Biology of Cox-2: An Application in Cancer Therapeutics
Zakir Khan*,1,5, Noor Khan2, Ram P. Tiwari3, Nand K. Sah4, GBKS Prasad5 and Prakash S. Bisen5
1INSERM U-955, Team No. 10, Institut Mondor de Recherche Biomédicale, Université Paris Est, 94010Créteil, Paris, France
2Division of Plant-Microbe Interactions, National Botanical Research Institute, Rana Pratap Marg, Lucknow, 226 001, India
3Research and Development Centre, Diagnova, RFCL Limited, New Delhi-110020, India
4Department of Botany/Biotechnology, TNB College, T.M. Bhagalpur University, Bhagalpur-812007, India
5School of Studies in Biotechnology, Jiwaji University, Gwalior-474011, India
Abstract: Cyclooxygenase-2 (Cox-2) is an inducible enzyme involved in the conversion of arachidonic acid to
prostaglandin and other eicosanoids. Molecular pathology studies have revealed that Cox-2 is over-expressed in cancer
and stroma cells during tumor progression, and anti-cancer chemo-radiotherapies induce expression of Cox-2 in cancer
cells. Elevated tumor Cox-2 is associated with increased angiogenesis, tumor invasion and promotion of tumor cell
resistance to apoptosis. Several experimental and clinical studies have established potent anti-cancer activity of NSAID
(Non-steroidal anti-inflammatory drugs) and other Cox-2 inhibitors such as celecoxib. Much attention is being focused on
Cox-2 inhibitors as a beneficial target for cancer chemotherapy. The mode of action of Cox-2 and its inhibitors remains
unclear. Further clinical application needs to be investigated for comprehending Cox-2 biological functions and
establishing it as an effective target in cancer therapy.
Keywords: Cyclooxygenase-2 (Cox-2), apoptosis, angiogenesis, cancer, prostaglandin, chemotherapy, radiotherapy, celecoxib.
INTRODUCTION
Cyclooxygenase (Cox), known as prostaglandin synthase is the key enzyme in prostaglandin (PG), prostacyclin and thromboxane synthesis from arachidonic acid [1, 2]. Two Cox isoforms have been described so far. Cox-1 is cons-titutively expressed in nearly all cells where as Cox-2 is an inducible gene which is expressed only under influence of certain oncoproteins, growth factors, cytokines and tumor promoters but not detectable in most normal tissues [1-6] and recently the relationship between Cox-2 and cancer has been projected [1, 5-7]. It has been well established that Cox-2 promotes overall growth of tumor and gets up-regulated in a high percentage of common cancers [8-11] where it is associated with neoplastic transformation, cell growth, angiogenesis, invasiveness and metastasis [8, 12-15]. It has been reported that conventional cancer therapies increase level of Cox-2 in cancer cells which leads to resist-ance [16-18] and down-regulation of Cox-2 with modern approaches significantly inducing sensitivity of cancer cells to these therapies [5, 10, 19, 20]. Molecular studies have demonstrated induction of apoptosis and angiogenesis by Cox-2 inhibition, two highly promising cancer therapeutic targets [19-24].
The Cox-2 inhibitors represent a new class of drugs that do not affect Cox-1, but selectively block only Cox-2. The Cox-2 inhibitor is now in the market as a form of celecoxib
*Address correspondence to this author at the INSERM, U955, Team no. 10, Institut Mondor de Recherche Biomédicale, Faculté de Médecine, H?pital Henri-Mondor, 8, rue du Général Sarrail 94010 Créteil Cedex, Paris, France; Tel: (+33) 01 49 81 37 10; Fax: (+33) 01 49 81 36 42; E-mail: zakirq.khan@https://www.doczj.com/doc/4417306471.html, (Celebrex M). It is widely accepted that Cox-2 inhibitors will
be of great value to people with arthritis and variety of pain conditions. Recently Cox-2 inhibitors and their derivatives in
combination with chemotherapy or radiation therapy are
rapidly emerging as a new generation of therapeutic drug for
the treatment of cancer [25, 26]. However, the mechanisms
underlying its antitumor effects are not fully understood, and
more thorough preclinical trials are needed to determine if Cox-2 inhibition represents a useful approach for prevention and treatment of cancer. This review article is focused on the molecular and clinical aspects of Cox-2 in tumor progression and treatment.
MOLECULAR CANCER BIOLOGY OF COX-2
Cox-2 and its Inhibitors: Mechanism of Action Cox-2 is rate-limiting enzyme of PGs biosynthesis from arachidonic acid. First step of PGs biosynthesis is the hydrolysis of phospholipids to produce free arachidonic acid which is catalyzed by phospholypase-A2 [23, 27, 28]. The next step is catalyzed by Cox-2 in which molecular oxygen inserts into arachidonic acid in order to synthesize an un-stable product PGG2 [29], and then after peroxidase activity of Cox-2 converts PGG2 to PGH2 that is the precursor for all other prostanoids. The production of individual prostanoids is catalyzed by different specific synthases which may vary in their expression between different types of cells (Fig. 1). Analogs of arachidonic acid, NSAID and other Cox-2 spe-cific inhibitors act as primary substrate for enzyme. There-fore, it competes for binding to the active site more promptly than arachidonic acid due to multiple favorable interactions and thus inhibits PGs synthesis [30].
1389-4501/11 $58.00+.00 ? 2011 Bentham Science Publishers Ltd.
Cox-2 Inhibitors Act beyond Cox-2
Evidence from the data also suggested that Cox-2 select-ive inhibitors may illustrate anti-proliferative activity in Cox-2-independent manner [29, 31]. As for example celecoxib inhibit the growth of various cancer cell lines that are Cox-2 deficient and also inhibit the growth of Cox-2 deficient colon cancer xenografts in nude mice [32, 33]. The underlying mechanisms are not well investigated. However, several molecular targets have been studied which may be involved in Cox-2-independent mechanisms. 15-lipoxyge-nase-1 is verified as one of the target enzyme which gets up-regulated by Cox-2 inhibitors (NS398 and sulindac sulfone) and is devoid of Cox-2 inhibitory activity [34]. The pro- duct of 15-lipoxygenase-1 enzyme is 13-S-HODE, which has both growth inhibitory and pro-apoptotic activities. Thompson et al. (2000) demonstrated that the anti-cancer activity of Cox-2 inhibitors may be attributed to the phosphodiesterase-2 and -5 [35]. It has also been reported that a product of Cox-2, PGI 2 activates PPAR-gamma [36] which in turn down-regulates NF-kB transcriptional activity and activator protein (AP-1) [37-39]. This pathway may signal growth inhibitory effects in cancer cells. The relation between Cox-2 inhibitors and classical cell cycle regulatory molecules has also been established [40]. Precisely, treat-ment of cancer cells by celecoxib reduces the level of p21 and p27 proteins, which decrease CDKs kinase activity. This reduction in kinase activity modulates the mechanisms of their down-stream targets such as pRB, E2F, ultimately causing cell cycle arrest [21, 40, 41]. Additional studies delineating the molecular mechanisms by which Cox-2 and
its inhibitors provide important therapeutic implications are required.
