models, despite their varied histological origin (breast, lung, prostate, colon, ovary, and vulva) and different growth rates. This was also evident in syngeneic tumor models (B16-F10 and Lewis Lung) in immunocompetent animals. In all cases, the percentage inhibition of tumor growth progressively increased as the duration of dosing was extended, which is indicative of a sustained antitumor effect. The broad spectrum activity observed with ZD6474 in tumor models is consistent with inhibition of VEGF signaling and an indirect (i.e., antiangiogenic) antitumor effect rather than direct antiproliferative effects on the tumor cell. Pharmacokinetic modeling (data not shown) suggests that the steady-state free levels of ZD6474 that are capable of producing a highly significant (P < 0.001) antitumor effect in vivo can be as much as 100-fold less than the free levels required to produce a direct inhibition (IC50) of tumor cell proliferation in vitro. The profile observed contrasts with that of tumor cell-directed therapies, which would not be expected to retain comparable activity against all tumor models examined. Histological analysis of Calu-6 tumor xenografts also indicated that ZD6474 doses of 50 mg/kg, administered for 24 days, reduced CD31 staining in viable tumor tissue and increased the proportion of necrosis within the tumor. However, the proportion of tumor cell apoptosis in areas of viable tumor did not appear to be affected. These data are compatible with inhibition of VEGF signaling because a significant reduction in tumor neovascularization and VEGF-induced vascular permeability could be expected to result in greater tumor ischemia and the induction of tumor cell necrosis.
ZD6474 gave a better antitumor effect than was reported previously with its predecessor ZD4190 (40) , when compared at doses of 50 and 100 mg/kg/day (p.o.). The greater effect of ZD6474 is not related to its additional submicromolar activity versus EGFR tyrosine kinase because ZD4190 also had activity versus this enzyme and proved comparatively more potent in an EGF-stimulated HUVEC proliferation assay (IC50 = 50 nM; Ref. 41 ). The increase in efficacy is most likely attributed to a gain in free drug levels in mouse (4.1% versus 2.5%) combined with a pharmacokinetic profile that gives extended plasma exposure until 24 h after administration of a single dose (in rat, the plasma half-life of ZD6474 has been shown to be approximately 12-fold greater than that of ZD4190; Ref. 41 ). We have previously observed in a series of anilinoquinazolines that extended plasma exposure for the duration of the dosing interval (i.e., for 24 h with once-daily dosing) is required for maximum therapeutic effect in tumor xenograft models (40) .
In addition to its anti-VEGF pharmacology, ZD6474 can also inhibit EGFR signaling in cells (IC50 for inhibition of EGF-stimulated HUVEC proliferation = 170 nM). EGFR overexpression by tumor cells has been found to correlate with poor prognosis in a range of malignancies (e.g., lung, colorectal, ovarian, breast, head and neck, bladder, ovarian, renal, and gastric cancers; Refs. 61
and 62
). This receptor can be activated by a number of structurally related ligands (e.g., EGF and transforming growth factor ), which can be produced in large amounts by epithelially derived tumor cells and induce autocrine-stimulated tumor cell proliferation (61)
. EGFR signaling has been further implicated in the induction of other tumor and host cell phenotypes that contribute to driving tumor progression, including migration, antiapoptosis, and angiogenesis (63, 64, 65)
. Inhibition of EGFR tyrosine kinase is therefore a promising therapeutic strategy in its own right, with antibody [e.g., C225 (66)
] and small molecule approaches [e.g., ZD1839 Iressa (67)
] currently in late-stage clinical development for the treatment of colorectal cancer and non-small cell lung cancer, respectively. It is possible that EGFR inhibition by ZD6474, particularly at higher doses, may afford additional antitumor activity in tumors that are dependent on EGFR-driven proliferation. From the panel of tumor xenografts examined, A431 and A549 are known to have a specific EGFR signaling dependency (68)
