| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Experimental Therapeutics |
Department of Cancer and Infection Research, AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom
 |
ABSTRACT |
|---|
 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
|
INTRODUCTION |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
At the outset of the drug discovery program, two significant issues were recognized. First, because EGFR is one of four members of the type I family of RTKs, which share a high degree of sequence homology in their kinase domains, and because the type I receptors are themselves part of a much larger "superfamily" of RTKs, would it be possible to synthesize EGFR-selective inhibitors? Second, given that EGFR is commonly expressed in normal tissues as well as in tumors, would EGFR-targeted inhibitors cause unacceptable toxicity? The synthesis of tyrphostins that inhibit EGFR-TK activity without affecting insulin receptor TK activity provided an important precedent for a small-molecule synthetic approach (7) . The issue of toxicity could be addressed only with the inhibitors at hand, but attenuation, rather than complete blockade, of the abnormally active signal in tumors, implied by the high levels of EGFR expression, could provide an opportunity to define an acceptable therapeutic ratio between efficacy and toxicity.
This study was undertaken to examine the efficacy of ZD1839 for the growth inhibition of a range of human tumor xenografts based on a once-a-day p.o. dosing regimen and to evaluate the pharmacology of this targeted therapy.
|
MATERIALS AND METHODS |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
was synthesized as described by Barker et al. (6)
.
|
Cell Growth Assays.
A standard MTT assay was used to measure cell growth (11)
. Briefly, KB cells were seeded into 96-well culture plates (1.25 x 103 cells/well) in DMEM containing 5% (v/v) charcoal-treated FCS (to deplete endogenous growth factors), 2.0 mM L-glutamine, and 1% (v/v) nonessential amino acids; after attachment, cells were incubated for 72 h at 37°C with ZD1839 in the absence (control) or presence of EGF (10 ng/ml). After incubation, 15 µl of MTT (Sigma) solution (10 mg/ml) were added to each well, and the plates were then incubated for 1 h at 37°C. Medium was replaced with 100 µl of acid alcohol (90% ethanol, 5% acetic acid, 5% deionized water) per well. Absorbance at 540 nm was measured using a Titertek Multiscan. Cell growth was calculated by subtracting the mean day 0 absorbance value from the mean absorbance value at day 3. Cell growth inhibition was confirmed, with KB cells grown under similar conditions in 12-well dishes, by trypsinization and cell counting (Coulter) after 3 or 5 days of growth in the absence or presence of EGF and ZD1839 (0.05–25 µM). ZD1839 inhibition of EGF-, FGF- and VEGF-stimulated growth of HUVECs was measured as described (8)
. Briefly, HUVECs isolated from umbilical cords were seeded into 96-well plates (1 x 103 cells/well) and incubated for 4 days with ZD1839 in the absence or presence of EGF (10 ng/ml), FGF (0.3 ng/ml), or VEGF (3 ng/ml). Four h before harvesting, [3H]thymidine (1 µCi/ml) was added. After the medium was removed and the cells were washed with PBS/A, 20 µl of trypsin-EDTA (2.5% trypsin, 1.6 g/l EDTA) solution was added to each well. The cells were harvested by use of a 96-well plate harvester (TomTek) onto filtermats (Wallac Printed Filtermat A). Once dry, scintillation fluid was added (Wallac ß-plate Scint) to the filtermats, and they were assayed in a ß-plate scintillation counter (Wallac 1205 ß-plate liquid scintillation counter) for incorporation of 3H.
Tumor Xenograft Studies.
Female nude mice (Alderley Park strain, derived from Swiss nu/nu; AstraZeneca) approximately 8–10 weeks of age and weighing >18 g were used. Mice were housed in air-filtered laminar flow cabinets and handled using aseptic procedures with a 12-h light cycle and food and water ad libitum. Procedures involving animals and their care were conducted in accordance with the institutional guidelines that comply with United Kingdom national policies [Animals (Scientific Procedures) Act 1986]. Fragments of tumor tissue (A431, Du145, CR10, HCT15, HT29, HX62, P246, MDA-MB-231, and MCF-7) or tumor cells (A549, LoVo, KB, MIA PaCa2, MKN45, and AR42J) were injected or implanted s.c. (left flank) under anesthesia. Tumors were allowed to establish growth, and at a designated time after implantation, treatment with ZD1839 commenced. ZD1839 at doses of 3–200 mg/kg was administered p.o. once a day as a ball-milled suspension in 0.5% (v/v) polysorbate 80. Mice were monitored daily for signs of toxicity and were weighed regularly. The maximum dose of ZD1839 administered was 200 mg/kg; this dose did not induce any significant adverse effect on body weight or produce any other signs of toxicity. Tumor growth was assessed at intervals by caliper measurement of tumor diameter in the longest dimension (L) and at right angles to that axis (W). Tumor volume was estimated by the formula, 
/6 x L x W x W, for prolate ellipsoids, and efficacy was determined as percentage inhibition compared with vehicle-treated controls. To assess the pharmacodynamic action of ZD1839 treatment, A431 tumors were excised 6 h after the last of four daily doses of 0, 12.5, 50, and 200 mg/kg ZD1839 or at 2, 4, 6, 24, 30, and 36 h after a single 50 mg/kg dose. Total RNA was extracted from the tumors to quantify c-fos mRNA by reverse transcription-PCR.
|
RESULTS |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
. Selectivity was demonstrated versus erbB2 and the VEGF TKs KDR and Flt-1, with at least a 100-fold difference in IC50 for EGFR compared with the other RTKs. Similarly, ZD1839 did not inhibit the activity of the serine-threonine kinases raf, MEK-1, and ERK-2 (MAPK). Enzyme kinetic studies to determine the characteristics of ZD1839 inhibition of EGFR TK (see Ref. 5
), in which peptide substrate concentration was fixed at 2 mM (
6-fold higher than the Km) and the ATP concentration was varied, showed that ZD1839 is a competitive inhibitor with respect to ATP (Ki = 2.1 ± 0.2 nM). Similarly, when the ATP concentration was fixed at 50 µM (6-fold higher than the Km) and peptide concentration was varied, ZD1839 showed noncompetitive kinetics (Ki = 15.0 ± 1.0 nM).
|
.
|
.
ZD1839 Inhibits EGFR Autophosphorylation.
Expression of phosphorylated EGFR varied among the selected tumor cell lines (Fig. 2A
, Lane 1), but brief treatment with EGF (100 ng/ml for 5 min) markedly increased tyrosine phosphorylation of EGFR in all four cell lines (Fig. 2A
, compare Lanes 1 and 2). Incubation with ZD1839 for 2 h before EGF stimulation produced a dose-dependent inhibition of EGFR autophosphorylation in all of the tumor cell lines (Fig. 2A
, Lanes 3–8). ZD1839 completely blocked EGF-stimulated EGFR phosphorylation at 0.16 µM in Du145 (prostate) and A549 (lung) cells, whereas complete inhibition was achieved at 0.8 µM in KB (oral squamous) and HT29 (colon) tumor cells.
|
.