Pathways of Cox-2 Up-Regulation in Cancer Cells In most tissues, Cox-2 expression is largely responsive to adverse stimuli such as inflammation and physiological imbalances. It is evident that Cox-2 gets up-regulated in cancer cells and is likely to be a consequence of multiple effects. Cox-2 expression can be regulated at several levels including transcriptional, post-transcriptional, translational and post-translational levels [3, 42]. The Cox-2 promoters have several putative regulatory regions that bind trans-criptional factors viz . CRE (c-AMP response element), NF-kB and NL-IL6 [43, 44]. These regulatory sites respond differentially to various stimuli. The NF-IL6 and NF-kB are required in response to tumor necrosis factor (TNF) in which MAPK (mitogen activated protein kinase) and c-jun signal-ing pathways are involved [45-48]. Lipopolysaccharide-mediated Cox-2 induction involves p38, MAPK and C-ζ (PKC-ζ) signal transduction pathways in which NF-IL6 and CRE have been identified as being critical [47, 49-51]. Ceramide and platelet derived growth factor induces Cox-2 expression via CRE-mediated activation of either Ras/Raf-1/MEK/MAPK or Ras/MEKK-1/JNK pathways (Fig. 2) [43, 52]. Reportedly CBP, AP constituents (c-fos and pc-jun), EGFR and p53 are associated positively with Cox-2 while the PPAR-gamma are negatively correlated [20, 37, 52]. However, it is suggested that down-regulation of PPAR-gamma and induction of the CBP transcription co-activator can augment NF-kB and AP-1 transcriptional activities
Fig. (1). Biosynthesis of Prostaglandins by cyclooxygenase pathway in vascular smooth muscle cells (VSMC). Membrane phospholipids are converted to arachidonic acid by phospholipase-A2 action. Cox-2 over-expresses in tumor tissues in response to specific oncogenic stimuli where its oxygenase activity metabolises arachidonic acid into PGG 2, which is thereafter converted to PGH 2 by the peroxidase activity of Cox-2. Several other eicosanoids are further synthesized from PGH 2 by tissue specific isomerase.
PG-D 2 PG-E 2 PG-F 2a PG-A 2 Prostacyclin Mast Cell Brain Uterus Platelets Endothelium Brain Kidney Airways Macrophages Kidney Airways Platelets Eye Kidney Platelets
VSMC VSMC VSMC Brain
1084 Current Drug Targets, 2011, Vol. 12, No. 7 Khan et al.
leading to up-regulation of Cox-2 in cancer cells [37, 53]. Recently Cox-2 has been identified as a new down-stream target of p53. Wild type p53 can induce Cox-2 expression via Ras/Raf/ERK pathway [54].
In breast and colon cancer, gene expression profiling revealed that Cox-2 is one of the most consistently up-regulated gene induced by NFAT, justified by presence of NFAT binding sites on Cox-2 promoter [55, 56]. In addition, several post-transcriptional factors also play an important role in the regulation of Cox-2 in cancer cells. Translation of immediate early Cox-2 gene is strictly controlled by mRNA splicing [3, 42]. Aberrant methylation of CpG island and subsequent silencing of the Cox-2 promoter have also been observed in colorectal and gastric tumors [57]. Further studies are needed to elucidate mechanisms of Cox-2 gene
regulation, which will help in designing effective cancer therapy based on Cox-2. Cox-2 in Cancer Progression
Cox-2 is likely to be a key player in a number of biological pathways leading to cancer [8, 10, 13-15, 58]. Over-expression of Cox-2 has been reported in majority of human cancers including colon, breast, lung, head and neck, cervical, prostate, pancreas and bladder. Existing evidences suggest that Cox-2 is elevated at early stage of tumor progression [59-61]. In general Cox-2 gets up-regulated throughout the tumorigenic process, from premalignant to malignant condition in human beings. In carcinomas, Cox-2 over-expression is often greater in well and moderately differentiated tumors as compared to poorly differentiated
Fig. (2). Proposed signal pathways of Cox-2 gene regulation.
Receptor Tyrosine Kinase
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Current Drug Targets, 2011, Vol. 12, No. 7 1085
ones [62]. Induced level of Cox-2 supports overall growth of tumor and provides resistance against therapies. Cox-2 interferes in several vital processes, as for example, it inhibits apoptosis, promotes tumor specific angiogenesis and induces proangiogenic factors such as VEGF, inducible nitrogen oxide synthase protein IL-6, IL-8 and TIE-2 [23, 63-70].
Metabolites derived from Cox-2 are reported to be involved in carcinogenesis. The malignant tumor cells constitute the bulk of the cellular mass in the vast majority of human cancers [71, 72]. Thus, the tumor cell production of Cox-2 would be predicted to have a great impact on local PGs production. It is well established that an increased level of PGs contributes in tumor cell progression. Enhanced PGs synthesis can directly stimulate mitogenesis which can induce oncogenesis in osteoblasts, fibroblast and mammary epithelial cells [73-75]. Certain PGs such as PGE 2 have been shown to promote both cancer cell growth and motility [76]. Cox-2 expression and consequent PGs production by tumor endothelium, infiltrating macrophages and other accessory cells in tumors resulted in paracrine growth stimulatory effects. However, PGs do not act as mitogens for all cell types and in fact are known to depress proliferation of some cells particularly involved in immune system [77]. Over-production of PGs, locally disrupts immune surveillance by down-regulating T and B cell proliferation [78, 79], cyto-toxic activity of natural killer cells [80], antigen processing and cytokine synthesis such as IL-12 and TNF-alpha [79-81]. However, immune suppression by PGs may contribute in tumorigenesis.
In breast cancer, a correlation between Cox-2 and aroma-tase has been established [82]. PGE 2 is shown to stimulate
aromatase transcription, leading to supraphysiological local estrogen levels which subsequently release growth factors and enhance proliferation [82, 83]. In all cases of human breast cancer, cytochrome p450 aromatase enzyme and Cox-2 were co-expressed [82, 84]. Thus there is a possibility that estrogen over-production mediated by PGs may be an organ specific consequence of Cox-2 up-regulation in breast cancer. Another important Cox-2 metabolite which contri-butes to carcinogenesis is PGH 2. By enzymatic and non-enzymatic reaction, PGH 2 isomerizes into a potent mutagen malondialdehyde which can induce frame shift and base substitution mutations in target genes [77]. In addition, per-oxidase activity of Cox-2 can also activate other mutagens by oxidation of heterocyclic and aromatic amines [85]. Thus mitogens derived from Cox-2 can induce DNA damages, thereby contributing to carcinogenesis.
Overall growth of tumor depends on nutrition supply which largely relies on angiogenesis. Ischemia (low nutrition supply) can induce tumor cell apoptosis, speeding up necrosis and cell extinction. Many researches verified relationship between Cox-2 and angiogenesis [8, 14, 23, 63]. Cox-2 derived PGE2 can promote angiogenesis and helps in tumor growth and metastasis [64, 67, 86]. Over-expression of Cox-2 can induce secretion of several angiogenic factors such as VEGF, TGF-1 and bFGF [87, 88]. These factors specially stimulate vascular tube formation and support tumor growth due to sufficient nutrition supply. Anti-angiogenic activity of Cox-2 inhibitors is an important mechanism by which they suppress tumor growth. Celecoxib inhibits angiogenesis by complete inhibition of angiogenic factors in tumor cells [8]. In an important study, Darmond et al. (2001) demonstrated that inhibition of Cox-2 in
Fig. (3). Role of PGE2 and other down-stream mediators of Cox-2 in tumor development. Primary signal of PGE2 in (1) an autocrine or paracrine (2) manner to tumor cell, promotes cell proliferation and survival. Another paracrine signaling pathway involves in production of PGE2 by tumor cells, which in turn acts in an autocrine/paracrine fashion to promote synthesis of angiogenic growth factors such as VEGF by tumor cell. These factors act in a paracrine fashion (3, 4) to promote proliferation, migration and tube formation. PGE2 also increase invasiveness by EGFR-P13K-Akt pathway.