, and it is interesting to note that when ZD6474 was administered at 50 mg/kg/day, there was evidence of some tumor regression in these two particular models. It is anticipated that the significant inhibition of A549-induced angiogenesis observed in the intradermal tumor angiogenesis model is predominantly a consequence of inhibition of VEGF signaling because this tumor xenograft secretes relatively high levels of VEGF, and similar data have been produced with selective KDR TKIs (data not shown). Nonetheless, it is still feasible that inhibition of EGFR signaling could also contribute to an antiangiogenic effect in an EGFR-dependent tumor, from inhibition of direct EGF-induced angiogenesis and/or EGF-induced VEGF expression by tumor cells (65
, 69)
. The advantages of targeting both EGFR and VEGFR pathways simultaneously have been recently been outlined in a study examining coadministration of antibodies to both KDR and EGFR (70)
. However, whereas there are potential therapeutic benefits to also inhibiting EGFR tyrosine kinase, this activity is not a prerequisite for obtaining an antitumor effect with ZD6474. Selective EGFR TKIs do not share the same broad spectrum of activity in the panel of tumor xenografts examined in this study (data not shown). For example, the activity of ZD6474 has been compared with a selective EGFR TKI, after administration of 50 mg/kg/day of either compound (p.o., 21 days) to mice bearing the EGFR-overexpressing vulval tumor A431 or the PC-3 prostate tumor. Whereas ZD6474 produced substantial inhibition of tumor growth in both tumors (87%; P < 0.001), the EGFR TKI produced a highly significant inhibition in the EGFR-overexpressing tumor A431 (94%; P < 0.001) but did not significantly affect the growth of PC-3 (P > 0.1). Subsequent experiments examining selective VEGFR TKIs have also demonstrated that activity versus KDR alone is sufficient to exert significant antitumor activity in the Calu-6 lung tumor xenograft (71)
. Hence, the antitumor activity of ZD6474 may extend to a wide range of solid tumor types by virtue of its ability to inhibit VEGF signal transduction.
Given that inhibition of VEGF signaling was required for activity in the PC-3 tumor model, it is perhaps surprising that well-established PC-3 tumor xenografts were observed to regress dramatically when treated with ZD6474. This was not apparent in well-established Calu-6 tumors; however, encouragingly, highly significant inhibition of tumor growth was observed in this model, irrespective of the tumor volume at start of ZD6474 treatment. The divergent responses observed in these tumor models may reflect different dependencies on VEGF as a survival factor for newly formed endothelium (7 , 72) . Such signaling is known to involve Akt/protein kinase B activation and has been suggested to depend on formation of a multimeric complex between the cytoplasmic domains of KDR, the endothelial adherens junction molecule VE-cadherin, ß-catenin, and phophoinositide 3-kinase (8) .
In summary, we have identified ZD6474, a potent nanomolar inhibitor of VEGF signaling with pharmacokinetic properties compatible with chronic oral administration. This compound is also a submicromolar inhibitor of EGFR tyrosine kinase, which, at higher doses, may offer added therapeutic benefit in tumors with EGFR-dependent proliferation or survival. ZD6474 is currently in Phase I clinical development as a once-daily oral therapy for the treatment of cancer (73) .
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 To whom requests for reprints should be addressed, at Cancer and Infection Research, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom. Phone: 44-1625-513236; Fax: 44-1625-513624; E-mail: steve.wedge{at}astrazeneca.com 
2 The abbreviations used are: VEGF, vascular endothelial growth factor-A; bFGF, basic fibroblast growth factor; KDR, kinase insert domain-containing receptor; Flt, fms-like tyrosine kinase; EGFR, epidermal growth factor receptor; PDGFR, platelet-derived growth factor receptor; Tie-2, tunica interna endothelial cell kinase;FGFR1, fibroblast growth factor receptor 1; IGF-1R, insulin-like growth factor I receptor; MAPK, mitogen-activated protein kinase; MEK, MAPK kinase; FAK, focal adhesion kinase; CDK2, cyclin-dependent kinase 2;PDK1, phosphoinositide-dependent kinase 1; HUVEC, human umbilical vein endothelial cell; TKI, tyrosine kinase inhibitor; VEGFR, vascular endothelial growth factor receptor; EGF, epidermal growth factor;TUNEL, terminal deoxynucleotidyl transferase-mediated nick end labeling.