Tumor Xenograft Activity.
In athymic nude mice bearing A431-derived xenografts, p.o. treatment once a day with ZD1839 (from day 7 after implantation for 3 weeks) inhibited tumor growth in a dose-dependent manner (Fig. 3)
. The ED50 was 50 mg/kg, and the highest dose, 200 mg/kg ZD1839, prevented tumor growth. Similarly, ZD1839 inhibited the growth of A549 lung (Fig. 3)
and Du145 prostate (Fig. 3)
tumor xenografts in a dose-dependent manner.
|
.
|
. No tumors grew during treatment, but drug withdrawal allowed tumors to grow in five of the eight mice during 44 days of follow-up in this experiment. A more stringent test was provided by tumors that were 1 month old at the start of therapy. ZD1839 treatment (200 mg/kg p.o. once a day) for 90 days produced rapid tumor regression in these more advanced tumors in all mice and, on drug withdrawal, four of six tumors rapidly reestablished (Fig. 5)
.
|
|
|
DISCUSSION |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
The requirement for an in vitro test that would distinguish between specific EGFR-TKI-mediated effects on EGF-stimulated growth and serum-stimulated cell growth was recognized at the outset of the drug discovery program and led to the selection for this purpose of the human vulval squamous tumor-derived KB cell line. KB cells grow well in growth factor-depleted medium (i.e., in 5% serum treated with charcoal to deplete growth factors), and addition of EGF increases KB cell growth rate in a reproducible manner. The selectivity of ZD1839 for inhibition of EGF-driven KB cell growth was demonstrated by the large difference in IC50 in the presence or absence of EGF. Cytotoxicity was not observed at ZD1839 concentrations up to 25 µM. The selectivity of ZD1839 for inhibition of EGF-stimulated cell growth was further exemplified in HUVECs. EGF-stimulated growth of HUVECs was potently inhibited by ZD1839, but bFGF- and VEGF-stimulated growth was relatively unaffected by ZD1839 at concentrations that block EGF effects.
Initiation of EGF-stimulated cell growth is triggered by trans autophosphorylation in ligand-binding-activated EGFR/erbB homo- or heterodimers. Western blots of several different human tumor-derived cell lines treated with ZD1839 before brief exposure to EGF showed that ZD1839 blocks EGF-stimulated EGFR autophosphorylation in a dose-dependent and complete manner. Drug washout studies showed that this inhibition is sustained for at least 24 h after a 2-h drug treatment. Other investigators also noted sustained inhibition of autophosphorylation in vitro by ZD1839 after drug washout and attributed this to drug sequestration in cells (12) . More recent studies indicate that quinazoline EGFR-TKIs sequester EGFR into signaling-inactive receptor-ligand complexes (13) .
Other investigators have studied the effects of ZD1839, alone and in combination with other drugs or radiation, on tumor cell proliferation. Ciardiello et al. (14)
demonstrated that ZD1839 inhibits the proliferation of ovarian, breast, and colon cancer cells and provides a synergistic enhancement of the inhibitory action of cytotoxic drugs. The effect of ZD1839 was cytostatic, but higher doses increased apoptotic cell death, and in combination with cytotoxic drugs, ZD1839 markedly enhanced apoptotic cell death. Ciardiello et al. (15)
also showed that ZD1839 inhibits tumor cell synthesis of tumor growth factor 
and of the proangiogenic growth factors VEGF and bFGF. The IC50 for tumor cell growth inhibition by ZD1839 was not strongly influenced by the level of expression of EGFR (14
, 15)
. Preliminary data indicate that combination of ZD1839 with ionizing radiation also has additive or synergistic effects in non-small cell lung cancer cell lines in vitro (16)
. ZD1839 also effectively inhibits the growth of antiestrogen-resistant human breast cancer cells (17)
and human tumor cells that overexpress HER2 (18)
. Additionally, ZD1839 inhibits ERK-1/2 (MAPK) activity, a downstream maker of EGFR signaling, in EGF-dependent human tumor cells at concentrations similar to those that inhibit cell proliferation (19)
.
Testing of drug candidate TKIs for in vivo activity was carried out with xenografts generated from KB cells, which have been used by others to demonstrate in vivo activity of TKIs (20) . This model identified the structural features of quinazolines necessary for in vivo antitumor activity (21) and indicated the importance for in vivo activity of sustaining sufficient drug concentrations in the blood to inhibit EGFR-TK activity throughout each 24-h period after once-a-day dosing (6) . ZD1839 was chosen as a candidate for development because it achieves high and sustained blood levels in vivo over a 24-h period (6) .
The antitumor activity of ZD1839 was demonstrated in tests with tumor xenografts derived from a range of different human tissues. ZD1839 was particularly effective against A431 xenografts, a recognized model for the testing of biological effects on EGFR signaling (22) . ZD1839 inhibited the growth of A431 xenografts in a dose-dependent manner, and complete inhibition was observed in animals receiving a daily p.o. doses of 200 mg/kg ZD1839. Long-term treatment (3–4 months) completely suppressed A431 tumor growth, and withdrawal of drug treatment allowed some tumors to resume growth in the 44-day follow-up period. When ZD1839 treatment was applied to large, well-established A431-derived tumors, rapid tumor regression was observed, which was sustained for the duration of drug treatment (3–4 months). The majority of these tumors resumed growth in the 21-day period after withdrawal of drug treatment, supporting the importance of continuous drug treatment to maintain antitumor activity. No evidence for the development of drug resistance emerged during these studies with A431 tumors because no tumor regrew during long-term ZD1839 treatment.