Tumor
1086 Current Drug Targets, 2011, Vol. 12, No. 7Khan et al.
endothelial cells by NSAID suppresses Alpha-V-beta-3-
dependent activation of cdc42 and Rac resulting in inhibition
of spreading and migration of endothelial cells and sup-
pression of angiogenesis [89]. PGE2can increase invasive-
ness and motility that is predominantly mediated by EGFR-phosphotidylenositol-3-kinase-Akt pathway [86, 90, 91]. In
brief the mechanisms of Cox-2 inhibition resisting the
growth of cancer might prevent angiogenesis and weaken
invasiveness which further enhances its potential in anti-
cancer therapy (Fig. 3).
Correlation between apoptosis and Cox-2 has also been
investigated [24, 92]. Over-expression of Cox-2 and its end
point metabolite, PGE2, protected cells against apoptosis and
majority of Cox-2 inhibitors enhance apoptotic cell death
[20, 23, 24, 76, 93, 94]. Till date mechanism of apoptosis
inhibition by Cox-2 is poorly understood. Cox-2 products have influence on both extrinsic (receptor mediated) and intrinsic (mitochondrial mediated) apoptotic pathways [93, 95, 96]. Many researches have demonstrated that Cox-2 directly or indirectly changes the ratio of pro-apoptotic and anti-apoptotic proteins toward anti-apoptosis. Over-expres-sion of Cox-2 reduced the levels of bax and bcl xl(pro-apoptotic) [71] and induced the levels of bcl2and survivin (anti-apoptotic) proteins [67, 76, 95-97]. Survivin is one of the key anti-apoptotic proteins which is over-expressed in most of the human cancers [98, 99] and provides resistance to conventional cancer therapies including chemotherapy and radiotherapy [100, 101]. Cox-2 stabilizes survivin due to ubiquitination levels which provide resistance to apoptosis [102]. Above findings suggested that Cox-2 inhibiting apop-tosis might be through the regulation of proteins that are predominantly involved in mitochondrial-mediated apop-tosis. PGE2 appears to have an inhibitory effect on Fas-me-diated apoptosis also [23, 93].PGE2 over-production repress-ses expression of DR-4 and DR-5 receptors consequently inhibiting recruitment of the intracellular adaptor molecules for Fas-associated death domain and thus attenuating caspase activation [103, 104]. It is interesting to note that inhibition of Cox-2 by a Cox-2 inhibitor sulindac sulfide restored expression of DR-4,5 and augmented Fas-mediated cell death [84].
Role of p53 in Cox-2-mediated apoptosis is poorly
understood. However, a possibility is that wild type of p53 in
cancer cells decreases Cox-2 expression while mutation in
p53 gene contributes in Cox-2 induction consequently result-ing in anti-apoptosis [105]. In an important study, Han et al. (2002) demonstrated that oxidative and genotoxic effects induced expression of Cox-2 in p53-dependent manner and inhibition of Cox-2 potentiates DNA damage/p53-mediated apoptosis [54]. Interaction between Cox-2 and apoptotic protein may represent additional mechanisms by which Cox-2 expression interferes with tumor growth (Fig. 4).
CLINICAL CANCER THERAPEUTICS OF COX-2 Pioneer Studies Associating Cox-2 with Cancer
Several in vivo studies have been conducted to evaluate the role of Cox-2 in tumorigenesis. In a frontline research, Oshima et al. (1996) engineered an Apc716 Cox-2 null mice and got up to 86% reduction in intestinal adenoma, thus providing for the first time definitive evidence of the role of Cox-2 in tumorigenesis [106]. Many of the same molecular
and biochemical changes underlying human colon cancer
were observed in the azoxymethane (AOM)-induced rat
colon cancer model, in which Cox-2 down-regulation
effectively prevented development of colon tumors by 93% and inhibited tumor initiation by approximately 80% [106,
107]. Similar trend was observed in 7,12-dimethyl-benz(a)
anthracene (DMBA)-treated animal model, which is well
suited for breast cancer studies [108, 109]. A significant
correlation between Cox-2 and HER-2 expression was
reported in mammary tumors expressing HER-2/neu gene in mice and consistently these findings have also been estab-lished in human breast cancer [110-112]. Interestingly, epidemiological researches also suggest a reduction in the risk of cancer development and cancer-related deaths by administration of Cox-2 inhibitors [113, 114].
Cox-2 Inhibitors in Cancer Prevention and Treatment On the confirmation of Cox-2 involvement in cancer progression, researches conducted using a variety of Cox-2 specific inhibitors demonstrate a decrease in cancer incidence in many animal models [106, 109, 115]. Celecoxib (Celebrex TM) is a well known Cox-2 inhibitor, approved by the U.S. Food and Drug Administration (FDA) for the treatment of arthritis. Since many prior studies suggested potential of Cox-2 inhibitors in cancer prevention, the National Cancer Institute (NCI) conducted many laboratory studies and clinical trials for the validation of Cox-2 inhibitors in the prevention and treatment of a variety of cancers including bladder, breast, cervical, colorectal, oeso-phageal, head and neck, lung, and prostate cancers at differ-ent research organizations. As of now NCI continues to test celecoxib in more than 50 clinical trials for the prevention and treatment of cancer.
Adenoma Prevention with Celecoxib (APC) Trial In Adenoma and Colorectal Sporadic Adenomatous Polyps Trials conducted on more than 3500 patients demonstrated the successful use of celecoxib [116, 117]. It is important to note that celecoxib was more effective against advance stage lesions and in patients at a greater risk for colorectal cancer. Despite reducing the adenoma recurrence in a dose-dependent manner, the cardiovascular risk posed on administration of celecoxib (400 mg/day) drew the attention. Furthermore, an adverse dose-response effect was observed, with higher toxicity in patients receiving higher dose. However, ongoing clinical trials (NCT00005094) with altered dose and time schedules of celecoxibs may provide better results with reduced side effects.
Cox-2 Clinical Studies in Breast Cancer
Breast tumor is well reported for over-expression of Cox-2. Several preclinical studies on breast tumor mice model showed involvement of Cox-2 and its metabolites at many key points throughout tumorigenesis, including premalignant hyperproliferation, transformation, tumor viability, growth, invasion and metastatic spread [118, 119].
Conventional therapeutic drugs such as trastuzumab and capecitabine are considered an active treatment strategy for breast tumor [120, 121]. A pilot study was conducted to
Biology of Cox-2
Current Drug Targets, 2011, Vol. 12, No. 7 1087
determine if the addition of celecoxib is useful in improving the response rate of breast cancers to neoadjuvant cytotoxic treatment [122]. It was followed by a phase-II study of celecoxib and trastuzumab in patients with HER-2/neu -over-expressing metastatic breast cancer which had progressed while receiving trastuzumab [123]. In this trial, an improved response rate of 20% was recorded as compared to trastuzu-mab alone. One more phase-II trial of celecoxib in combi-nation with capecitabine was conducted on advanced meta-static breast cancer patients [124]. This combination was found to be very effective with a response rate of 20-30%. Interestingly lower toxicity was observed in combination as compared to capecitabine alone. Currently this trial is moving in its further stage with larger series of patients. Additionally, in both the mentioned trials, the Cox-2 level was significantly higher in tumors that showed a clinical response to the addition of celecoxib as compared to non-responders whereas this was not observed in patients treated with chemotherapy alone. Moreover, both regimens were well tolerated and there were no clinical signs and symptoms of cardiac failure.