Received 12/13/01. Accepted 6/17/03.
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J. N. Rich, S. Sathornsumetee, S. T. Keir, M. W. Kieran, A. Laforme, A. Kaipainen, R. E. McLendon, M. W. Graner, B.K. A. Rasheed, L. Wang, et al. ZD6474, a Novel Tyrosine Kinase Inhibitor of Vascular Endothelial Growth Factor Receptor and Epidermal Growth Factor Receptor, Inhibits Tumor Growth of Multiple Nervous System Tumors Clin. Cancer Res., November 15, 2005; 11(22): 8145 - 8157. [Abstract] [Full Text] [PDF]
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I. Roodink, J. Raats, B. van der Zwaag, K. Verrijp, B. Kusters, H. van Bokhoven, M. Linkels, R. M.W. de Waal, and W. P.J. Leenders Plexin D1 Expression Is Induced on Tumor Vasculature and Tumor Cells: A Novel Target for Diagnosis and Therapy? Cancer Res., September 15, 2005; 65(18): 8317 - 8323. [Abstract] [Full Text] [PDF]
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S. N. Holden, S. G. Eckhardt, R. Basser, R. de Boer, D. Rischin, M. Green, M. A. Rosenthal, C. Wheeler, A. Barge, and H. I. Hurwitz Clinical evaluation of ZD6474, an orally active inhibitor of VEGF and EGF receptor signaling, in patients with solid, malignant tumors Ann. Onc., August 1, 2005; 16(8): 1391 - 1397. [Abstract] [Full Text] [PDF]
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L. Ma, G. Francia, A. Viloria-Petit, D. J. Hicklin, J. du Manoir, J. Rak, and R. S. Kerbel In vitro Procoagulant Activity Induced in Endothelial Cells by Chemotherapy and Antiangiogenic Drug Combinations: Modulation by Lower-Dose Chemotherapy Cancer Res., June 15, 2005; 65(12): 5365 - 5373. [Abstract] [Full Text] [PDF]
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L. S. Rosen VEGF-Targeted Therapy: Therapeutic Potential and Recent Advances Oncologist, June 1, 2005; 10(6): 382 - 391. [Abstract] [Full Text] [PDF]
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S. R. Wedge, J. Kendrew, L. F. Hennequin, P. J. Valentine, S. T. Barry, S. R. Brave, N. R. Smith, N. H. James, M. Dukes, J. O. Curwen, et al. AZD2171: A Highly Potent, Orally Bioavailable, Vascular Endothelial Growth Factor Receptor-2 Tyrosine Kinase Inhibitor for the Treatment of Cancer Cancer Res., May 15, 2005; 65(10): 4389 - 4400. [Abstract] [Full Text] [PDF]
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R. S. Herbst, A. Onn, and A. Sandler Angiogenesis and Lung Cancer: Prognostic and Therapeutic Implications J. Clin. Oncol., May 10, 2005; 23(14): 3243 - 3256. [Abstract] [Full Text] [PDF]
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M. Vidal, S. Wells, A. Ryan, and R. Cagan ZD6474 Suppresses Oncogenic RET Isoforms in a Drosophila Model for Type 2 Multiple Endocrine Neoplasia Syndromes and Papillary Thyroid Carcinoma Cancer Res., May 1, 2005; 65(9): 3538 - 3541. [Abstract] [Full Text] [PDF]
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K. D. Miller, J. M. Trigo, C. Wheeler, A. Barge, J. Rowbottom, G. Sledge, and J. Baselga A Multicenter Phase II Trial of ZD6474, a Vascular Endothelial Growth Factor Receptor-2 and Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, in Patients with Previously Treated Metastatic Breast Cancer Clin. Cancer Res., May 1, 2005; 11(9): 3369 - 3376. [Abstract] [Full Text] [PDF]
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P. Beaudry, J. Force, G. N. Naumov, A. Wang, C. H. Baker, A. Ryan, S. Soker, B. E. Johnson, J. Folkman, and J. V. Heymach Differential Effects of Vascular Endothelial Growth Factor Receptor-2 Inhibitor ZD6474 on Circulating Endothelial Progenitors and Mature Circulating Endothelial Cells: Implications for Use as a Surrogate Marker of Antiangiogenic Activity Clin. Cancer Res., May 1, 2005; 11(9): 3514 - 3522. [Abstract] [Full Text] [PDF]