Dose-dependent tumor growth inhibition by ZD1839 was also demonstrated in mice bearing xenografts of human lung (A549), colon (LoVo, HT29, and HCT15) and prostate (Du145) tumors; additionally, antitumor activity was demonstrated in a breast (MCF-7) and a pancreatic (MIA PaCa-2) model, but some tumors failed to respond to drug treatment [P246 (bronco-epithelial), MKN45 (gastric), and AR42J (pancreatic)]. Review of literature reports on the level of EGFR expression in the cells from which these xenografts were derived reveals a very wide range of expression of EGFR; however, there was no clear correlation between the level of EGFR expression and xenograft sensitivity to ZD1839. Other investigators have also noted that the level of expression of EGFR in cells or tumors did not predict sensitivity to ZD1839 (14 , 23) . The level of EGFR expression may not indicate the degree to which any individual tumor or tumor cell line is dependent on the EGFR signaling pathway for growth. Additional biomarkers that would more specifically indicate this dependence have yet to be defined. Additionally, coexpression of other members of the erbB family that heterodimerize with EGFR but whose signaling would also be inhibited by ZD1839 through its action on the EGFR component of such heterodimers may also play an important role in determining drug sensitivity (18) . Increased EGFR expression is only one mechanism by which enhancement of EGFR signaling drive can be achieved: increased levels of ligand, heterodimerization of EGFR, decreased intracellular phosphatase (which prolongs the activation of EGFR), and mutations in EGFR that lead to constitutive activation of the TK can all contribute to signaling drive. EGFRvIII is a mutated EGFR in which part of the ligand-binding domain of EGFR is missing and the TK is constitutively active. EGFR-TKIs are likely to target this mutant receptor because the kinase domains of EGFRvIII and EGFR are identical.
In addition to the studies reported by Barker et al. (6) discussed above, which indicated the importance to biological activity of sustained exposure to drug throughout the dosing interval (24 h in a once-a-day p.o. dosing regimen), additional biomarker studies were performed in tumor-bearing mice. c-fos transcription represents one end point of EGFR signaling in tumors because c-fos is transiently expressed only in proliferating cells transiting the early, G1 phase of the cell cycle. Reverse transcription-PCR measurements of c-fos mRNA in extracts of A431 tumor xenografts from mice treated with ZD1839 showed that 4 days of drug treatment reduced c-fos in a dose-dependent and complete manner, paralleling drug effects on tumor size. When c-fos was measured in A431 tumors after a single p.o. dose of 50 mg/kg ZD1839, c-fos transcription reached a nadir (5% of control) 6 h after dosing, partially recovered at 24 h (20% of control), and was completely restored at 36 h. Although no complete pharmacokinetic/pharmacodynamic relationship for ZD1839 in the mouse has been defined, these studies indicate that once-a-day p.o. dosing effectively inhibits EGFR signaling throughout the dosing interval and that once-a-day p.o. administration might be a regimen suitable for therapeutic studies in humans.
The studies reported here have indicated the potential utility of ZD1839 as an antitumor agent, but because patients with locally advanced or metastatic cancer undergoing treatment with cytotoxic chemotherapy are most often the target population in which new anticancer agents are tested, combinations of ZD1839 with various cytotoxic drugs with different mechanisms of action have been investigated. These studies showed that combining ZD1839 with platins (cisplatin, oxaliplatin, carboplatin), taxanes (paclitaxel, docetaxel), and topoisomerase inhibitors (doxorubicin, etoposide, topotecan) or the antimetabolite raltitrexed markedly potentiated cytotoxic drug activity in vitro and in vivo (14 , 23) . They also suggest that the addition of ZD1839 to the treatment regimen for patients undergoing cytotoxic chemotherapy might confer significant additional clinical benefits.
In conclusion, these studies demonstrate the potential of ZD1839 (Iressa) in the treatment of many tumors and indicate that continuous once-a-day p.o. dosing may be a suitable therapeutic regimen.
|
FOOTNOTES |
|---|
1 To whom requests for reprints should be addressed, at Department of Cancer and Infection Research, AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom. Phone: 44 1625 515116; Fax: 44 1625 513624. 
2 Iressa is a trademark of the AstraZeneca group of companies.
3 The abbreviations used are: EGFR, epidermal growth factor receptor; TK, tyrosine kinase; TKI, tyrosine kinase inhibitor; RTK, receptor tyrosine kinase; MEK, mitogen-activated protein/extracellular signal-related kinase kinase; ERK, extracellular signal-related kinase; MAPK, mitogen-activated protein kinase; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; HUVEC, human umbilical vascular endothelial cell; FGF, fibroblast growth factor; VEGF, vascular endothelial growth factor; TGF, transforming growth factor .
Received . Accepted 8/16/02.
|
REFERENCES |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
expression in head and neck squamous carcinoma and inhibition by anti-epidermal growth factor receptor treatments. Cancer Res., 61: 6500-6510, 2001.This article has been cited by other articles:
|
|
 |
|