Endocrine therapy is another treatment for breast cancer. Importantly, as we described above, Cox-2 and aromitase expressed in a significantly positive manner in human breast cancer, suggest the involvement of autocrine and paracrine mechanisms in hormone-dependent breast cancer develop-ment via growth stimulation from local estrogen biosynthesis
[82-84, 125]. Induced vascularization and estrogen synthesis adversely affect the endocrine therapy and this portrays Cox-2 blocking as an important remedy to combine with hormone therapy. A successful preclinical study was conducted to test the potential of celecoxib and exemestane combination on DMBA rat model [108, 109]. Then after a CAAN (Celecoxib anti-aromatase neoadjuvant) trial was conducted to investi-gate the efficacy combining aromatase inhibitors with Cox-2 inhibitor in postmenopausal hormone sensitive breast cancer patients [126, 127]. The preliminary results of these trials show that celecoxib and anti-aromatase combination therapy works well in breast cancer. Cox-2 in Head and Neck Cancer
Several studies have been undertaken to investigate Cox-2 as a therapeutic target in head and neck cancer prevention and treatment. Pathological studies indicate a higher expression of Cox-2 in head and neck cancer tissues [128, 129]. Treatment of head and neck cancer cell lines with celecoxib induced cell death in vitro and suppressed the in vivo tumor growth in animal model [130]. NCI and other Cancer Research Centers across the world have started clinical trials of celecoxib alone and in combination with other drugs to treat head and neck cancer. It is well known that celecoxib suppresses tumor growth by reducing blood supply. However, NCI started a phase-I/II trial in year 2008 (NCT00357617) to determine, if celecoxib could be useful in
Fig. (4). Schematic representation of Cox-2 apoptotic targets. Elevated Cox-2 level has influence on both mitochondrial and receptor-mediated apoptosis. Cox-2 over expression induces apoptotic resistance in cancer cells by increasing anti-apoptotic and suppressing pro-apoptotic proteins involved in both apoptotic pathways. In mitochondrial pathway Cox-2 showed negative effect on bcl-xl and Bax (pro-apoptotic) and positive effect on bcl2 and survivin (anti-apoptotic) and in receptor mediated pathway Cox-2 over expression constrains
formation of death domain complex by decreasing DR-4 and DR-5 receptor proteins. It is hypothesized that anti-cancer therapies can induce Cox-2 expression in p53-dependent manner, which in turn attenuate p53-mediated apoptosis by regulating pro and anti-apoptotic proteins.
1088 Current Drug Targets, 2011, Vol. 12, No. 7Khan et al.
reducing the amount of normal tissues that need to be
removed by surgery. The results of this ongoing trial could
be useful for doctors in learning more about the cancer and
predict how well patients will respond to treatment with
celecoxib. NCI had also conducted a phase-II trial in order to check the molecular effects of short-term celecoxib treatment
on head and neck squamous cell carcinoma (HNSCC)
(NCT00596219). This study aims to measure how celecoxib
affects those chemicals, which can be found in the tumor,
blood and urine of patients with head and neck cancer. Cox-
2 inhibitors are also testing in combination with other key therapeutic targets of head and neck cancer. A clinical trial is going on at Winship Cancer Institute of Emory University to test the feasibility and efficacy of Cox-2 inhibitor (celecoxib), EGFR inhibitor (ZD1839) and Tyrosine Kinase Inhibitor (OSI-774) in Early Stage (Stage I/II) of HNSCC (NCT00400374). Preliminary reports of these trials showed chemopreventive effect of Cox-2 inhibition in head and cancer. Upcoming data may help in the treatment of head and neck cancer in clinical settings.
Cox-2 was found highly up-regulated in primary tumors
and cell lines of neuroblastoma also. Inhibition of Cox-2 by celecoxib significantly induced apoptosis of neuroblastoma cell lines and suppressed in vivo tumor growth [7, 131]. Furthermore, use of NSAID was found to be effective in treating paediatric neuroblastoma [7]. All together, these findings suggest that Cox-2 inhibitors may be a novel adjuvant therapy for neuroblastoma.
Cox-2 in Lung Cancer
Lung cancer tissues were also identified with high expression of Cox-2 [132, 133]. The level of Cox-2 in both types of non-small cell lung carcinomas (NSCLC: adenocar-cinomas and squamous cell carcinomas) was significantly higher than in normal lung tissues. In vitro cell studies have demonstrated that over-expression of Cox-2 stabilizes anti-apoptotic genes and induces invasiveness in NSCLC (Dohadwala M et al. 2001, Krysan K et al. 2004) leading to resistance of NSCLC against chemotherapy and radiotherapy [134, 135]. Preclinical studies on NSCLC animal models have shown that treatment with either NSAID or celecoxib reduced tumor growth by acting on multiple tumor-progres-sion targets such as angiogenesis, tumor invasion, resistance to apoptosis, and suppression of antitumor immunity via both Cox-2-dependent and-independent pathways [136]. In
sync with preclinical studies, epidemiological evidence has
shown a decreased incidence of lung cancer in patients who
used cox-2 inhibitor. Based on these observations, many
clinical studies have been initiated to evaluate the effect of celecoxib in combination with chemotherapy and radio-
therapy [137, 138]. Phase I/II, III/IV clinical trials in colla-
boration with NCI and University of California are in prog-
ress to test celecoxib on NSCLC patients (NCT00104767,
NCT00055978).A combination trial of celecoxib, paclitaxel
and carboplatin is being conducted by Bimodality Lung Oncology Team (BLOT).
In NSCLC, Cox-2 has shown a significant positive
correlation with EGFR. Preclinical studies have demons-
trated successful use of Cox-2 inhibitors with EGFR inhi-
bition [138]. Ongoing clinical trials are also evaluating the combination of celecoxib with epidermal growth factor receptor inhibitors (ZD1839) of NSCLC (NCT00068653). Initial trends of these clinical studies have shown that cele-coxib can be safely administered alone and in combination with other chemoradiotherapeutic agents in NSCLC patients.
Cox-2 Clinical Studies in Other Cancers
Like various mentioned cancers, high expression of Cox-2 was significantly associated with poor prognosis and shorter patient’s survival in cervical, prostate, skin and bladder cancers [139-141]. In addition, high levels of Cox-2 have also been found in gastric, liver, pancreatic and biliary tumors [142]. Cox-2 inhibitors are already in clinical trials for the prevention of skin cancers and for the treatment of cervical and prostate cancer (Table 1).
In the above preclinical and clinical studies regarding different cancers, celecoxib was promisingly shown to reduce tumorigenesis alone and in combination with other conventional chemoradiotherapies. It is interesting to note that celecoxib is effective in the advanced stages of cancer. Overall clinical successes of trials are stepping stones to progress.Further studies are warranted to clarify if Cox-2-inhibition has an impact in clinical settings.
