Apatinib for the treatment of gastric cancer.

1.Introduction

2.Introduction to apatinib

3.Clinical efficacy

4.Safety and tolerability

5.Regulatory affairs

6.Conclusion

7.Expert opinion

Drug Evaluation Apatinib for the treatment of gastric cancer

Ruixuan Geng&Jin Li?

?Fudan University Shanghai Cancer Center,Shanghai Medical College,Department of Medical Oncology,Shanghai,China

Introduction:Antiangiogenesis therapy plays an important role in cancer treatment.Apatinib mesylate,a small molecule tyrosine kinase inhibitor tar-geting vascular endothelial growth factor receptor-2,has been recommended as third-line treatment for metastatic gastric cancer patients.

Areas covered:The current review summarizes the publications and confer-ence reports relating to apatinib from preclinical and clinical research in gas-tric cancer.Apatinib showed good safety,tolerance and treatment efficacy in Phase I/II studies.In a Phase III study,apatinib prolonged the median overall survival of patients with chemotherapy-refractory metastatic gastric cancer by55days and the median progression-free survival by25days compared with placebo.

Expert opinion:Apatinib is a new treatment option for advanced gastric can-cer.Apatinib is expected to have a broader application when it has been eval-uated worldwide.The key issues are to find biomarkers and overcome drug resistance.

Keywords:apatinib,stomach neoplasms,tyrosine kinase inhibitor,VEGF receptor-2

Expert Opin.Pharmacother.(2015)16(1):117-122

1.Introduction

Angiogenesis plays an important role in the growth and metastasis of malignant tumors.Ever since Folkman et al.raised the concept of antiangiogenic therapy in the1970s[1],this treatment has been widely accepted as an effective anticancer strat-egy.Antiangiogenic therapy mainly targets VEGF or its receptor VEGFR.The VEGF family includes VEGF-A to E and placenta growth factor1and2,whereas the VEGFR family includes VEGFR-1(Flt-1),VEGFR-2(KDR/Flk-1), VEGFR-3(Flt-4),and VEGFR co-receptors neuropilin1and2[2].Many VEGF/ VEGFR inhibitors,including bevacizumab,ramucirumab,aflibercept,sunitinib, sorafenib,regorafenib and axitinib,have proven activity against different solid tumors.Gastric cancer is one of the indications for VEGF/VEGFR-targeted therapy based on the angiogenic evidence[3,4].

Gastric cancer is the fourth most common malignant tumor and ranks as the sec-ond leading cause of cancer-related mortality,with a survival time of3--5months if left untreated[5-7].Although first-line chemotherapy provided a6-month survival benefit for patients with advanced gastric cancer,second-line chemotherapy with iri-notecan or docetaxel added only~1.5months to the overall survival(OS)com-pared with best supportive care[8-11].There is no standard third-line treatment if second-line chemotherapy fails.The need for treatments providing extended sur-vival led to the investigation of targeted therapy,including antiangiogenic strategies. Indeed,antiangiogenesis treatment has shown efficacy and safety in advanced gastric cancer in several Phase III trials.

In the past decade,many clinical studies have been performed to investigate tar-geted therapy for advanced gastric cancer.However,most of the therapies failed to provide efficacy.Although trastuzumab achieved2.7months improvement in OS

10.1517/14656566.2015.981526?2015Informa UK,Ltd.ISSN1465-6566,e-ISSN1744-7666117

when added to chemotherapy in patients with tumors overex-pressing human epidermal growth factor receptor-2(HER-2), other novel agents,including cetuximab,panitumumab,and everolimus,failed to show superiority compared with a con-trol regimen for metastatic gastric cancer[12-17].However, antiangiogenic therapies may signal a new era for the treat-ment of advanced gastric cancer,with attractive data from sev-eral Phase III studies[18,19].

The anti-VEGFR-2monoclonal antibody ramucirumab has been shown to be effective in treating chemotherapy-refractory advanced gastric or gastroesophageal junction adenocarcinoma[18].A further Phase III clinical trial,RAIN-BOW,found that patients in the ramucirumab plus paclitaxel arm lived2.2months longer than those in the placebo plus paclitaxel arm[19].

Recently,oral apatinib has shown good safety and efficacy results for heavily treated patients in a Phase III clinical trial. Apatinib is the first oral VEGFR tyrosine kinase inhibitor to show active control of tumor growth in gastric cancer.The Phase II/III studies of apatinib suggest that apatinib could be a new option for the treatment of advanced metastatic gastric cancer.

2.Introduction to apatinib

2.1Chemistry

Apatinib mesylate is a small molecule tyrosine kinase inhibitor targeting VEGFR-2.The structure of apatinib is similar to that of vatalanib(PTK787),on which its synthesis is based. The main hexatomic ring has remained intact,whereas the benzene ring has been changed to a pyridine group to increase the hydrophilicity of the molecule and,consequently,increase the water solubility and permeability of the drug.The picolyl and the para-substituents in the benzene ring have been retained and multiple fatty acid rings have been introduced to increase the lipophilicity and improve the interaction and binding of the drug to receptors(Box1).

2.2Pre-clinical studies

In vitro,apatinib inhibited proliferation and migration of human umbilical vein endothelial cells and tube formation induced by VEGF,and the budding of rat aortic rings[20]. In vivo,apatinib showed good inhibitory effects on various tumors implanted into nude mice,including colon and gastric cancer.Moreover,apatinib significantly improved the efficacy of traditional chemotherapy drugs such as oxaliplatin,5-fluo-rouracil,docetaxel,and doxorubicin in vivo[20].Apatinib also reversed multidrug resistance through the inhibition of ABCB-1and ABCG-2excretion[21]and improved the killing effect of doxorubicin on leukemia cells and side population cells with ABCB-1overexpression[22].