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 X.-F. Zhu, B.-F. Xie, J.-M. Zhou, G.-K. Feng, Z.-C. Liu, X.-Y. Wei, F.-X. Zhang, M.-F. Liu, and Y.-X. Zeng Blockade of Vascular Endothelial Growth Factor Receptor Signal Pathway and Antitumor Activity of ON-III (2',4'-Dihydroxy-6'-methoxy-3',5'-dimethylchalcone), a Component from Chinese Herbal Medicine Mol. Pharmacol., May 1, 2005; 67(5): 1444 - 1450. [Abstract] [Full Text] [PDF]
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J. Baselga and C. L. Arteaga Critical Update and Emerging Trends in Epidermal Growth Factor Receptor Targeting in Cancer J. Clin. Oncol., April 10, 2005; 23(11): 2445 - 2459. [Abstract] [Full Text] [PDF]
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 K Gupta and J Zhang Angiogenesis: a curse or cure? Postgrad. Med. J., April 1, 2005; 81(954): 236 - 242. [Abstract] [Full Text] [PDF]
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 M. Fujita, I. Hayashi, S. Yamashina, A. Fukamizu, M. Itoman, and M. Majima Angiotensin type 1a receptor signaling-dependent induction of vascular endothelial growth factor in stroma is relevant to tumor-associated angiogenesis and tumor growth Carcinogenesis, February 1, 2005; 26(2): 271 - 279. [Abstract] [Full Text] [PDF]
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D. W. Siemann, M. C. Bibby, G. G. Dark, A. P. Dicker, F. A.L.M. Eskens, M. R. Horsman, D. Marme, and P. M. LoRusso Differentiation and Definition of Vascular-Targeted Therapies Clin. Cancer Res., January 15, 2005; 11(2): 416 - 420. [Abstract] [Full Text] [PDF]
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K. J. Williams, B. A. Telfer, S. Brave, J. Kendrew, L. Whittaker, I. J. Stratford, and S. R. Wedge ZD6474, a Potent Inhibitor of Vascular Endothelial Growth Factor Signaling, Combined With Radiotherapy: Schedule-Dependent Enhancement of Antitumor Activity Clin. Cancer Res., December 15, 2004; 10(24): 8587 - 8593. [Abstract] [Full Text] [PDF]
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B. Nicholson, K. Gulding, M. Conaway, S. R. Wedge, and D. Theodorescu Combination Antiangiogenic and Androgen Deprivation Therapy for Prostate Cancer: A Promising Therapeutic Approach Clin. Cancer Res., December 15, 2004; 10(24): 8728 - 8734. [Abstract] [Full Text] [PDF]
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K. Nakamura, A. Yamamoto, M. Kamishohara, K. Takahashi, E. Taguchi, T. Miura, K. Kubo, M. Shibuya, and T. Isoe KRN633: A selective inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase that suppresses tumor angiogenesis and growth Mol. Cancer Ther., December 1, 2004; 3(12): 1639 - 1649. [Abstract] [Full Text] [PDF]
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S. M. Wilhelm, C. Carter, L. Tang, D. Wilkie, A. McNabola, H. Rong, C. Chen, X. Zhang, P. Vincent, M. McHugh, et al. BAY 43-9006 Exhibits Broad Spectrum Oral Antitumor Activity and Targets the RAF/MEK/ERK Pathway and Receptor Tyrosine Kinases Involved in Tumor Progression and Angiogenesis Cancer Res., October 1, 2004; 64(19): 7099 - 7109. [Abstract] [Full Text] [PDF]
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W. P. J. Leenders, B. Kusters, K. Verrijp, C. Maass, P. Wesseling, A. Heerschap, D. Ruiter, A. Ryan, and R. de Waal Antiangiogenic Therapy of Cerebral Melanoma Metastases Results in Sustained Tumor Progression via Vessel Co-Option Clin. Cancer Res., September 15, 2004; 10(18): 6222 - 6230. [Abstract] [Full Text] [PDF]