Future Prospects
Role of Cox-2 in tumor progression still has many unknown variables and might be much more complex than
Table 1. Clinical Trials of Celecoxib in Skin, Cervical and Prostate Cancer
Prevention Trial Phase Number of Patients Participants Skin II 36 Basal cell nevus syndrome [142]
Skin II, III 240 Actinic keratoses [142]
Skin II, III 240 No elevated risk [142]
Treatment Trial
Cervical I, II 62 Radiation, 5-FU, cisplatin, NCT00023660
Cervical II/III 130 Intraepithelial neoplasia, placebo, NCT00081263 Prostate I 60–70 Surgery, NCT00022399
Prostate II, III 85 Recurrent, placebo, NCT00136487
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currently believed. It is a key challenge to researchers and
scientists across the world for better understanding of
argument as regarding their mode of action throughout the
body and, therefore, an improved strategy based on Cox-2
needs to be designed for treating cancer. Since it is well established that most of the tumors produce high levels of
Cox-2, investigations are being directed towards elucidating
the role of Cox-2 inhibitors in preventing cancer. An anti-
cancer effect of Cox-2 inhibitors is widely accepted but its
utilization is controversial due to side effects including
cardiovascular risk [143]. It is important to note that only high dose (400 mg/d) of celecoxib showed this side effect in colon cancer trial. Researchers may investigate giving lower doses of celecoxib or different dose regimens to determine if this causes less cardiovascular risk. Still it is unclear whether cardiovascular side effects are a class effect or all Cox-2 inhibitors exhibit the same behavioral pattern. More resear-ches in this direction will assist in the development of novel drugs with lesser side effects once the mechanisms through which Cox-2 inhibitors reduce tumor progression are understood. Many clinical trials from phase-I to IV are still in progress with most of the cancers to test celecoxib alone and in combination with other chemoradiotherapeutic agents in different doses and time schedules. The preliminary results are very exciting to carry on further study with celecoxib with fewer side effects. It is interesting to mention that Cox-2 inhibitors have shown good results in personal medication according to the status of Cox-2 expression. For example, celecoxib used in combination with ZD1839 (EGFR inhibitor), which is an excellent therapeutic target in head and neck and lung cancer (NCT00068653). Many more studies are needed to test the feasibility and efficacy of celecoxib with other specific tumor marker inhibitors in particular cancer. As it is reported that Cox-2 inhibitors have capacity to reduce tumorigenesis even without involving Cox-2 [33, 131]. Now researchers are being initiated in order to unravel other targets for Cox-2 inhibitors in cancers. This will aid in the construction of innovative derivatives of Cox-2 inhibitors to enhance effectiveness with reduce side effects in cancer cure.
CONCLUSION
Cox-2 is an inducible isoform of cyclooxygenase and its over-expression is found in many cancers including head and neck, lung, colon and breast. Cox-2 generated biomarkers such as PGs or other down-stream mediators have an important role in regulating cell proliferation and survival. Elevated level of Cox-2 gives anti-apoptotic and angiogenic signals thus resisting cancer cells to conventional cancer therapies. Hence it is becoming interestingly evident that selective Cox-2 inhibitors have a growing potential as a beneficial target for chemopreventive and tumor regression for many cancers.
ACKNOWLEDGEMENT
Authors are thankful to Council of Scientific and Industrial Research (CSIR), New Delhi for the award of Emeritus Scientist to Prof. P.S. Bisen. ABBREVIATIONS
GRB = Growth Factor Receptor-Bound Protein SOS = Son-of-sevenless
MAPK = Mitogen-Activated Protein Kinase
ERK = Extracellular Signal-Regulated Kinase MEK = MAPK/Erk kinase
MEKK = MAPK/Erk Kinase Kinase
JNK = Jun N-terminal kinase
PKC = Protein Kinase C
EGFR = Epidermal Growth Factor Receptor
PI3K-Akt = Phosphatidylinositol-3-Kinase and Protein
Kinase B
VEGF= Vascular Endothelial Growth Factor
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The way 的用法 Ⅰ常见用法： 1)the way+ that 2)the way + in which（最为正式的用法） 3)the way + 省略（最为自然的用法） 举例：I like the way in which he talks. I like the way that he talks. I like the way he talks. Ⅱ习惯用法： 在当代美国英语中，the way用作为副词的对格，“the way+ 从句”实际上相当于一个状语从句来修饰整个句子。 1)The way =as I am talking to you just the way I’d talk to my own child. He did not do it the way his friends did. Most fruits are naturally sweet and we can eat them just the way they are—all we have to do is to clean and peel them. 2）The way= according to the way/ judging from the way The way you answer the question, you are an excellent student. The way most people look at you, you’d think trash man is a monster. 3）The way =how/ how much No one can imagine the way he missed her. 4）The way =because
The way的用法及其含义（二） 二、the way在句中的语法作用 the way在句中可以作主语、宾语或表语： 1.作主语 The way you are doing it is completely crazy.你这个干法简直发疯。 The way she puts on that accent really irritates me. 她故意操那种口音的样子实在令我恼火。The way she behaved towards him was utterly ruthless. 她对待他真是无情至极。 Words are important, but the way a person stands, folds his or her arms or moves his or her hands can also give us information about his or her feelings. 言语固然重要,但人的站姿,抱臂的方式和手势也回告诉我们他(她)的情感。 2.作宾语 I hate the way she stared at me.我讨厌她盯我看的样子。 We like the way that her hair hangs down.我们喜欢她的头发笔直地垂下来。 You could tell she was foreign by the way she was dressed. 从她的穿著就可以看出她是外国人。 She could not hide her amusement at the way he was dancing. 她见他跳舞的姿势，忍俊不禁。 3.作表语 This is the way the accident happened.这就是事故如何发生的。 Believe it or not, that's the way it is. 信不信由你, 反正事情就是这样。 That's the way I look at it, too. 我也是这么想。 That was the way minority nationalities were treated in old China. 那就是少数民族在旧中
定冠词the的用法： 定冠词the与指示代词this ,that同源,有“那(这)个”的意思,但较弱,可以和一个名词连用,来表示某个或某些特定的人或东西. (1)特指双方都明白的人或物 Take the medicine.把药吃了. (2)上文提到过的人或事 He bought a house.他买了幢房子. I've been to the house.我去过那幢房子. (3)指世界上独一无二的事物 the sun ,the sky ,the moon, the earth (4)单数名词连用表示一类事物 the dollar 美元 the fox 狐狸 或与形容词或分词连用,表示一类人 the rich 富人 the living 生者 (5)用在序数词和形容词最高级,及形容词等前面 Where do you live?你住在哪? I live on the second floor.我住在二楼. That's the very thing I've been looking for.那正是我要找的东西. (6)与复数名词连用,指整个群体 They are the teachers of this school.(指全体教师) They are teachers of this school.(指部分教师) (7)表示所有,相当于物主代词,用在表示身体部位的名词前 She caught me by the arm.她抓住了我的手臂. (8)用在某些有普通名词构成的国家名称,机关团体,阶级等专有名词前 the People's Republic of China 中华人民共和国 the United States 美国 (9)用在表示乐器的名词前 She plays the piano.她会弹钢琴. (10)用在姓氏的复数名词之前,表示一家人 the Greens 格林一家人(或格林夫妇) (11)用在惯用语中 in the day, in the morning... the day before yesterday, the next morning... in the sky... in the dark... in the end... on the whole, by the way...