2.3Pharmacodynamics and pharmacokinetics Apatinib selectively inhibits VEGFR-2with a50%median inhibitory concentration(IC50)of0.001μM.When VEGFR-2is inhibited,downstream p-erk is also blocked. Moreover,apatinib also has selective inhibition effects on Ret,c-kit,and c-SRC with IC50of0.013,0.429,and 0.53μM,respectively.However,apatinib has little effect on inhibiting EGFR,HER-2,or FGFR1[20].

The bioavailability of apatinib through oral intake is between10and20%(Dr.Liguang Lou;Unpublished data; 2008).Ninety-six hours after oral intake of apatinib,excretion of the drug was76.8%,with69.8%in feces and7.0%in urine.The excreted drug in feces was mainly intact and had not been metabolized,whereas that in the urine had been

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118Expert Opin.Pharmacother.(2015)16(1)

almost completely metabolized[23].The binding efficiencies of apatinib to multiple plasma proteins(in rats,canines,mon-keys and humans)range from86--93%(Dr.Liguang Lou; Unpublished data;2008).Under treatment with the enzymes CYP3A4/5,CYP2C9,CYP2D6,CYP2E1,or UGT2B7,apa-tinib has four types of metabolites:cis-3-hydroxy-apatinib (M1-1),trans-3-hydroxy-apatinib(M1-2),apatinib-25-N-oxide(M1-6),and cis-3-hydroxy-apatinib-O-glucuronide (M9-2),with M9-2as the main metabolite[23].

A Phase I clinical trial investigated the pharmacokinetics of apatinib in single and multiple dose evaluations.In the single-dose evaluation,28patients were divided into three groups according to drug doses of500mg(n=8),750mg (n=12),and850mg(n=8).3--4h after oral apatinib intake, the plasma drug concentration reached the peak.The mean maximum plasma drug concentration(C max)of the three groups were1521,2379and2833ng/ml,respectively,and the areas under the concentration-time curve0--24h (AUC0-24h)were11295,18172,and21975ng·h/ml,respec-tively.The C max and AUC0--24h both showed dose-dependent increases with significant individual differences. The elimination half-life of apatinib was9h,which was con-sistent among the three groups.In the750mg group, 11patients enrolled in the multiple dosing study and received apatinib750mg daily.Plasma drug concentrations were titrated at days1,6,28,and56.The results showed that both C max and AUC0--24h at day6were higher than those at day1,but there were no further increases after day6,indi-cating that apatinib has little accumulation in patients[24].

3.Clinical efficacy

3.1Phase I and II studies

The Phase I study of apatinib recruited46patients with advanced solid tumors for whom no standard treatment was available.Among the46patients,34had gastrointestinal cancer,3had lung cancer,3had breast cancer,and6had other types of cancer.Apatinib250,500,750,850or 1000mg per day was given using the standard3+3dose-escalation method.The study found that the maximum toler-ated dose of apatinib was850mg/day and a dose of750mg/ day was chosen for the anti-tumor study[24].

Of37evaluable patients,7achieved partial response(PR), including3with colon cancer,1with gastric cancer,1with gastrointestinal stromal tumor,1with kidney cancer and 1with an unknown primary cancer.Twenty-four patients were defined as having stable disease and the disease control rate(DCR)was83.8%[24].

Li et al.conducted a multi-center,Phase II,clinical study of apatinib and recruited144patients with advanced metastatic gastric cancer in whom second-line or above chemotherapy had failed.Patients were randomly assigned to receive placebo (group A,n=48),oral apatinib850mg once daily(q.d.; group B,n=47),or oral apatinib425mg twice daily (b.i.d.;group C,n=46).The primary end point was progression-free survival(PFS).The median age of the patients was54,55,and53years,respectively,and male patients were75,83,and74%,respectively.The Eastern Cooperative Oncology Group performance status scores of all patients were0--1.Metastatic sites were the liver(48, 60,43%for groups A,B,and C,respectively),lung(19,11, and24%,respectively),and retroperitoneal lymph nodes (23,19,and24%,respectively).The median PFS(mPFS) for groups A,B,and C were1.4months(95%confidence interval[CI], 1.20-- 1.83months), 3.7months(95% CI, 2.17-- 6.80months)and 3.2months(95%CI, 2.37--4.53months),respectively.The median OS(mOS) for groups A,B and C were 2.5months(95%CI, 1.87-- 3.70months), 4.83months(95%CI, 4.03--5.97months)and 4.27months(95%CI, 3.83--4.77months),https://www.wendangku.net/doc/f614581445.html,pared with group A,the mPFS and mOS of groups B and C were significantly pro-longed(mPFS:group B vs group A,p<0.001,group C vs group A,p<0.001;mOS:group B vs group A,p<0.001, group C vs group A,p=0.0017).In the objective response rate(ORR)assessment,9patients(3from group B and 6from group C)achieved PR.In the DCR assessment, intent-to-treat analysis found that groups B and C had higher DCRs than group A:group A,5patients(10.42%);group B, 24patients(51.06%);and group C,16patients(34.78%)[25].

3.2Phase III studies

A multi-center,randomized,double-blind,placebo-controlled Phase III study of apatinib has recently been com-pleted.A total of273patients were randomly assigned to oral apatinib850mg q.d.(28-day treatment cycles)or placebo at a ratio of2:1.The primary end point was OS.Patients receiving apatinib had significantly prolonged mOS(195vs140days; hazard ratio[HR]=0.71;95%CI,0.54--0.94;p<0.016) and mPFS(78vs53days;HR=0.44;95%CI, 0.33--0.61;p<0.0001)compared with those receiving pla-cebo.The ORRs for the apatinib and placebo groups were 2.84and0.00%,respectively[26].