  J.-S. Guillamo, S. de Bouard, S. Valable, L. Marteau, P. Leuraud, Y. Marie, M.-F. Poupon, J.-J. Parienti, E. Raymond, and M. Peschanski Molecular Mechanisms Underlying Effects of Epidermal Growth Factor Receptor Inhibition on Invasion, Proliferation, and Angiogenesis in Experimental Glioma Clin. Cancer Res., June 1, 2009; 15(11): 3697 - 3704. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. I. Sherman Advances in Chemotherapy of Differentiated Epithelial and Medullary Thyroid Cancers J. Clin. Endocrinol. Metab., May 1, 2009; 94(5): 1493 - 1499. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.-H. Gow, Y.-L. Chang, Y.-C. Hsu, M.-F. Tsai, C.-T. Wu, C.-J. Yu, C.-H. Yang, Y.-C. Lee, P.-C. Yang, and J.-Y. Shih Comparison of epidermal growth factor receptor mutations between primary and corresponding metastatic tumors in tyrosine kinase inhibitor-naive non-small-cell lung cancer Ann. Onc., April 1, 2009; 20(4): 696 - 702. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Hernandez, T. Smirnova, D. Kedrin, J. Wyckoff, L. Zhu, E. R. Stanley, D. Cox, W. J. Muller, J. W. Pollard, N. Van Rooijen, et al. The EGF/CSF-1 Paracrine Invasion Loop Can Be Triggered by Heregulin {beta}1 and CXCL12 Cancer Res., April 1, 2009; 69(7): 3221 - 3227. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. B. McGovern, R. E. Francis, B. Peck, S. K. Guest, J. Wang, S. S. Myatt, J. Krol, J. M-M. Kwok, A. Polychronis, R. C. Coombes, et al. Gefitinib (Iressa) represses FOXM1 expression via FOXO3a in breast cancer Mol. Cancer Ther., March 1, 2009; 8(3): 582 - 591. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. H. Kesarwala, M. M. Samrakandi, and D. Piwnica-Worms Proteasome Inhibition Blocks Ligand-Induced Dynamic Processing and Internalization of Epidermal Growth Factor Receptor via Altered Receptor Ubiquitination and Phosphorylation Cancer Res., February 1, 2009; 69(3): 976 - 983. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Meco, T. Servidei, A. Riccardi, C. Ferlini, G. Cusano, G. F. Zannoni, F. Giangaspero, and R. Riccardi Antitumor effect in medulloblastoma cells by gefitinib: Ectopic HER2 overexpression enhances gefitinib effects in vivo Neuro-oncol, January 1, 2009; 11(3): 250 - 259. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-C. Ko, J.-H. Hong, L.-H. Wang, C.-M. Cheng, S.-C. Ciou, S.-T. Lin, M.-Y. Jheng, and Y.-W. Lin Role of repair protein Rad51 in regulating the response to gefitinib in human non-small cell lung cancer cells Mol. Cancer Ther., November 1, 2008; 7(11): 3632 - 3641. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Van Schaeybroeck, D. M. Kelly, J. Kyula, S. Stokesberry, D. A. Fennell, P. G. Johnston, and D. B. Longley Src and ADAM-17-Mediated Shedding of Transforming Growth Factor-{alpha} Is a Mechanism of Acute Resistance to TRAIL Cancer Res., October 15, 2008; 68(20): 8312 - 8321. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Vlotides, E. Siegel, I. Donangelo, S. Gutman, S.-G. Ren, and S. Melmed Rat Prolactinoma Cell Growth Regulation by Epidermal Growth Factor Receptor Ligands Cancer Res., August 1, 2008; 68(15): 6377 - 6386. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-C. Ko, S.-C. Ciou, C.-M. Cheng, L.-H. Wang, J.-H. Hong, M.-Y. Jheng, S.-T. Ling, and Y.-W. Lin Involvement of Rad51 in cytotoxicity induced by epidermal growth factor receptor inhibitor (gefitinib, IressaR) and chemotherapeutic agents in human lung cancer cells Carcinogenesis, July 1, 2008; 29(7): 1448 - 1458. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. J. Gonzales, K. E. Hook, I. W. Althaus, P. A. Ellis, E. Trachet, A. M. Delaney, P. J. Harvey, T. A. Ellis, D. M. Amato, J. M. Nelson, et al. Antitumor activity and pharmacokinetic properties of PF-00299804, a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor Mol. Cancer Ther., July 1, 2008; 7(7): 1880 - 1889. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. G. Jeong, M. S. Kim, H. K. Nam, C. K. Min, S. Lee, Y. J. Chung, N. J. Yoo, and S. H. Lee Somatic Mutations of JAK1 and JAK3 in Acute Leukemias and Solid Cancers Clin. Cancer Res., June 15, 2008; 14(12): 3716 - 3721. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Ren, B. Korchin, Q.-S. Zhu, C. Wei, A. Dicker, J. Heymach, A. Lazar, R. E. Pollock, and D. Lev Epidermal Growth Factor Receptor Blockade in Combination with Conventional Chemotherapy Inhibits Soft Tissue Sarcoma Cell Growth In vitro and In vivo Clin. Cancer Res., May 1, 2008; 14(9): 2785 - 2795. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Soeda, A. Inagaki, N. Oka, Y. Ikegame, H. Aoki, S.-i. Yoshimura, S. Nakashima, T. Kunisada, and T. Iwama Epidermal Growth Factor Plays a Crucial Role in Mitogenic Regulation of Human Brain Tumor Stem Cells J. Biol. Chem., April 18, 2008; 283(16): 10958 - 10966. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Dougherty, A. Sehdev, S. Cerda, R. Mustafi, N. Little, W. Yuan, S. Jagadeeswaran, A. Chumsangsri, J. Delgado, M. Tretiakova, et al. Epidermal Growth Factor Receptor Controls Flat Dysplastic Aberrant Crypt Foci Development and Colon Cancer Progression in the Rat Azoxymethane Model Clin. Cancer Res., April 15, 2008; 14(8): 2253 - 2262. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Okabe, I. Okamoto, S. Tsukioka, J. Uchida, T. Iwasa, T. Yoshida, E. Hatashita, Y. Yamada, T. Satoh, K. Tamura, et al. Synergistic antitumor effect of S-1 and the epidermal growth factor receptor inhibitor gefitinib in non-small cell lung cancer cell lines: role of gefitinib-induced down-regulation of thymidylate synthase Mol. Cancer Ther., March 1, 2008; 7(3): 599 - 606. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Benedetti, P. Perego, G. Luca Beretta, E. Corna, S. Tinelli, S. C. Righetti, R. Leone, P. Apostoli, C. Lanzi, and F. Zunino Modulation of survival pathways in ovarian carcinoma cell lines resistant to platinum compounds Mol. Cancer Ther., March 1, 2008; 7(3): 679 - 687. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Tanaka, A. Munshi, C. Brooks, J. Liu, M. L. Hobbs, and R. E. Meyn Gefitinib Radiosensitizes Non-Small Cell Lung Cancer Cells by Suppressing Cellular DNA Repair Capacity Clin. Cancer Res., February 15, 2008; 14(4): 1266 - 1273. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Wang, P. Guo, X. Wang, Q. Zhou, and J. M. Gallo Preclinical pharmacokinetic/pharmacodynamic models of gefitinib and the design of equivalent dosing regimens in EGFR wild-type and mutant tumor models Mol. Cancer Ther., February 1, 2008; 7(2): 407 - 417. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. L. Emanuel, T. V. Hughes, M. Adams, C. A. Rugg, A. Fuentes-Pesquera, P. J. Connolly, N. Pandey, S. Moreno-Mazza, J. Butler, V. Borowski, et al. Cellular and in Vivo Activity of JNJ-28871063, A Nonquinazoline Pan-ErbB Kinase Inhibitor That Crosses the Blood-Brain Barrier and Displays Efficacy against Intracranial Tumors Mol. Pharmacol., February 1, 2008; 73(2): 338 - 348. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. M. Gilmer, L. Cable, K. Alligood, D. Rusnak, G. Spehar, K. T. Gallagher, E. Woldu, H. L. Carter, A. T. Truesdale, L. Shewchuk, et al. Impact of Common Epidermal Growth Factor Receptor and HER2 Variants on Receptor Activity and Inhibition by Lapatinib Cancer Res., January 15, 2008; 68(2): 571 - 579. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Krol, R. E. Francis, A. Albergaria, A. Sunters, A. Polychronis, R. C. Coombes, and E. W.-F. Lam The transcription factor FOXO3a is a crucial cellular target of gefitinib (Iressa) in breast cancer cells Mol. Cancer Ther., December 1, 2007; 6(12): 3169 - 3179. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. A. Janne, J. von Pawel, R. B. Cohen, L. Crino, C. A. Butts, S. S. Olson, I. A. Eiseman, A. A. Chiappori, B. Y. Yeap, P. F. Lenehan, et al. Multicenter, Randomized, Phase II Trial of CI-1033, an Irreversible Pan-ERBB Inhibitor, for Previously Treated Advanced Non Small-Cell Lung Cancer J. Clin. Oncol., September 1, 2007; 25(25): 3936 - 3944. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. E. Smith, G. Walsh, A. Skene, A. Llombart, J. I. Mayordomo, S. Detre, J. Salter, E. Clark, P. Magill, and M. Dowsett A Phase II Placebo-Controlled Trial of Neoadjuvant Anastrozole Alone or With Gefitinib in Early Breast Cancer J. Clin. Oncol., September 1, 2007; 25(25): 3816 - 3822. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Yamasaki, D. Zhang, C. Bartholomeusz, T. Sudo, G. N. Hortobagyi, K. Kurisu, and N. T. Ueno Sensitivity of breast cancer cells to erlotinib depends on cyclin-dependent kinase 2 activity Mol. Cancer Ther., August 1, 2007; 6(8): 2168 - 2177. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Rosano, V. Di Castro, F. Spinella, G. Tortora, M. R. Nicotra, P. G. Natali, and A. Bagnato Combined Targeting of Endothelin A Receptor and Epidermal Growth Factor Receptor in Ovarian Cancer Shows Enhanced Antitumor Activity Cancer Res., July 1, 2007; 67(13): 6351 - 6359. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. S. Tsao, D. He, B. Saigal, S. Liu, J. J. Lee, S. Bakkannagari, N. G. Ordonez, W. K. Hong, I. Wistuba, and F. M. Johnson Inhibition of c-Src expression and activation in malignant pleural mesothelioma tissues leads to apoptosis, cell cycle arrest, and decreased migration and invasion Mol. Cancer Ther., July 1, 2007; 6(7): 1962 - 1972. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Yamasaki, M. J. Johansen, D. Zhang, S. Krishnamurthy, E. Felix, C. Bartholomeusz, R. J. Aguilar, K. Kurisu, G. B. Mills, G. N. Hortobagyi, et al. Acquired Resistance to Erlotinib in A-431 Epidermoid Cancer Cells Requires Down-regulation of MMAC1/PTEN and Up-regulation of Phosphorylated Akt Cancer Res., June 15, 2007; 67(12): 5779 - 5788. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. T. Olejniczak, C. Van Sant, M. G. Anderson, G. Wang, S. K. Tahir, G. Sauter, R. Lesniewski, and D. Semizarov Integrative Genomic Analysis of Small-Cell Lung Carcinoma Reveals Correlates of Sensitivity to Bcl-2 Antagonists and Uncovers Novel Chromosomal Gains Mol. Cancer Res., April 1, 2007; 5(4): 331 - 339. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. M. Stadler The randomized discontinuation trial: a phase II design to assess growth-inhibitory agents Mol. Cancer Ther., April 1, 2007; 6(4): 1180 - 1185. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Daniele, L. Macri, M. Schena, D. Dongiovanni, L. Bonello, E. Armando, L. Ciuffreda, O. Bertetto, G. Bussolati, and A. Sapino Predicting gefitinib responsiveness in lung cancer by fluorescence in situ hybridization/chromogenic in situ hybridization analysis of EGFR and HER2 in biopsy and cytology specimens Mol. Cancer Ther., April 1, 2007; 6(4): 1223 - 1229. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. V. Sequist Second-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer Oncologist, March 1, 2007; 12(3): 325 - 330. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. V. Sequist, D. W. Bell, T. J. Lynch, and D. A. Haber Molecular Predictors of Response to Epidermal Growth Factor Receptor Antagonists in Non-Small-Cell Lung Cancer J. Clin. Oncol., February 10, 2007; 25(5): 587 - 595. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Fichera, N. Little, S. Jagadeeswaran, U. Dougherty, A. Sehdev, R. Mustafi, S. Cerda, W. Yuan, S. Khare, M. Tretiakova, et al. Epidermal Growth Factor Receptor Signaling Is Required for Microadenoma Formation in the Mouse Azoxymethane Model of Colonic Carcinogenesis Cancer Res., January 15, 2007; 67(2): 827 - 835. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Yan, Y. Lu, M. Wang, H. Vikis, R. Yao, Y. Wang, R. A. Lubet, and M. You Effect of an Epidermal Growth Factor Receptor Inhibitor in Mouse Models of Lung Cancer Mol. Cancer Res., December 1, 2006; 4(12): 971 - 981. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. E Jones, J. M W Gee, I. R Hutcheson, J. M Knowlden, D. Barrow, and R. I Nicholson Growth factor receptor interplay and resistance in cancer Endocr. Relat. Cancer, December 1, 2006; 13(Supplement_1): S45 - S51. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. R Hutcheson, J. M Knowlden, H. E Jones, R. S Burmi, R. A McClelland, D. Barrow, J. M W Gee, and R. I Nicholson Inductive mechanisms limiting response to anti-epidermal growth factor receptor therapy Endocr. Relat. Cancer, December 1, 2006; 13(Supplement_1): S89 - S97. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Ishii, S. Fujimoto, and T. Fukuda Gefitinib Prevents Bleomycin-induced Lung Fibrosis in Mice Am. J. Respir. Crit. Care Med., September 1, 2006; 174(5): 550 - 556. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Dimitroulakos, I. A. Lorimer, and G. Goss Strategies to enhance epidermal growth factor inhibition: targeting the mevalonate pathway. Clin. Cancer Res., July 15, 2006; 12(14): 4426s - 4431s. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. H. Johnson Targeted therapies in combination with chemotherapy in non-small cell lung cancer. Clin. Cancer Res., July 15, 2006; 12(14): 4451s - 4457s. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Ho, G. Bebb, and N. Murray In Reply J. Clin. Oncol., July 1, 2006; 24(19): 3214 - 3215. [Full Text] [PDF]