“tｈｅwａｙ+从句”结构的意义及用法 首先让我们来看下面这个句子: Ｒead the foｌloｗｉnｇpassagｅａnd talkａbout ｉt wi ｔh your classmaｔes．Try tｏｔeｌl whaｔyｏu thiｎk ｏf Tom aｎd ｏｆｔhe ｗay the chiｌｄrenｔrｅated ｈim. 在这个句子中，ｔhe waｙ是先行词,后面是省略了关系副词that或in whｉch的定语从句。 下面我们将叙述“the ｗaｙ+从句”结构的用法。 1.tｈe wａy之后，引导定语从句的关系词是tｈat而不是hoｗ,因此，<<现代英语惯用法词典＞＞中所给出的下面两个句子是错误的：Ｔhｉs is ｔｈeｗayｈowｉtｈａppened. This is the way how he ａlwａｙs treats me. 2．在正式语体中,thaｔ可被in which所代替;在非正式语体中，ｔhat则往往省略。由此我们得到theｗay后接定语从句时的三种模式：1) tｈe ｗaｙ＋ｔhａt-从句２）the way +ｉn whiｃh－从句3) the ｗay +从句 例如：Ｔｈe way(in whiｃh ，thａt) ｔhｅｓｅｃomｒade ｓloｏｋａｔｐrobｌems is wrong．这些同志看问题的方法
不对。 Ｔｈｅｗａy(that ,ｉn ｗhiｃh)yoｕ’ｒe doinｇit is comple ｔeｌy crａzy.你这么个干法,简直发疯。 Wｅａdmiｒｅd him for thｅｗay ｉｎｗhｉch he fａｃeｓdiｆficultieｓ． Waｌlａｃe ａｎd Ｄarwiｎｇreed ｏn the way ｉｎwhi ｃh ｄｉfｆｅrｅnt forms ｏf life had ｂegｕn.华莱士和达尔文对不同类型的生物是如何起源的持相同的观点。 Thｉs is ｔｈe ｗaｙ（tｈａｔ) hｅdｉd it. I lｉkeｄｔhe waｙ(ｔhat) ｓｈeｏｒganized ｔhe ｍeetｉng． 3.theｗay(tｈat)有时可以与hｏw(作“如何”解）通用。例如： That’s tｈe ｗaｙ(tｈaｔ) shｅspoke. = Tｈat’s how shｅspoke.
表示“方式”、“方法”，注意以下用法： 1.表示用某种方法或按某种方式，通常用介词in(此介词有时可省略)。如： Do it (in) your own way. 按你自己的方法做吧。 Please do not talk (in) that way. 请不要那样说。 2.表示做某事的方式或方法，其后可接不定式或of doing sth。 如： It’s the best way of studying [to study] English. 这是学习英语的最好方法。 There are different ways to do [of doing] it. 做这事有不同的办法。 3.其后通常可直接跟一个定语从句(不用任何引导词)，也可跟由that 或in which 引导的定语从句，但是其后的从句不能由how 来引导。如： 我不喜欢他说话的态度。 正：I don’t like the way he spoke. 正：I don’t like the way that he spoke. 正：I don’t like the way in which he spoke. 误：I don’t like the way how he spoke. 4.注意以下各句the way 的用法： That’s the way (=how) he spoke. 那就是他说话的方式。 Nobody else loves you the way(=as) I do. 没有人像我这样爱你。 The way (=According as) you are studying now, you won’tmake much progress. 根据你现在学习情况来看，你不会有多大的进步。 2007年陕西省高考英语中有这样一道单项填空题： ——I think he is taking an active part insocial work. ——I agree with you_____. A、in a way B、on the way C、by the way D、in the way 此题答案选A。要想弄清为什么选A，而不选其他几项，则要弄清选项中含way的四个短语的不同意义和用法，下面我们就对此作一归纳和小结。 一、in a way的用法 表示：在一定程度上，从某方面说。如： In a way he was right.在某种程度上他是对的。注：in a way也可说成in one way。 二、on the way的用法 1、表示：即将来(去)，就要来(去)。如： Spring is on the way.春天快到了。 I'd better be on my way soon.我最好还是快点儿走。 Radio forecasts said a sixth-grade wind was on the way.无线电预报说将有六级大风。 2、表示：在路上，在行进中。如： He stopped for breakfast on the way.他中途停下吃早点。 We had some good laughs on the way.我们在路上好好笑了一阵子。 3、表示：(婴儿)尚未出生。如： She has two children with another one on the way.她有两个孩子，现在还怀着一个。 She's got five children，and another one is on the way.她已经有5个孩子了，另一个又快生了。 三、by the way的用法
The way的用法及其含义（一） 有这样一个句子：In 1770 the room was completed the way she wanted. 1770年，这间琥珀屋按照她的要求完成了。 the way在句中的语法作用是什么？其意义如何？在阅读时，学生经常会碰到一些含有the way 的句子，如：No one knows the way he invented the machine. He did not do the experiment the way his teacher told him.等等。他们对the way 的用法和含义比较模糊。在这几个句子中，the way之后的部分都是定语从句。第一句的意思是，“没人知道他是怎样发明这台机器的。”the way的意思相当于how；第二句的意思是，“他没有按照老师说的那样做实验。”the way 的意思相当于as。在In 1770 the room was completed the way she wanted.这句话中，the way也是as的含义。随着现代英语的发展，the way的用法已越来越普遍了。下面，我们从the way的语法作用和意义等方面做一考查和分析： 一、the way作先行词，后接定语从句 以下3种表达都是正确的。例如：“我喜欢她笑的样子。” 1. the way+ in which +从句 I like the way in which she smiles. 2. the way+ that +从句 I like the way that she smiles. 3. the way + 从句(省略了in which或that) I like the way she smiles. 又如：“火灾如何发生的，有好几种说法。” 1. There were several theories about the way in which the fire started. 2. There were several theories about the way that the fire started.
way 的用法 【语境展示】 1. Now I’ll show you how to do the experiment in a different way. 下面我来演示如何用一种不同的方法做这个实验。 2. The teacher had a strange way to make his classes lively and interesting. 这位老师有种奇怪的办法让他的课生动有趣。 3. Can you tell me the best way of working out this problem? 你能告诉我算出这道题的最好方法吗？ 4. I don’t know the way (that / in which) he helped her out. 我不知道他用什么方法帮助她摆脱困境的。 5. The way (that / which) he talked about to solve the problem was difficult to understand. 他所谈到的解决这个问题的方法难以理解。 6. I don’t like the way that / which is being widely used for saving water. 我不喜欢这种正在被广泛使用的节水方法。 7. They did not do it the way we do now. 他们以前的做法和我们现在不一样。 【归纳总结】 ●way作“方法，方式”讲时，如表示“以……方式”，前面常加介词in。如例1； ●way作“方法，方式”讲时，其后可接不定式to do sth.，也可接of doing sth. 作定语，表示做某事的方法。如例2，例3；
t h e-w a y-的用法
The way 的用法 "the way+从句"结构在英语教科书中出现的频率较高, the way 是先行词, 其后是定语从句.它有三种表达形式:1) the way+that 2)the way+ in which 3)the way + 从句(省略了that或in which),在通常情况下, 用in which 引导的定语从句最为正式,用that的次之,而省略了关系代词that 或 in which 的, 反而显得更自然,最为常用.如下面三句话所示,其意义相同. I like the way in which he talks. I like the way that he talks. I like the way he talks. 一.在当代美国英语中,the way用作为副词的对格,"the way+从句"实际上相当于一个状语从句来修饰全句. the way=as 1)I'm talking to you just the way I'd talk to a boy of my own. 我和你说话就象和自己孩子说话一样. 2)He did not do it the way his friend did. 他没有象他朋友那样去做此事. 3)Most fruits are naturally sweet and we can eat them just the way they are ----all we have to do is clean or peel them . 大部分水果天然甜润,可以直接食用,我们只需要把他们清洗一下或去皮.