4.Safety and tolerability

Apatinib is an oral drug with a good safety profile.During the Phase I clinical trial of37evaluable patients,the three most common adverse events(AEs)were hypertension(69.5%, n=3for grade3--4),proteinuria(47.8%,n=6for grade 3--4),and hand-foot syndrome(45.6%,n=6for grade 3--4).After the treatment stopped,these reactions were alleviated to some degree.Other minor AEs included pain, thrombocytopenia,fatigue and hyperbilirubinemia.In the group receiving apatinib1000mg q.d.,two patients demon-strated dose-limiting toxicity;namely,grade4hematologic AEs or grade3--4non-hematologic AEs.Among the 37patients,15completed at least1week of apatinib treat-ment at the original doses,1from the apatinib250mg q.d. group withdrew due to disease progression,and3from the

Apatinib

Expert Opin.Pharmacother.(2015)16(1)119

apatinib1000mg q.d.group withdrew because of AEs, whereas the remaining18patients completed the study with decreased dosing[24].

Apatinib also showed acceptable tolerability in a Phase II study.Grade3--4AEs occurring in>5%of patients included hand--foot syndrome,hypertension,thrombocyto-penia,anemia,liver function impairment(elevated amino-transferase and bilirubin)and diarrhea.Grade3--4AEs reported in>10%of patients were hand--foot syndrome and high blood pressure.Fatigue,a common symptom among patients with advanced tumors,was present for 10.4,17.0,and15.2%of patients in the placebo,apatinib 850mg q.d.,and apatinib425mg b.i.d.groups,respectively. Severe fatigue(grade3--4)was present at a rate of~2%in each of the3groups[25].

A Phase III clinical study further reinforced the general tolerability of apatinib.About60%of patients experienced grade3--4AEs,which included hypertension,hand--foot syndrome,proteinuria,fatigue,anorexia and elevated ami-notransferase.The rate of grade3--4AEs in the apatinib arm was significantly higher than that in the placebo arm (41%,p=0.0045),whereas no significant difference in severe AEs was observed between the two groups.The AEs were manageable and reversible,and patients were treated with symptomatic therapy and dose interruptions or reductions[26].

5.Regulatory affairs

Based on the results of a Phase III clinical trial in China,apa-tinib has been approved by the Chinese Food and Drug Administration recently.

6.Conclusion

To date,there has been no standard treatment strategy for patients with advanced metastatic gastric cancer who have failed at least two chemotherapeutic regimens.The develop-ment of apatinib has shown the potential of the anti-VEGFR-2strategy in the treatment of patients with advanced metastatic gastric cancer.As a novel oral small molecule VEGFR-2inhibitor,apatinib has demonstrated good safety, tolerability and efficacy in these patients.Given the positive results obtained in the Phase III clinical study,apatinib offers a new option for patients with advanced metastatic gastric cancer.

7.Expert opinion

The results for apatinib in the Phase III study are definitely exciting.For patients with advanced metastatic gastric cancer, the total OS is about1year,and treatment with apatinib could prolong survival by nearly2months when patients have previously failed with second-line chemotherapy.As anti-VEGFR-2drugs,ramucirumab and apatinib share some similarities.In the REGARD and the Phase III apatinib stud-ies of patients with previously treated gastric cancer,both drugs achieved>1month mOS(1.8and1.4months for ramucirumab and apatinib,respectively)and mPFS of 0.8months(for both drugs).The difference between the two studies is that apatinib was given as third-line treatment and ramucirumab was given as second-line therapy.Heavily treated patients receiving apatinib seemed to experience more AEs than those receiving ramucirumab.It has been reported that the only AE in the ramucirumab group that occurred more commonly than in the placebo group was hypertension,whereas apatinib is associated with proteinuria, hypertension,and hand--foot syndrome.All toxicities occurring in apatinib-treated patients are related to antiangio-genesis,as reported previously for other VEGF/VEGFR inhibitors.There have been no new toxicities found for apatinib.

In terms of patient populations,REGARD is a worldwide study that enrolled patients from29countries,including Caucasians and Asians.However,in the RAINBOW study, ramucirumab did not show additional survival benefit in the Asian population when compared with the control[27].The Phase III clinical trial of apatinib was conducted in China. Its global significance is limited until it has been tested and proven to be effective in other populations.A Phase I clinical trial has therefore been started in the US and South Korea (NCT01726101)[28],which is recruiting participants currently.

As bevacizumab failed to benefit survival in first-line treat-ment of gastric cancer[13,29],researchers are not optimistic about an anti-VEGF/VEGFR strategy in the first-line setting. It is widely accepted that any following treatment will dilute the marginal benefit of first-line treatment if OS is designated as a primary end point.This may be why there is no plan to conduct clinical trials in patients with previously untreated advanced gastric cancer.However,other indications for apati-nib could be other previously treated solid tumors.Current clinical studies of apatinib in lung[30,31],breast[32]and liver[33]cancers have all been in the chemotherapy-refractory setting.

A challenge to the use of apatinib is the need to find bio-markers to predict drug efficacy.A study of biomarkers for apatinib in breast cancer patients showed that both hyperten-sion and high expression of p-VEGFR2could be biomarkers for good treatment efficacy[34].Moreover,in the biomarker analysis of the Avastin in Gastric Cancer trial,bevacizumab response was positively correlated with the levels of VEGF-A in plasma and neuropilin-1in tumor tissue[35].However, there has been no final outcome on finding biomarkers for antiangiogenesis drugs,although reliable biomarkers are of great importance,both for individualized treatment and for improving efficacy.

Drug resistance is a problem encountered with every tar-geted therapy,and this does occur with apatinib.Drug resis-tance is especially important for patients who proceed to

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120Expert Opin.Pharmacother.(2015)16(1)

second-line or above chemotherapy because there are no fur-ther drugs available once resistance to apatinib occurs.Many studies of resistance of antiangiogenic agents have shown that resistance is mainly related to activation of cell adhesion-associated or other growth-associated signaling pathways[36,37],implying that blockage of these pathways may solve the problem.Solving the drug resistance issue would be a major benefit to antiangiogenic therapy.Declaration of interest

The authors have no relevant affiliations or financial involve-ment with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.This includes employment,con-sultancies,honoraria,stock ownership or options,expert testi-mony,grants or patents received or pending,or royalties.