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M. F. McCarty, J. Wey, O. Stoeltzing, W. Liu, F. Fan, C. Bucana, P. F. Mansfield, A. J. Ryan, and L. M. Ellis ZD6474, a vascular endothelial growth factor receptor tyrosine kinase inhibitor with additional activity against epidermal growth factor receptor tyrosine kinase, inhibits orthotopic growth and angiogenesis of gastric cancer Mol. Cancer Ther., September 1, 2004; 3(9): 1041 - 1048. [Abstract] [Full Text] [PDF]
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S. Emanuel, R. H. Gruninger, A. Fuentes-Pesquera, P. J. Connolly, J. A. Seamon, S. Hazel, R. Tominovich, B. Hollister, C. Napier, M. R. D'Andrea, et al. A Vascular Endothelial Growth Factor Receptor-2 Kinase Inhibitor Potentiates the Activity of the Conventional Chemotherapeutic Agents Paclitaxel and Doxorubicin in Tumor Xenograft Models Mol. Pharmacol., September 1, 2004; 66(3): 635 - 647. [Abstract] [Full Text] [PDF]
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P. Traxler, P. R. Allegrini, R. Brandt, J. Brueggen, R. Cozens, D. Fabbro, K. Grosios, H. A. Lane, P. McSheehy, J. Mestan, et al. AEE788: A Dual Family Epidermal Growth Factor Receptor/ErbB2 and Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor with Antitumor and Antiangiogenic Activity Cancer Res., July 15, 2004; 64(14): 4931 - 4941. [Abstract] [Full Text] [PDF]
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D. W. Davis, K. Inoue, C. P. N. Dinney, D. J. Hicklin, J. L. Abbruzzese, and D. J. McConkey Regional Effects of an Antivascular Endothelial Growth Factor Receptor Monoclonal Antibody on Receptor Phosphorylation and Apoptosis in Human 253J B-V Bladder Cancer Xenografts Cancer Res., July 1, 2004; 64(13): 4601 - 4610. [Abstract] [Full Text] [PDF]
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R. S. Herbst and A. B. Sandler Non-Small Cell Lung Cancer and Antiangiogenic Therapy: What Can Be Expected of Bevacizumab? Oncologist, June 1, 2004; 9(suppl_1): 19 - 26. [Abstract] [Full Text] [PDF]
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 S. H. Rudolfsson, P. Wikstrom, A. Jonsson, O. Collin, and A. Bergh Hormonal Regulation and Functional Role of Vascular Endothelial Growth Factor A in the Rat Testis Biol Reprod, February 1, 2004; 70(2): 340 - 347. [Abstract] [Full Text] [PDF]
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L. Sepp-Lorenzino, E. Rands, X. Mao, B. Connolly, J. Shipman, J. Antanavage, S. Hill, L. Davis, S. Beck, K. Rickert, et al. A Novel Orally Bioavailable Inhibitor of Kinase Insert Domain-Containing Receptor Induces Antiangiogenic Effects and Prevents Tumor Growth in Vivo Cancer Res., January 15, 2004; 64(2): 751 - 756. [Abstract] [Full Text] [PDF]
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F. Ciardiello, R. Bianco, R. Caputo, R. Caputo, V. Damiano, T. Troiani, D. Melisi, F. De Vita, S. De Placido, A. R. Bianco, et al. Antitumor Activity of ZD6474, a Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor, in Human Cancer Cells with Acquired Resistance to Antiepidermal Growth Factor Receptor Therapy Clin. Cancer Res., January 15, 2004; 10(2): 784 - 793. [Abstract] [Full Text] [PDF]
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J. S. Beebe, J. P. Jani, E. Knauth, P. Goodwin, C. Higdon, A. M. Rossi, E. Emerson, M. Finkelstein, E. Floyd, S. Harriman, et al. Pharmacological Characterization of CP-547,632, a Novel Vascular Endothelial Growth Factor Receptor-2 Tyrosine Kinase Inhibitor for Cancer Therapy Cancer Res., November 1, 2003; 63(21): 7301 - 7309. [Abstract] [Full Text] [PDF]