way的用法总结大全 way的用法你知道多少，今天给大家带来way的用法，希望能够帮助到大家，下面就和大家分享，来欣赏一下吧。 way的用法总结大全 way的意思 n. 道路,方法,方向,某方面 adv. 远远地，大大地 way用法 way可以用作名词 way的基本意思是“路,道,街,径”,一般用来指具体的“路,道路”,也可指通向某地的“方向”“路线”或做某事所采用的手段,即“方式,方法”。way还可指“习俗,作风”“距离”“附近,周围”“某方面”等。 way作“方法,方式,手段”解时,前面常加介词in。如果way前有this, that等限定词,介词可省略,但如果放在句首,介词则不可省略。
way作“方式,方法”解时,其后可接of v -ing或to- v 作定语,也可接定语从句,引导从句的关系代词或关系副词常可省略。 way用作名词的用法例句 I am on my way to the grocery store.我正在去杂货店的路上。 We lost the way in the dark.我们在黑夜中迷路了。 He asked me the way to London.他问我去伦敦的路。 way可以用作副词 way用作副词时意思是“远远地,大大地”,通常指在程度或距离上有一定的差距。 way back表示“很久以前”。 way用作副词的用法例句 It seems like Im always way too busy with work.我工作总是太忙了。 His ideas were way ahead of his time.他的思想远远超越了他那个时代。 She finished the race way ahead of the other runners.她第一个跑到终点,远远领先于其他选手。 way用法例句
t h e_w a y的用法大全
The way 在the way+从句中, the way 是先行词, 其后是定语从句.它有三种表达形式:1) the way+that 2)the way+ in which 3)the way + 从句(省略了that或in which),在通常情况下, 用in which 引导的定语从句最为正式,用that的次之,而省略了关系代词that 或 in which 的, 反而显得更自然,最为常用.如下面三句话所示,其意义相同. I like the way in which he talks. I like the way that he talks. I like the way he talks. 如果怕弄混淆，下面的可以不看了 另外，在当代美国英语中,the way用作为副词的对格,"the way+从句"实际上相当于一个状语从句来修饰全句. the way=as 1)I'm talking to you just the way I'd talk to a boy of my own. 我和你说话就象和自己孩子说话一样. 2)He did not do it the way his friend did. 他没有象他朋友那样去做此事. 3)Most fruits are naturally sweet and we can eat them just the way they are ----all we have to do is clean or peel them . 大部分水果天然甜润,可以直接食用,我们只需要把他们清洗一下或去皮. the way=according to the way/judging from the way 4)The way you answer the qquestions, you must be an excellent student. 从你回答就知道,你是一个优秀的学生. 5)The way most people look at you, you'd think a trashman was a monster. 从大多数人看你的目光中,你就知道垃圾工在他们眼里是怪物. the way=how/how much 6)I know where you are from by the way you pronounce my name. 从你叫我名字的音调中,我知道你哪里人. 7)No one can imaine the way he misses her. 人们很想想象他是多么想念她. the way=because 8) No wonder that girls looks down upon me, the way you encourage her. 难怪那姑娘看不起我, 原来是你怂恿的
The way 的用法 "the way+从句"结构在英语教科书中出现的频率较高, the way 是先行词, 其后是定语从句.它有三种表达形式:1) the way+that 2)the way+ in which 3)the way + 从句(省略了that或in which),在通常情况下, 用in which 引导的定语从句最为正式,用that的次之,而省略了关系代词that 或in which 的, 反而显得更自然,最为常用.如下面三句话所示,其意义相同. I like the way in which he talks. I like the way that he talks. I like the way he talks. 一.在当代美国英语中,the way用作为副词的对格,"the way+从句"实际上相当于一个状语从句来修饰全句. the way=as 1)I'm talking to you just the way I'd talk to a boy of my own. 我和你说话就象和自己孩子说话一样. 2)He did not do it the way his friend did. 他没有象他朋友那样去做此事. 3)Most fruits are naturally sweet and we can eat them just the way they are ----all we have to do is clean or peel them . 大部分水果天然甜润,可以直接食用,我们只需要把他们清洗一下或去皮.
the way=according to the way/judging from the way 4)The way you answer the qquestions, you must be an excellent student. 从你回答就知道,你是一个优秀的学生. 5)The way most people look at you, you'd think a trashman was a monster. 从大多数人看你的目光中,你就知道垃圾工在他们眼里是怪物. the way=how/how much 6)I know where you are from by the way you pronounce my name. 从你叫我名字的音调中,我知道你哪里人. 7)No one can imaine the way he misses her. 人们很想想象他是多么想念她. the way=because 8) No wonder that girls looks down upon me, the way you encourage her. 难怪那姑娘看不起我, 原来是你怂恿的 the way =while/when(表示对比) 9)From that day on, they walked into the classroom carrying defeat on their shoulders the way other students carried textbooks under their arms. 从那天起,其他同学是夹着书本来上课,而他们却带着"失败"的思想负担来上课.
The way的用法及其含义（三） 三、the way的语义 1. the way=as（像） Please do it the way I’ve told you.请按照我告诉你的那样做。 I'm talking to you just the way I'd talk to a boy of my own.我和你说话就像和自己孩子说话一样。 Plant need water the way they need sun light. 植物需要水就像它们需要阳光一样。 2. the way=how（怎样，多么） No one can imagine the way he misses her.没人能够想象出他是多么想念她！ I want to find out the way a volcano has formed.我想弄清楚火山是怎样形成的。 He was filled with anger at the way he had been treated.他因遭受如此待遇而怒火满腔。That’s the way she speaks.她就是那样讲话的。 3. the way=according as （根据） The way you answer the questions, you must be an excellent student.从你回答问题来看，你一定是名优秀的学生。 The way most people look at you, you'd think a trash man was a monster.从大多数人看你的目光中,你就知道垃圾工在他们眼里是怪物。 The way I look at it, it’s not what you do that matters so much.依我看，重要的并不是你做什么。 I might have been his son the way he talked.根据他说话的样子，好像我是他的儿子一样。One would think these men owned the earth the way they behave.他们这样行动，人家竟会以为他们是地球的主人。
一．Way：“方式”、“方法” 1.表示用某种方法或按某种方式 Do it (in) your own way. Please do not talk (in) that way. 2.表示做某事的方式或方法 It’s the best way of studying [to study] English.。 There are different ways to do [of doing] it. 3.其后通常可直接跟一个定语从句(不用任何引导词)，也可跟由that 或in which 引导的定语从句 正：I don’t like the way he spoke. I don’t like the way that he spoke. I don’t like the way in which he spoke.误：I don’t like the way how he spoke. 4. the way 的从句 That’s the way (=how) he spoke. I know where you are from by the way you pronounce my name. That was the way minority nationalities were treated in old China. Nobody else loves you the way(=as) I do. He did not do it the way his friend did. 二．固定搭配 1. In a/one way：In a way he was right. 2. In the way /get in one’s way I'm afraid your car is in the way， If you are not going to help，at least don't get in the way. You'll have to move－you're in my way. 3. in no way Theory can in no way be separated from practice. 4. On the way (to……) Let’s wait a few moments. He is on the way Spring is on the way. Radio forecasts said a sixth-grade wind was on the way. She has two children with another one on the way. 5. By the way By the way，do you know where Mary lives? 6. By way of Learn English by way of watching US TV series. 8. under way 1. Elbow one’s way He elbowed his way to the front of the queue. 2. shoulder one’s way 3. feel one‘s way 摸索着向前走；We couldn’t see anything in the cave, so we had to feel our way out 4. fight/force one’s way 突破。。。而前进The surrounded soldiers fought their way out. 5.. push/thrust one‘s way（在人群中）挤出一条路He pushed his way through the crowd. 6. wind one’s way 蜿蜒前进 7. lead the way 带路，领路；示范 8. lose one‘s way 迷失方向 9. clear the way 排除障碍，开路迷路 10. make one’s way 前进，行进The team slowly made their way through the jungle.