Bibliography

Papers of special note have been highlighted as either of interest( )or of considerable interest ( )to readers.

1.Folkman J,Merler E,Abernathy C,et al.

Isolation of a tumor factor responsible

for angiogenesis.J Exp Med

1971;133:275-88

2.Hicklin DJ,Ellis LM.Role of the

vascular endothelial growth factor

pathway in tumor growth and

angiogenesis.J Clin Oncol

2005;23:1011-27

3.Amedei A,Munari F,Bella CD,et al.

Helicobacter pylori secreted peptidyl

prolyl cis,trans-isomerase drives

Th17inflammation in gastric

adenocarcinoma.Intern Emerg Med

2014;9:303-9

4.Hirashima Y,Yamada Y,Matsubara J,

et al.Impact of vascular endothelial

growth factor receptor1,2,and

3expression on the outcome of patients

with gastric cancer.Cancer Sci

2009;100:310-15

5.Jemal A,Bray F,Center MM,et al.

Global cancer statistics.

CA Cancer J Clin2011;61:69-90

6.Crew KD,Neugut AI.Epidemiology of

upper gastrointestinal malignancies.

Semin Oncol2004;31:450-64

7.Glimelius B,Ekstr€o m K,Hoffman K,

et al.Randomized comparison between

chemotherapy plus best supportive care

with best supportive care in advanced

gastric cancer.Ann Oncol1997;8:163-8 8.Cunningham D,Starling N,Rao S,et al.

Capecitabine and oxaliplatin for

advanced esophagogastric cancer.N Engl

J Med2008;358:36-46

9.Thuss-Patience PC,Kretzschmar A,

Bichev D,et al.Survival advantage for

irinotecan versus best supportive care as

second-line chemotherapy in gastric

cancer--a randomised phase III study of

the Arbeitsgemeinschaft Internistische

Onkologie(AIO).Eur J Cancer

2011;47:2306-14

10.Kang JH,Lee SI,Lim do H,et al.

Salvage chemotherapy for pretreated

gastric cancer:a randomized phase III

trial comparing chemotherapy plus best

supportive care with best supportive care

alone.J Clin Oncol2012;30:1513-18

11.Ford HE,Marshall A,Bridgewater JA,

et al.Docetaxel versus active symptom

control for refractory oesophagogastric

adenocarcinoma(COUGAR-02):

an open-label,phase3randomised

controlled https://www.wendangku.net/doc/f614581445.html,ncet Oncol

2014;15:78-86

12.Bang YJ,Van Cutsem E,Feyereislova A,

et al.Trastuzumab in combination with

chemotherapy versus chemotherapy alone

for treatment of HER2-positive advanced

gastric or gastro-oesophageal junction

cancer(ToGA):a phase3,open-label,

randomised controlled https://www.wendangku.net/doc/f614581445.html,ncet

2010;376(9742):687-97

13.Ohtsu A,Shah MA,Van Cutsem E,

et al.Bevacizumab in combination with

chemotherapy as first-line therapy in

advanced gastric cancer:a randomized,

double-blind,placebo-controlled phase

III study.J Clin Oncol2011;29:3968-76

14.Ohtsu A,Ajani JA,Bai YX,et al.

Everolimus for previously treated

advanced gastric cancer:results of the

randomized,double-blind,phase III

GRANITE-1study.J Clin Oncol

2013;31:3935-43

15.Okines AF,Ashley SE,Cunningham D,

et al.Epirubicin,oxaliplatin,and

capecitabine with or without

panitumumab for advanced

esophagogastric cancer:dose-finding

study for the prospective multicenter,

randomized,phase II/III REAL-3trial.

J Clin Oncol2010;28:3945-50

16.Lordick F,Kang YK,Chung HC,et al.

Capecitabine and cisplatin with or

without cetuximab for patients with

previously untreated advanced gastric

cancer(EXPAND):a randomised,open-

label https://www.wendangku.net/doc/f614581445.html,ncet Oncol

2013;14:490-9

17.Satoh T,Xu RH,Chung HC,et al.

Lapatinib plus paclitaxel versus paclitaxel

alone in the second-line treatment of

HER2-amplified advanced gastric cancer

in Asian populations:tyTAN-a

randomized,phase III study.

J Clin Oncol2014;32:2039-49

18.Fuchs CS,Tomasek J,Yong CJ,et al.

Ramucirumab monotherapy for

previously treated advanced gastric or

gastro-oesophageal junction

adenocarcinoma(REGARD):

an international,randomised,

multicentre,placebo-controlled,

https://www.wendangku.net/doc/f614581445.html,ncet

2014;383(9911):31-9

.Phase III trial demonstrating benefit of

ramucirumab in second-line treatment

of advanced gastric cancer or

gastro-esophageal

junction adenocarcinoma.

19.Wilke H,Muro K,Van Cutsem E,et al.

Ramucirumab plus paclitaxel versus

placebo plus paclitaxel in patients with

previously treated advanced gastric or

gastro-oesophageal junction

adenocarcinoma(RAINBOW):a double-

blind,randomised phase3trial.

Lancet Oncol2014;15:1224-35

20.Tian S,Quan H,Xie C,et al.

YN968D1is a novel and selective

inhibitor of vascular endothelial growth

factor receptor-2tyrosine kinase with

potent activity in vitro and in vivo.

Cancer Sci2011;102:1374-80

.First study to demonstrate efficacy of

apatinib in vivo.

21.Mi YJ,Liang YJ,Huang HB,et al.

Apatinib(YN968D1)reverses multidrug

resistance by inhibiting the efflux

function of multiple ATP-binding

cassette transporters.Cancer Res

2010;70:7981-91

Apatinib Expert Opin.Pharmacother.(2015)16(1)121

22.Tong XZ,Wang F,Liang S,et al.

Apatinib(YN968D1)enhances the

efficacy of conventional

chemotherapeutical drugs in side

population cells and ABCB1-

overexpressing leukemia cells.