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L. M. Ellis Antiangiogenic Therapy: More Promise and, Yet Again, More Questions J. Clin. Oncol., November 1, 2003; 21(21): 3897 - 3899. [Full Text] [PDF]
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G. Petrangolini, G. Pratesi, M. De Cesare, R. Supino, C. Pisano, M. Marcellini, V. Giordano, D. Laccabue, C. Lanzi, and F. Zunino Antiangiogenic Effects of the Novel Camptothecin ST1481 (Gimatecan) in Human Tumor Xenografts Mol. Cancer Res., October 1, 2003; 1(12): 863 - 870. [Abstract] [Full Text] [PDF]
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B. Ruggeri, J. Singh, D. Gingrich, T. Angeles, M. Albom, H. Chang, C. Robinson, K. Hunter, P. Dobrzanski, S. Jones-Bolin, et al. CEP-7055: A Novel, Orally Active Pan Inhibitor of Vascular Endothelial Growth Factor Receptor Tyrosine Kinases with Potent Antiangiogenic Activity and Antitumor Efficacy in Preclinical Models Cancer Res., September 15, 2003; 63(18): 5978 - 5991. [Abstract] [Full Text] [PDF]
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 L. Zilberberg, S. Shinkaruk, O. Lequin, B. Rousseau, M. Hagedorn, F. Costa, D. Caronzolo, M. Balke, X. Canron, O. Convert, et al. Structure and Inhibitory Effects on Angiogenesis and Tumor Development of a New Vascular Endothelial Growth Inhibitor J. Biol. Chem., September 12, 2003; 278(37): 35564 - 35573. [Abstract] [Full Text] [PDF]
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S. Williams, C. Pettaway, R. Song, C. Papandreou, C. Logothetis, and D. J. McConkey Differential effects of the proteasome inhibitor bortezomib on apoptosis and angiogenesis in human prostate tumor xenografts Mol. Cancer Ther., September 1, 2003; 2(9): 835 - 843. [Abstract] [Full Text] [PDF]
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M. Braga-Basaria and M. D. Ringel Beyond Radioiodine: A Review of Potential New Therapeutic Approaches for Thyroid Cancer J. Clin. Endocrinol. Metab., May 1, 2003; 88(5): 1947 - 1960. [Abstract] [Full Text] [PDF]
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 H. Amano, I. Hayashi, H. Endo, H. Kitasato, S. Yamashina, T. Maruyama, M. Kobayashi, K. Satoh, M. Narita, Y. Sugimoto, et al. Host Prostaglandin E2-EP3 Signaling Regulates Tumor-Associated Angiogenesis and Tumor Growth J. Exp. Med., January 20, 2003; 197(2): 221 - 232. [Abstract] [Full Text] [PDF]
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F. Carlomagno, D. Vitagliano, T. Guida, F. Ciardiello, G. Tortora, G. Vecchio, A. J. Ryan, G. Fontanini, A. Fusco, and M. Santoro ZD6474, an Orally Available Inhibitor of KDR Tyrosine Kinase Activity, Efficiently Blocks Oncogenic RET Kinases Cancer Res., December 15, 2002; 62(24): 7284 - 7290. [Abstract] [Full Text] [PDF]
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, 12.5 mg/kg/day; 
, 25 mg/kg/day;
, 50 mg/kg/day; 
, 100 mg/kg/day) or vehicle (
) on the growth of selected human tumor xenografts (a, Calu-6;b, PC-3; c, SW620; d, A431). Xenografts were established s.c. in athymic mice and allowed to reach a volume of 0.16–0.34 cm3 before treatment. Once-daily oral administration of ZD6474 or vehicle was then started and continued for the duration of the experiment. Data points represent a mean from 10 mice, with SEs shown in one direction.
): comparative activity in (a) Calu-6, (b) MDA-MB-231, (c) PC-3, and (d) SKOV-3 human tumor xenografts. Tumor growth inhibition data from previous experiments with ZD4190 