在the way+从句中, the way 是先行词, 其后是定语从句.它有三种表达形式:1) the way+that 2)the way+ in which 3)the way + 从句(省略了that或in which),在通常情况下, 用in which 引导的定语从句最为正式,用that的次之,而省略了关系代词that 或in which 的, 反而显得更自然,最为常用.如下面三句话所示,其意义相同. I like the way in which he talks. I like the way that he talks. I like the way he talks. 如果怕弄混淆，下面的可以不看了 另外，在当代美国英语中,the way用作为副词的对格,"the way+从句"实际上相当于一个状语从句来修饰全句. the way=as 1)I'm talking to you just the way I'd talk to a boy of my own. 我和你说话就象和自己孩子说话一样. 2)He did not do it the way his friend did. 他没有象他朋友那样去做此事. 3)Most fruits are naturally sweet and we can eat them just the way they are ----all we have to do is clean or peel them . 大部分水果天然甜润,可以直接食用,我们只需要把他们清洗一下或去皮. the way=according to the way/judging from the way 4)The way you answer the qquestions, you must be an excellent student. 从你回答就知道,你是一个优秀的学生. 5)The way most people look at you, you'd think a trashman was a monster. 从大多数人看你的目光中,你就知道垃圾工在他们眼里是怪物. the way=how/how much 6)I know where you are from by the way you pronounce my name. 从你叫我名字的音调中,我知道你哪里人. 7)No one can imaine the way he misses her. 人们很想想象他是多么想念她. the way=because 8) No wonder that girls looks down upon me, the way you encourage her. 难怪那姑娘看不起我, 原来是你怂恿的 the way =while/when(表示对比) 9)From that day on, they walked into the classroom carrying defeat on their shoulders the way other students carried textbooks under their arms.
“the way+从句”结构的意义及用法 首先让我们来看下面这个句子： Read the following passage and talk about it with your classmates. Try to tell what you think of Tom and of the way the children treated him. 在这个句子中，the way是先行词，后面是省略了关系副词that 或in which的定语从句。 下面我们将叙述“the way+从句”结构的用法。 1．the way之后，引导定语从句的关系词是that而不是how,因此，<<现代英语惯用法词典>>中所给出的下面两个句子是错误的：This is the way how it happened. This is the way how he always treats me. 2. 在正式语体中，that可被in which所代替；在非正式语体中，that则往往省略。由此我们得到the way后接定语从句时的三种模式：1) the way +that-从句2) the way +in which-从句3) the way +从句 例如：The way(in which ,that) these comrades look at problems is wrong.这些同志看问题的方法不对。
The way(that ,in which)you’re doing it is completely crazy.你这么个干法，简直发疯。 We admired him for the way in which he faces difficulties. Wallace and Darwin greed on the way in which different forms of life had begun.华莱士和达尔文对不同类型的生物是如何起源的持相同的观点。 This is the way (that) he did it. I liked the way (that) she organized the meeting. 3.the way(that)有时可以与how(作“如何”解)通用。例如： That’s the way (that) she spoke. = That’s how she spoke. I should like to know the way/how you learned to master the fundamental technique within so short a time. 4．the way的其它用法：以上我们讲的都是用作先行词的the way，下面我们将叙述它的一些用法。
定冠词the的12种用法 定冠词the 的12 种用法，全知道?快来一起学习吧。下面就和大家分享，来欣赏一下吧。 定冠词the 的12 种用法，全知道? 定冠词the用在各种名词前面，目的是对这个名词做个记号，表示它的特指属性。所以在词汇表中，定冠词the 的词义是“这个，那个，这些，那些”，可见，the 即可以放在可数名词前，也可以修饰不可数名词，the 后面的名词可以是单数，也可以是复数。 定冠词的基本用法： (1) 表示对某人、某物进行特指，所谓的特指就是“不是别的，就是那个!”如： The girl with a red cap is Susan. 戴了个红帽子的女孩是苏珊。 (2) 一旦用到the，表示谈话的俩人都知道说的谁、说的啥。如：
The dog is sick. 狗狗病了。(双方都知道是哪一只狗) (3) 前面提到过的，后文又提到。如： There is a cat in the tree.Thecat is black. 树上有一只猫，猫是黑色的。 (4) 表示世界上唯一的事物。如： The Great Wall is a wonder.万里长城是个奇迹。(5) 方位名词前。如： thenorth of the Yangtze River 长江以北地区 (6) 在序数词和形容词最高级的前面。如： Who is the first?谁第一个? Sam is the tallest.山姆最高。 但是不能认为，最高级前必须加the，如： My best friend. 我最好的朋友。 (7) 在乐器前。如： play the flute 吹笛子
Way用法 A:I think you should phone Jenny and say sorry to her. B:_______. It was her fault. A. No way B. Not possible C. No chance D. Not at all 说明：正确答案是A. No way，意思是“别想！没门！决不！” 我认为你应该打电话给珍妮并向她道歉。 没门！这是她的错。 再看两个关于no way的例句： （1）Give up our tea break? NO way! 让我们放弃喝茶的休息时间？没门儿！ （2）No way will I go on working for that boss. 我决不再给那个老板干了。 way一词含义丰富，由它构成的短语用法也很灵活。为了便于同学们掌握和用好它，现结合实例将其用法归纳如下： 一、way的含义 1. 路线
He asked me the way to London. 他问我去伦敦的路。 We had to pick our way along the muddy track. 我们不得不在泥泞的小道上择路而行。 2. （沿某）方向 Look this way, please. 请往这边看。 Kindly step this way, ladies and gentlemen. 女士们、先生们，请这边走。 Look both ways before crossing the road. 过马路前向两边看一看。 Make sure that the sign is right way up. 一定要把符号的上下弄对。 3. 道、路、街，常用以构成复合词 a highway（公路），a waterway（水路），a railway（铁路），wayside（路边）
way/time的特殊用法 1、当先行词是way意思为”方式.方法”的时候,引导定语从句的关系词有下列3种形式： Way在从句中做宾语 The way that / which he explained to us is quite simple. Way在从句中做状语 The way t hat /in which he explained the sentence to us is quite simple. 2、当先行词是time时,若time表示次数时,应用关系代词that引导定语从句,that可以省略; 若time表示”一段时间”讲时,应用关系副词when或介词at/during + which引导定语从句 1.Is this factory _______ we visited last year? 2.Is this the factory-------we visited last year? A. where B in which C the one D which 3. This is the last time _________ I shall give you a lesson. A. when B that C which D in which 4.I don’t like the way ________ you laugh at her. A . that B on which C which D as 5.He didn’t understand the wa y ________ I worked out the problem. A which B in which C where D what 6.I could hardly remember how many times----I’ve failed. A that B which C in which D when 7.This is the second time--------the president has visited the country. A which B where C that D in which 8.This was at a time------there were no televisions, no computers or radios. A what B when C which D that