Biochem Pharmacol2012;83:586-97 23.Ding J,Chen X,Gao Z,et al.

Metabolism and pharmacokinetics of

novel selective vascular endothelial

growth factor receptor-2inhibitor

apatinib in humans.Drug Metab Dispos

2013;41:1195-210

24.Li J,Zhao X,Chen L,et al.Safety and

pharmacokinetics of novel selective

vascular endothelial growth factor

receptor-2inhibitor YN968D1in

patients with advanced malignancies.

BMC Cancer2010;10:529

..Phase I study of apatinib in advanced solid tumors.

25.Li J,Qin S,Xu J,et al.Apatinib for

chemotherapy-refractory advanced

metastatic gastric cancer:results from a

randomized,placebo-controlled,parallel-

arm,phase II trial.J Clin Oncol

2013;31:3219-25

..Phase II study of apatinib

demonstrating benefit in

chemotherapy-refractory advanced

metastatic gastric cancer.

26.Qin S.Phase III study of apatinib in

advanced gastric cancer:A randomized,

double-blind,placebo-controlled trial.

J Clin Oncol

2014;32(15Suppl):abstract4003

..Phase III study of apatinib

demonstrating effectiveness in third-

line chemotherapy for advanced

gastric cancer.

27.Hironaka S,Shimada Y,Sugimoto N,

et al.RAINBOW:a global,phase III,

randomized,double-blind study of

ramucirumab(RAM)plus paclitaxel

(PTX)versus placebo(PL)plus PTX in

the treatment of metastatic

gastroesophageal junction and gastric

adenocarcinoma(mGC)following disease

progression on first-line platinum-and

fluoropyrimidine-containing combination

therapy--Efficacy analysis in Japanese and

Western patients.J Clin Oncol

2014;32(15Suppl):abstract4005

28.Dose-escalation and safety trial of

YN968D1.Available from:http://

https://www.wendangku.net/doc/f614581445.html,/ct2/show/NCT01726101

[Last accessed20October2014]

29.Shen L,Li J,Xu J,et al.Bevacizumab

plus capecitabine and cisplatin in

Chinese patients with inoperable locally

advanced or metastatic gastric or

gastroesophageal junction cancer:

randomized,double-blind,phase III

study(AVATAR study).Gastric Cancer

2014.[Epub ahead of print]

30.A study of apatinib in patients with

advanced non-squamous and non-small

cell lung cancer.Available from:http://

https://www.wendangku.net/doc/f614581445.html,/ct2/show/NCT01270386

[Last accessed20October2014]

31.Apatinib in the treatment of advanced

non-squamous non-small cell lung

cancer.Available from:http://

https://www.wendangku.net/doc/f614581445.html,/ct2/show/NCT01287962

[Last accessed20October2014]

32.Hu X,Zhang J,Xu B,et al.Multicenter

phase II study of apatinib,a novel

VEGFR inhibitor in heavily pretreated

patients with metastatic triple-negative

breast cancer.Int J Cancer

2014;135:1961-9

.Phase II study of apatinib in

metastatic triple-negative breast cancer.

33.Qin S.Apatinib in Chinese patients with

advanced hepatocellular carcinoma:

a phase II randomized,open-label trial.

J Clin Oncol

2014;32(15Suppl):abstract4019

34.Fan M,Zhang J,Wang Z,et al.

Phosphorylated VEGFR2and

hypertension:potential biomarkers to

indicate VEGF-dependency of advanced

breast cancer in anti-angiogenic therapy.

Breast Cancer Res Treat

2014;143:141-51

.First study to show p-VEGFR2as a

potential biomarker for apatinib.

35.Van Cutsem E,de Haas S,Kang YK,

et al.Bevacizumab in combination with

chemotherapy as first-line therapy in

advanced gastric cancer:a biomarker

evaluation from the AVAGAST

randomized phase III trial.J Clin Oncol

2012;30:2119-27

36.Jahangiri A,Aghi MK,Carbonell WS.

b1integrin:Critical path to

antiangiogenic therapy resistance and

beyond.Cancer Res2014;74:3-7

37.Soda Y,Myskiw C,Rommel A,

Verma IM.Mechanisms of

neovascularization and resistance to anti-

angiogenic therapies in glioblastoma

multiforme.J Mol Med(Berl)

2013;91:439-48

Affiliation

Ruixuan Geng1MD&Jin Li?2MD PhD

?Author for correspondence

1Fudan University Shanghai Cancer Center,

Shanghai Medical College,Department of

Medical Oncology,Shanghai200032,China

2Professor and Dean,

Fudan University Shanghai Cancer Center,

Shanghai Medical College,Department of

Medical Oncology,Shanghai200032,China

Tel:+862164433755;

Fax:+862164170366;

E-mail:fudanlijin@https://www.wendangku.net/doc/f614581445.html,

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122Expert Opin.Pharmacother.(2015)16(1)

的、地、得的用法和区别

“的、地、得”的用法和区别 导入（进入美妙的世界啦~） “的、地、得”口诀儿歌 的地得，不一样，用法分别记心上， 左边白，右边勺，名词跟在后面跑。 美丽的花儿绽笑脸，青青的草儿弯下腰， 清清的河水向东流，蓝蓝的天上白云飘， 暖暖的风儿轻轻吹，绿绿的树叶把头摇， 小小的鱼儿水中游，红红的太阳当空照， 左边土，右边也，地字站在动词前， 认真地做操不马虎，专心地上课不大意， 大声地朗读不害羞，从容地走路不着急， 痛快地玩耍来放松，用心地思考解难题， 勤奋地学习要积极，辛勤地劳动花力气， 左边两人双人得，形容词前要用得， 兔子兔子跑得快，乌龟乌龟爬得慢， 青青竹子长得快，参天大树长得慢， 清晨锻炼起得早，加班加点睡得晚， 欢乐时光过得快，考试题目出得难。 知识典例（注意咯，下面可是黄金部分！） 的、地、得 “的”、“地”、“得”的用法区别本是中小学语文教学中最基本的常识，但在使用中也最容易发生混淆，再加上一段时间里，中学课本中曾将这三个词的用法统一为“的”，因此造成了很多人对它们的用法含混不清进而乱用一通的现象。