|
|
|
|
|
|
E. E. W. Cohen, M. W. Lingen, B. Zhu, H. Zhu, M. W. Straza, C. Pierce, L. E. Martin, and M. R. Rosner Protein Kinase C{zeta} Mediates Epidermal Growth Factor-Induced Growth of Head and Neck Tumor Cells by Regulating Mitogen-Activated Protein Kinase. Cancer Res., June 15, 2006; 66(12): 6296 - 6303. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Ando, I. Okamoto, N. Yamamoto, K. Takeda, K. Tamura, T. Seto, Y. Ariyoshi, and M. Fukuoka Predictive Factors for Interstitial Lung Disease, Antitumor Response, and Survival in Non-Small-Cell Lung Cancer Patients Treated With Gefitinib J. Clin. Oncol., June 1, 2006; 24(16): 2549 - 2556. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Cohen, R. Mustafi, A. Chumsangsri, N. Little, J. Nathanson, S. Cerda, S. Jagadeeswaran, U. Dougherty, L. Joseph, J. Hart, et al. Epidermal Growth Factor Receptor Signaling Is Up-regulated in Human Colonic Aberrant Crypt Foci Cancer Res., June 1, 2006; 66(11): 5656 - 5664. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Van Schaeybroeck, J. Kyula, D. M. Kelly, A. Karaiskou-McCaul, S. A. Stokesberry, E. Van Cutsem, D. B. Longley, and P. G. Johnston Chemotherapy-induced epidermal growth factor receptor activation determines response to combined gefitinib/chemotherapy treatment in non-small cell lung cancer cells Mol. Cancer Ther., May 1, 2006; 5(5): 1154 - 1165. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Nicolle, A. Daher, P. Maille, M. Vermey, S. Loric, A. Bakkar, H. Wallerand, D. Vordos, F. Vacherot, S. G. D. de Medina, et al. Gefitinib Inhibits the Growth and Invasion of Urothelial Carcinoma Cell Lines in which Akt and MAPK Activation Is Dependent on Constitutive Epidermal Growth Factor Receptor Activation. Clin. Cancer Res., May 1, 2006; 12(9): 2937 - 2943. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. Janmaat, M. I. Gallegos-Ruiz, J. A. Rodriguez, G. A. Meijer, W. L. Vervenne, D. J. Richel, C. Van Groeningen, and G. Giaccone Predictive Factors for Outcome in a Phase II Study of Gefitinib in Second-Line Treatment of Advanced Esophageal Cancer Patients J. Clin. Oncol., April 1, 2006; 24(10): 1612 - 1619. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Sakaguchi, Y. Kuroda, and M. Hirose The antiproliferative effect of lidocaine on human tongue cancer cells with inhibition of the activity of epidermal growth factor receptor. Anesth. Analg., April 1, 2006; 102(4): 1103 - 1107. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Angelucci, G. L. Gravina, N. Rucci, D. Millimaggi, C. Festuccia, P. Muzi, A. Teti, C. Vicentini, and M. Bologna Suppression of EGF-R signaling reduces the incidence of prostate cancer metastasis in nude mice. Endocr. Relat. Cancer, March 1, 2006; 13(1): 197 - 210. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Sato, M. B. Vaughan, L. Girard, M. Peyton, W. Lee, D. S. Shames, R. D. Ramirez, N. Sunaga, A. F. Gazdar, J. W. Shay, et al. Multiple Oncogenic Changes (K-RASV12, p53 Knockdown, Mutant EGFRs, p16 Bypass, Telomerase) Are Not Sufficient to Confer a Full Malignant Phenotype on Human Bronchial Epithelial Cells Cancer Res., February 15, 2006; 66(4): 2116 - 2128. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Xue, J. Wyckoff, F. Liang, M. Sidani, S. Violini, K.-L. Tsai, Z.-Y. Zhang, E. Sahai, J. Condeelis, and J. E. Segall Epidermal Growth Factor Receptor Overexpression Results in Increased Tumor Cell Motility In vivo Coordinately with Enhanced Intravasation and Metastasis Cancer Res., January 1, 2006; 66(1): 192 - 197. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. Rothenberg, B. LaFleur, D. E. Levy, M. K. Washington, S. L. Morgan-Meadows, R. K. Ramanathan, J. D. Berlin, A. B. Benson III, and R. J. Coffey Randomized Phase II Trial of the Clinical and Biological Effects of Two Dose Levels of Gefitinib in Patients With Recurrent Colorectal Adenocarcinoma J. Clin. Oncol., December 20, 2005; 23(36): 9265 - 9274. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Gasparini, R. Sarmiento, S. Amici, R. Longo, D. Gattuso, M. Zancan, and M. Gion Gefitinib (ZD1839) combined with weekly epirubicin in patients with metastatic breast cancer: a phase I study with biological correlate Ann. Onc., December 1, 2005; 16(12): 1867 - 1873. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Kassouf, C. P.N. Dinney, G. Brown, D. J. McConkey, A. J. Diehl, M. Bar-Eli, and L. Adam Uncoupling between Epidermal Growth Factor Receptor and Downstream Signals Defines Resistance to the Antiproliferative Effect of Gefitinib in Bladder Cancer Cells Cancer Res., November 15, 2005; 65(22): 10524 - 10535. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Ho, J. E. Minturn, T. Hishiki, H. Zhao, Q. Wang, A. Cnaan, J. Maris, A. E. Evans, and G. M. Brodeur Proliferation of Human Neuroblastomas Mediated by the Epidermal Growth Factor Receptor Cancer Res., November 1, 2005; 65(21): 9868 - 9875. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. W. Bell, T. J. Lynch, S. M. Haserlat, P. L. Harris, R. A. Okimoto, B. W. Brannigan, D. C. Sgroi, B. Muir, M. J. Riemenschneider, R. B. Iacona, et al. Epidermal Growth Factor Receptor Mutations and Gene Amplification in Non-Small-Cell Lung Cancer: Molecular Analysis of the IDEAL/INTACT Gefitinib Trials J. Clin. Oncol., November 1, 2005; 23(31): 8081 - 8092. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Ishikawa, Y. Daigo, A. Takano, M. Taniwaki, T. Kato, S. Hayama, H. Murakami, Y. Takeshima, K. Inai, H. Nishimura, et al. Increases of Amphiregulin and Transforming Growth Factor-{alpha} in Serum as Predictors of Poor Response to Gefitinib among Patients with Advanced Non-Small Cell Lung Cancers Cancer Res., October 15, 2005; 65(20): 9176 - 9184. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Van Schaeybroeck, A. Karaiskou-McCaul, D. Kelly, D. Longley, L. Galligan, E. Van Cutsem, and P. Johnston Epidermal Growth Factor Receptor Activity Determines Response of Colorectal Cancer Cells to Gefitinib Alone and in Combination with Chemotherapy Clin. Cancer Res., October 15, 2005; 11(20): 7480 - 7489. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Stegmaier, S. M. Corsello, K. N. Ross, J. S. Wong, D. J. DeAngelo, and T. R. Golub Gefitinib induces myeloid differentiation of acute myeloid leukemia Blood, October 15, 2005; 106(8): 2841 - 2848. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. R Gunthert, C. Grundker, A. Olota, J. Lasche, N. Eicke, and G. Emons Analogs of GnRH-I and GnRH-II inhibit epidermal growth factor-induced signal transduction and resensitize resistant human breast cancer cells to 4OH-tamoxifen Eur. J. Endocrinol., October 1, 2005; 153(4): 613 - 625. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. M. Johnson, B. Saigal, M. Talpaz, and N. J. Donato Dasatinib (BMS-354825) Tyrosine Kinase Inhibitor Suppresses Invasion and Induces Cell Cycle Arrest and Apoptosis of Head and Neck Squamous Cell Carcinoma and Non-Small Cell Lung Cancer Cells Clin. Cancer Res., October 1, 2005; 11(19): 6924 - 6932. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. C. Daw, W. L. Furman, C. F. Stewart, L. C. Iacono, M. Krailo, M. L. Bernstein, J. E. Dancey, R. A. Speights, S. M. Blaney, J. M. Croop, et al. Phase I and Pharmacokinetic Study of Gefitinib in Children With Refractory Solid Tumors: A Children's Oncology Group Study J. Clin. Oncol., September 1, 2005; 23(25): 6172 - 6180. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Solomon, D. Binns, P. Roselt, L. I. Weibe, G. A. McArthur, C. Cullinane, and R. J. Hicks Modulation of intratumoral hypoxia by the epidermal growth factor receptor inhibitor gefitinib detected using small animal PET imaging Mol. Cancer Ther., September 1, 2005; 4(9): 1417 - 1422. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. S. Siegel-Lakhai, J. H. Beijnen, and J. H.M. Schellens Current Knowledge and Future Directions of the Selective Epidermal Growth Factor Receptor Inhibitors Erlotinib (Tarceva(R)) and Gefitinib (Iressa(R)) Oncologist, September 1, 2005; 10(8): 579 - 589. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Jain, C. A. Tindell, I. Laux, J. B. Hunter, J. Curran, A. Galkin, D. E. Afar, N. Aronson, S. Shak, R. B. Natale, et al. Epithelial membrane protein-1 is a biomarker of gefitinib resistance PNAS, August 16, 2005; 102(33): 11858 - 11863. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Taron, Y. Ichinose, R. Rosell, T. Mok, B. Massuti, L. Zamora, J. L. Mate, C. Manegold, M. Ono, C. Queralt, et al. Activating Mutations in the Tyrosine Kinase Domain of the Epidermal Growth Factor Receptor Are Associated with Improved Survival in Gefitinib-Treated Chemorefractory Lung Adenocarcinomas Clin. Cancer Res., August 15, 2005; 11(16): 5878 - 5885. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Baselga, J. Albanell, A. Ruiz, A. Lluch, P. Gascon, V. Guillem, S. Gonzalez, S. Sauleda, I. Marimon, J. M. Tabernero, et al. Phase II and Tumor Pharmacodynamic Study of Gefitinib in Patients with Advanced Breast Cancer J. Clin. Oncol., August 10, 2005; 23(23): 5323 - 5333. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-H. Yang, C.-J. Huang, C.-S. Yang, Y.-C. Chu, A.-L. Cheng, J. Whang-Peng, and P.-C. Yang Gefitinib Reverses Chemotherapy Resistance in Gefitinib-Insensitive Multidrug Resistant Cancer Cells Expressing ATP-Binding Cassette Family Protein Cancer Res., August 1, 2005; 65(15): 6943 - 6949. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. J. Schilder, M. W. Sill, X. Chen, K. M. Darcy, S. L. Decesare, G. Lewandowski, R. B. Lee, C. A. Arciero, H. Wu, and A. K. Godwin Phase II Study of Gefitinib in Patients with Relapsed or Persistent Ovarian or Primary Peritoneal Carcinoma and Evaluation of Epidermal Growth Factor Receptor Mutations and Immunohistochemical Expression: A Gynecologic Oncology Group Study Clin. Cancer Res., August 1, 2005; 11(15): 5539 - 5548. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Kiguchi, L. Ruffino, T. Kawamoto, T. Ajiki, and J. DiGiovanni Chemopreventive and Therapeutic Efficacy of Orally Active Tyrosine Kinase Inhibitors in a Transgenic Mouse Model of Gallbladder Carcinoma Clin. Cancer Res., August 1, 2005; 11(15): 5572 - 5580. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A Agrawal, E Gutteridge, J M W Gee, R I Nicholson, and J F R Robertson Overview of tyrosine kinase inhibitors in clinical breast cancer Endocr. Relat. Cancer, July 1, 2005; 12(Supplement_1): S135 - S144. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H E Jones, J M W Gee, K M Taylor, D Barrow, H D Williams, M Rubini, and R I Nicholson Development of strategies for the use of anti-growth factor treatments Endocr. Relat. Cancer, July 1, 2005; 12(Supplement_1): S173 - S182. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A E Wakeling Inhibitors of growth factor signalling Endocr. Relat. Cancer, July 1, 2005; 12(Supplement_1): S183 - S187. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. L. Mu, L. Y. Li, X. T. Zhang, M. Z. Wang, R. E. Feng, Q. C. Cui, H. S. Zhou, and B. Q. Guo Gefitinib-Sensitive Mutations of the Epidermal Growth Factor Receptor Tyrosine Kinase Domain in Chinese Patients with Non-Small Cell Lung Cancer Clin. Cancer Res., June 15, 2005; 11(12): 4289 - 4294. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Sini, L. Wyder, C. Schnell, T. O'Reilly, A. Littlewood, R. Brandt, N. E. Hynes, and J. Wood The Antitumor and Antiangiogenic Activity of Vascular Endothelial Growth Factor Receptor Inhibition Is Potentiated by ErbB1 Blockade Clin. Cancer Res., June 15, 2005; 11(12): 4521 - 4532. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. L. Kwak, R. Sordella, D. W. Bell, N. Godin-Heymann, R. A. Okimoto, B. W. Brannigan, P. L. Harris, D. R. Driscoll, P. Fidias, T. J. Lynch, et al. Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib PNAS, May 24, 2005; 102(21): 7665 - 7670. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. F. Petricoin III, V. E. Bichsel, V. S. Calvert, V. Espina, M. Winters, L. Young, C. Belluco, B. J. Trock, M. Lippman, D. A. Fishman, et al. Mapping Molecular Networks Using Proteomics: A Vision for Patient-Tailored Combination Therapy J. Clin. Oncol., May 20, 2005; 23(15): 3614 - 3621. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Yoshimoto, K. Kasahara, M. Nishio, T. Hourai, T. Sone, H. Kimura, M. Fujimura, and S. Nakao Changes in Angiogenic Growth Factor Levels After Gefitinib Treatment in Non-small Cell Lung Cancer Jpn. J. Clin. Oncol., May 1, 2005; 35(5): 233 - 238. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Liu, S. Majumder, W. McCall, C. I. Sartor, J. L. Mohler, C. W. Gregory, H. S. Earp, and Y. E. Whang Inhibition of HER-2/neu Kinase Impairs Androgen Receptor Recruitment to the Androgen Responsive Enhancer Cancer Res., April 15, 2005; 65(8): 3404 - 3409. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. W. Lee, Y. H. Soung, S. Y. Kim, H. K. Nam, W. S. Park, S. W. Nam, M. S. Kim, D. I. Sun, Y. S. Lee, J. J. Jang, et al. Somatic Mutations of EGFR Gene in Squamous Cell Carcinoma of the Head and Neck Clin. Cancer Res., April 15, 2005; 11(8): 2879 - 2882. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Pao and V. A. Miller Epidermal Growth Factor Receptor Mutations, Small-Molecule Kinase Inhibitors, and Non-Small-Cell Lung Cancer: Current Knowledge and Future Directions J. Clin. Oncol., April 10, 2005; 23(11): 2556 - 2568. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. McKillop, E. A. Partridge, J. V. Kemp, M. P. Spence, J. Kendrew, S. Barnett, P. G. Wood, P. B. Giles, A. B. Patterson, F. Bichat, et al. Tumor penetration of gefitinib (Iressa), an epidermal growth factor receptor tyrosine kinase inhibitor Mol. Cancer Ther., April 1, 2005; 4(4): 641 - 649. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Giaccone HER1/EGFR-targeted agents: predicting the future for patients with unpredictable outcomes to therapy Ann. Onc., April 1, 2005; 16(4): 538 - 548. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. H. Yang, L. E. Mechanic, P. Yang, M. T. Landi, E. D. Bowman, J. Wampfler, D. Meerzaman, K. M. Hong, F. Mann, T. Dracheva, et al. Mutations in the Tyrosine Kinase Domain of the Epidermal Growth Factor Receptor in Non-Small Cell Lung Cancer Clin. Cancer Res., March 15, 2005; 11(6): 2106 - 2110. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K.-S. Kim, J.-Y. Jeong, Y.-C. Kim, K.-J. Na, Y.-H. Kim, S.-J. Ahn, S.-M. Baek, C.-S. Park, C.-M. Park, Y.-I. Kim, et al. Predictors of the Response to Gefitinib in Refractory Non-Small Cell Lung Cancer Clin. Cancer Res., March 15, 2005; 11(6): 2244 - 2251. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. J. Mantha, J. E.L. Hanson, G. Goss, A. E. Lagarde, I. A. Lorimer, and J. Dimitroulakos Targeting the Mevalonate Pathway Inhibits the Function of the Epidermal Growth Factor Receptor Clin. Cancer Res., March 15, 2005; 11(6): 2398 - 2407. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Engelman, P. A. Janne, C. Mermel, J. Pearlberg, T. Mukohara, C. Fleet, K. Cichowski, B. E. Johnson, and L. C. Cantley ErbB-3 mediates phosphoinositide 3-kinase activity in gefitinib-sensitive non-small cell lung cancer cell lines PNAS, March 8, 2005; 102(10): 3788 - 3793. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Shigematsu, L. Lin, T. Takahashi, M. Nomura, M. Suzuki, I. I. Wistuba, K. M. Fong, H. Lee, S. Toyooka, N. Shimizu, et al. Clinical and Biological Features Associated With Epidermal Growth Factor Receptor Gene Mutations in Lung Cancers J Natl Cancer Inst, March 2, 2005; 97(5): 339 - 346. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. W. Gregory, Y. E. Whang, W. McCall, X. Fei, Y. Liu, L. A. Ponguta, F. S. French, E. M. Wilson, and H. S. Earp III Heregulin-Induced Activation of HER2 and HER3 Increases Androgen Receptor Transactivation and CWR-R1 Human Recurrent Prostate Cancer Cell Growth Clin. Cancer Res., March 1, 2005; 11(5): 1704 - 1712. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R.K. THOMAS, H. GREULICH, Y. YUZA, J.C. LEE, T. TENGS, W. FENG, T.-H. CHEN, E. NICKERSON, J. SIMONS, M. EGHOLM, et al. Detection of Oncogenic Mutations in the EGFR Gene in Lung Adenocarcinoma with Differential Sensitivity to EGFR Tyrosine Kinase Inhibitors Cold Spring Harb Symp Quant Biol, January 1, 2005; 70(0): 73 - 81. [Abstract] [PDF]
|
|
|
|
|
|
D.A. HABER, D.W. BELL, R. SORDELLA, E.L. KWAK, N. GODIN-HEYMANN, S.V. SHARMA, T.J. LYNCH, and J. SETTLEMAN Molecular Targeted Therapy of Lung Cancer: EGFR Mutations and Response to EGFR Inhibitors Cold Spring Harb Symp Quant Biol, January 1, 2005; 70(0): 419 - 426. [Abstract] [PDF]
|
|
|
|
|
|
N. T. Shah, M. G. Kris, W. Pao, L. B. Tyson, B. M. Pizzo, M.-H. Heinemann, L. Ben-Porat, D. L. Sachs, R. T. Heelan, and V. A. Miller Practical Management of Patients With Non-Small-Cell Lung Cancer Treated With Gefitinib J. Clin. Oncol., January 1, 2005; 23(1): 165 - 174. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. De Pas, G. Pelosi, F. de Braud, G. Veronesi, G. Curigliano, M. E. Leon, R. Danesi, C. Noberasco, M. d'Aiuto, G. Catalano, et al. Modulation of Epidermal Growth Factor Receptor Status by Chemotherapy in Patients With Locally Advanced Non-Small-Cell Lung Cancer Is Rare J. Clin. Oncol., December 15, 2004; 22(24): 4966 - 4970. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Kakiuchi, Y. Daigo, N. Ishikawa, C. Furukawa, T. Tsunoda, S. Yano, K. Nakagawa, T. Tsuruo, N. Kohno, M. Fukuoka, et al. Prediction of sensitivity of advanced non-small cell lung cancers to gefitinib (Iressa, ZD1839) Hum. Mol. Genet., December 15, 2004; 13(24): 3029 - 3043. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
H E Jones, L Goddard, J M W Gee, S Hiscox, M Rubini, D Barrow, J M Knowlden, S Williams, A E Wakeling, and R I Nicholson Insulin-like growth factor-I receptor signalling and acquired resistance to gefitinib (ZD1839; Iressa) in human breast and prostate cancer cells Endocr. Relat. Cancer, December 1, 2004; 11(4): 793 - 814. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. L. Matheson, J. P. McNamee, T. Wang, M. A. Alaoui-Jamali, A. M. Tari, and B. J. Jean-Claude The Combi-Targeting Concept: Dissection of the Binary Mechanism of Action of the Combi-Triazene SMA41 in Vitro and Antitumor Activity in Vivo J. Pharmacol. Exp. Ther., December 1, 2004; 311(3): 1163 - 1170. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
) or ZD1839 [3.125 mg/kg (
), 12.5 mg/kg (
), 50 mg/kg (
), or 200 mg/kg (
)] was administered by oral gavage once daily. Data are expressed as mean (bars, SD) tumor volume.