一、“的、地、得”的基本概念 1、“的、地、得”的相同之处。 “的、地、得”是现代汉语中高频度使用的三个结构助词，都起着连接作用；它们在普通话中都读轻声“de”，没有语音上的区别。 2、“的、地、得”的不同之处。 吕叔湘、朱德熙所著《语法修辞讲话》认为“的”兼职过多，负担过重，而力主“的、地、得”严格分工。50 年代以来的诸多现代汉语论著和教材，一般也持这一主张。从书面语中的使用情况看，“的”与“地”、“得”的分工日趋明确，特别是在逻辑性很强的论述性、说明性语言中，如法律条款、学术论著、外文译著、教科书等，更是将“的”与“地”、“得”分用。 “的、地、得”在普通话里都读轻声“de”，但在书面语中有必要写成三个不同的字：在定语后面写作“的”，在状语后面写作“地”，在补语前写作“得”。这样做的好处，就是可使书面语言精确化。 二、“的、地、得”的用法 1、的——定语的标记，一般用在主语和宾语的前面。“的”前面的词语一般用来修饰、限制“的”后面的事物，说明“的”后面的事物怎么样。结构形式一般为：形容词、名词（代词）+的+名词。如： ①颐和园(名词)的湖光山色（主语）美不胜收。 ②她是一位性格开朗的女子(名词，宾语)。 2、地——状语的标记，一般用在谓语（动词、形容词）前面。“地”前面的词语一般用来形容“地”后面的动作，说明“地”后面的动作怎么样。结构方式一般为：形容词（副词）+地+动词（形容词）。如： ③她愉快(形容词)地接受(动词，谓语)了这件礼物。 ④天渐渐(时间副词)地冷(形容词，谓语)起来。 3、得——补语的标记，一般用在谓语后面。“得”后面的词语一般用来补充说明“得”前面的动作怎么样，结构形式一般为：动词（形容词）+得+副词。如： ⑤他们玩(动词，谓语)得真痛快(补语)。

of与for的用法以及区别

of与for的用法以及区别 for 表原因、目的 of 表从属关系 介词of的用法 （1）所有关系 this is a picture of a classroom （2）部分关系 a piece of paper a cup of tea a glass of water a bottle of milk what kind of football，American of soccer？ （3）描写关系 a man of thirty 三十岁的人 a man of shanghai 上海人 （4）承受动作 the exploitation of man by man．人对人的剥削。 （5）同位关系 It was a cold spring morning in the city of London in England． （6）关于，对于 What do you think of Chinese food？ 你觉得中国食品怎么样？ 介词 for 的用法小结 1. 表示“当作、作为”。如: I like some bread and milk for breakfast. 我喜欢把面包和牛奶作为早餐。What will we have for supper? 我们晚餐吃什么?

2. 表示理由或原因,意为“因为、由于”。如: Thank you for helping me with my English. 谢谢你帮我学习英语。 Thank you for your last letter. 谢谢你上次的来信。 Thank you for teaching us so well. 感谢你如此尽心地教我们。 3. 表示动作的对象或接受者,意为“给……”、“对…… (而言)”。如: Let me pick it up for you. 让我为你捡起来。 Watching TV too much is bad for your health. 看电视太多有害于你的健康。 4. 表示时间、距离,意为“计、达”。如: I usually do the running for an hour in the morning. 我早晨通常跑步一小时。We will stay there for two days. 我们将在那里逗留两天。 5. 表示去向、目的,意为“向、往、取、买”等。如: let’s go for a walk. 我们出去散步吧。 I came here for my schoolbag.我来这儿取书包。 I paid twenty yuan for the dictionary. 我花了20元买这本词典。 6. 表示所属关系或用途,意为“为、适于……的”。如: It’s time for school. 到上学的时间了。 Here is a letter for you. 这儿有你的一封信。 7. 表示“支持、赞成”。如: Are you for this plan or against it? 你是支持还是反对这个计划? 8. 用于一些固定搭配中。如: Who are you waiting for? 你在等谁? For example, Mr Green is a kind teacher. 比如,格林先生是一位心地善良的老师。

to与for的用法和区别

to与for的用法和区别 一般情况下, to后面常接对象; for后面表示原因与目的为多。 Thank you for helping me. Thanks to all of you. to sb.表示对某人有直接影响比如，食物对某人好或者不好就用to; for表示从意义、价值等间接角度来说，例如对某人而言是重要的，就用for. for和to这两个介词，意义丰富，用法复杂。这里仅就它们主要用法进行比较。 1. 表示各种“目的” 1. What do you study English for? 你为什么要学英语？ 2. She went to france for holiday. 她到法国度假去了。 3. These books are written for pupils. 这些书是为学生些的。 4. hope for the best, prepare for the worst. 作最好的打算，作最坏的准备。 2．对于 1．She has a liking for painting. 她爱好绘画。 2．She had a natural gift for teaching. 她对教学有天赋/ 3．表示赞成同情，用for不用to. 1. Are you for the idea or against it? 你是支持还是反对这个想法？ 2. He expresses sympathy for the common people.. 他表现了对普通老百姓的同情。 3. I felt deeply sorry for my friend who was very ill. 4 for表示因为，由于（常有较活译法） 1 Thank you for coming. 谢谢你来。 2. France is famous for its wines. 法国因酒而出名。 5．当事人对某事的主观看法，对于（某人），对…来说（多和形容词连用）用介词to，不用for.. He said that money was not important to him. 他说钱对他并不重要。 To her it was rather unusual. 对她来说这是相当不寻常的。 They are cruel to animals. 他们对动物很残忍。 6．for和fit, good, bad, useful, suitable 等形容词连用，表示适宜，适合。 Some training will make them fit for the job. 经过一段训练，他们会胜任这项工作的。 Exercises are good for health. 锻炼有益于健康。 Smoking and drinking are bad for health. 抽烟喝酒对健康有害。 You are not suited for the kind of work you are doing. 7. for表示不定式逻辑上的主语，可以用在主语、表语、状语、定语中。 1．It would be best for you to write to him. 2．The simple thing is for him to resign at once. 3．There was nowhere else for me to go. 4．He opened a door and stood aside for her to pass.

“的、地、得”的用法和区别

的、地、得的用法和区别 的、地、得的用法和区别老班教育 一、的、地、得的基本概念 1、的、地、得的相同之处。 的、地、得是现代汉语中高频度使用的三个结构助词，都起着连接作用；它们在普通话中都读轻声de，没有语音上的区别。 2、的、地、得的不同之处。 吕叔湘、朱德熙所著《语法修辞讲话》认为的兼职过多，负担过重，而力主的、地、得严格分工。50 年代以来的诸多现代汉语论著和教材，一般也持这一主张。从书面语中的使用情况看，的与地、得的分工日趋明确，特别是在逻辑性很强的论述性、说明性语言中，如法律条款、学术论著、外文译著、教科书等，更是将的与地、得分用。 的、地、得在普通话里都读轻声de，但在书面语中有必要写成三个不同的字：在定语后面写作的，在状语后面写作地，在补语前写作得。这样做的好处，就是可使书面语言精确化。 二、的、地、得的用法 （一）、用法 1、的——定语的标记，一般用在主语和宾语的前面。的前面的词语一般用来修饰、限制的后面的事物，说明的后面的事物怎么样。 结构形式一般为：形容词、名词（代词）+的+名词。如： 颐和园(名词)的湖光山色（主语）美不胜收。 她是一位性格开朗的女子(名词，宾语)。 2、地——状语的标记，一般用在谓语（动词、形容词）前面。地前面的词语一般用来形容地后面的动作，说明地后面的动作怎么样。 结构方式一般为：形容词（副词）+地+动词（形容词）。如： 她愉快(形容词)地接受(动词，谓语)了这件礼物。 天渐渐(时间副词)地冷(形容词，谓语)起来。 3、得——补语的标记，一般用在谓语后面。得后面的词语一般用来补充说明得前面的动作怎么样。 结构形式一般为：动词（形容词）+得+副词。如： 他们玩(动词，谓语)得真痛快(补语)。 她红(形容词，谓语)得发紫(补语)。 （二）、例说 的，一般用在名词和形容词的后面，用在描述或限制人物、事物时，形容的词语与被形容的词语之间，表示一种描述的结果。如：漂亮的衣服、辽阔的土地、高大的山脉。结构一般为名词（代词或形容词）+的+名词。如，我的书、你的衣服、他的孩子，美丽的景色、动听的歌曲、灿烂的笑容。 地，用法简单些，用在描述或限制一种运动性质、状态时，形容的词语与被形容的词语之间。结构通常是形容词+地+动词。前面的词语一般用来形容后面的动作。一般地的后面只跟动词。比如高兴地跳、兴奋地叫喊、温和地说、飞快地跑；匆匆地离开；慢慢地移动......... 得，用在说明动作的情况或结果的程度时，说明的词语与被说明的词语之间，后面的词语一般用来补充和说明前面的情况。比如。跑得飞快、跳得很高、显得高雅、显得很壮、馋得直流口水、跑得快、飞得高、走得慢、红得很……得通常用在动词和形容词（动词之间）。

常用介词用法(for to with of)

For的用法 1. 表示“当作、作为”。如: I like some bread and milk for breakfast. 我喜欢把面包和牛奶作为早餐。 What will we have for supper? 我们晚餐吃什么? 2. 表示理由或原因,意为“因为、由于”。如: Thank you for helping me with my English. 谢谢你帮我学习英语。 3. 表示动作的对象或接受者,意为“给……”、“对…… (而言)”。如: Let me pick it up for you. 让我为你捡起来。 Watching TV too much is bad for your health. 看电视太多有害于你的健康。 4. 表示时间、距离,意为“计、达”。如: I usually do the running for an hour in the morning. 我早晨通常跑步一小时。 We will stay there for two days. 我们将在那里逗留两天。 5. 表示去向、目的,意为“向、往、取、买”等。如: Let’s go for a walk. 我们出去散步吧。 I came here for my schoolbag.我来这儿取书包。 I paid twenty yuan for the dictionary. 我花了20元买这本词典。 6. 表示所属关系或用途,意为“为、适于……的”。如: It’s time for school. 到上学的时间了。 Here is a letter for you. 这儿有你的一封信。 7. 表示“支持、赞成”。如: Are you for this plan or against it? 你是支持还是反对这个计划? 8. 用于一些固定搭配中。如: Who are you waiting for? 你在等谁? For example, Mr Green is a kind teacher. 比如,格林先生是一位心地善良的老师。 尽管for 的用法较多，但记住常用的几个就可以了。 to的用法: 一：表示相对，针对 be strange (common, new, familiar, peculiar) to This injection will make you immune to infection. 二：表示对比，比较 1：以-ior结尾的形容词，后接介词to表示比较，如：superior ,inferior,prior,senior,junior 2: 一些本身就含有比较或比拟意思的形容词，如equal，similar，equivalent，analogous A is similar to B in many ways.

(完整版)介词for用法归纳

介词for用法归纳 用法1：(表目的)为了。如： They went out for a walk. 他们出去散步了。 What did you do that for? 你干吗这样做？ That’s what we’re here for. 这正是我们来的目的。 What’s she gone for this time? 她这次去干什么去了？ He was waiting for the bus. 他在等公共汽车。 【用法说明】在通常情况下，英语不用for doing sth 来表示目的。如： 他去那儿看他叔叔。 误：He went there for seeing his uncle. 正：He went there to see his uncle. 但是，若一个动名词已名词化，则可与for 连用表目的。如： He went there for swimming. 他去那儿游泳。(swimming 已名词化) 注意：若不是表目的，而是表原因、用途等，则其后可接动名词。(见下面的有关用法) 用法2：(表利益)为，为了。如： What can I do for you? 你想要我什么？ We study hard for our motherland. 我们为祖国努力学习。 Would you please carry this for me? 请你替我提这个东西好吗？ Do more exercise for the good of your health. 为了健康你要多运动。 【用法说明】(1) 有些后接双宾语的动词(如buy, choose, cook, fetch, find, get, order, prepare, sing, spare 等)，当双宾语易位时，通常用for 来引出间接宾语，表示间接宾语为受益者。如： She made her daughter a dress. / She made a dress for her daughter. 她为她女儿做了件连衣裙。 He cooked us some potatoes. / He cooked some potatoes for us. 他为我们煮了些土豆。 注意，类似下面这样的句子必须用for： He bought a new chair for the office. 他为办公室买了张新办公椅。 (2) 注意不要按汉语字面意思，在一些及物动词后误加介词for： 他们决定在电视上为他们的新产品打广告。 误：They decided to advertise for their new product on TV. 正：They decided to advertise their new product on TV. 注：advertise 可用作及物或不及物动词，但含义不同：advertise sth＝为卖出某物而打广告；advertise for sth＝为寻找某物而打广告。如：advertise for a job=登广告求职。由于受汉语“为”的影响，而此处误加了介词for。类似地，汉语中的“为人民服务”，说成英语是serve the people，而不是serve for the people，“为某人的死报仇”，说成英语是avenge sb’s death，而不是avenge for sb’s death，等等。用法3：(表用途)用于，用来。如： Knives are used for cutting things. 小刀是用来切东西的。 This knife is for cutting bread. 这把小刀是用于切面包的。 It’s a machine for slicing bread. 这是切面包的机器。 The doctor gave her some medicine for her cold. 医生给了她一些感冒药。 用法4：为得到，为拿到，为取得。如： He went home for his book. 他回家拿书。 He went to his friend for advice. 他去向朋友请教。 She often asked her parents for money. 她经常向父母要钱。

的地得的用法和区分

《“的、地、得”的用法》语文微课教案 一、教学背景 在语言文字规范化大背景下，帮助学生解决应用“的地得”的疑惑与困难。 二、设计思路 针对学生对于“的地得”的误用与忽视展开教学，规范结构助词“的地得”的使用。按照“问题的提出、问题的分析、问题的解决”的思路展开教学，总结归纳优化的方式方法。 三、教学目标 1、知道“怎么样的什么、怎么样地干什么、干得怎么样”三种固定搭配。 2、掌握“的、地、得”的区别与联系。 3、运用小儿歌“动前土、名前白、行动后面双人来”的口诀帮助正确使用“的、地、得”。 四、教学重难点 1、知道“的、地、得”的区别。 2、在实际情境中正确运用“的、地、得”。 五、教学时间 8分钟微课堂 六、教学适用对象 义务教育九年制内的学生 七、教学准备

多媒体课件、录屏软件 八、教学设计与过程 开场白： 同学们好！今天我们一起来学习“的、地、得”的正确用法。首先我们来了解一下它们的区别。 1、相同之处：原来它们都是念轻声“de”，都是结构助词，起连接作用。 2、不同之处：在书面语中要写成三个不同的字，而且它们的搭配及用法也各不相同。 （1）怎么样的什么 （2）怎样样地干什么 （3）干得怎么样 下面我们就来学习一下它们的正确用法。 白勺“的”的结构是用“形容词或名词或代词+的+名词”来表示，而我们最常见，用得最多的还是“形容词+的+名词”的结构。 而土也“地”的用法可以用“形容词+地+动词”的结构来表示。 双人“得”是用“动词+得+形容词”的结构来表示 3、练习巩固 （1）形近区分 静静（的）河面静静（地）写字欢乐（的）山谷

欢乐（地）歌唱满意（地）点头满意（的）作品 （2）类别区分 1）跑（得）飞快飞快（地）跑 2）愉快（的）旅行旅行（得）愉快 3）强烈（的）渴望强烈（地）渴望 （3）综合杂糅 小雏鹰飞到大树的上方，高兴地喊起来：“我真的会飞啦！而且飞（得）很高呢！” 小结：能填对这个句子的你肯定就已经学会它们的用法了！ 4、特殊情况 质疑：假如遇到特殊情况怎么办呢？ 我从书包里拿出书交给她们，她们高兴得．围着我跳起舞来。（出自二年级上册《日记两则》） （1）质疑：为什么这里要使用“得”呢？ （2）释疑：原来这里强调的是心情，动词在后，形容词在前，相当于后置，“得”修饰“跳舞”而非“围”。现在你明白了吧？ 5、小结归纳： 怎么样，你们学会了吗？为了让同学们能够更快的记住它们的用法，老师送给大家一首口诀来帮助你们熟记三个“的”的正确使用方法：动前土、名前白、行动后面双人来。

of和for的用法

of 1....的,属于 One of the legs of the table is broken. 桌子的一条腿坏了。 Mr.Brown is a friend of mine. 布朗先生是我的朋友。 2.用...做成的;由...制成 The house is of stone. 这房子是石建的。 3.含有...的;装有...的 4....之中的;...的成员 Of all the students in this class,Tom is the best. 在这个班级中,汤姆是最优秀的。 5.(表示同位) He came to New York at the age of ten. 他在十岁时来到纽约。 6.(表示宾格关系) He gave a lecture on the use of solar energy. 他就太阳能的利用作了一场讲演。 7.(表示主格关系) We waited for the arrival of the next bus. 我们等待下一班汽车的到来。

I have the complete works of Shakespeare. 我有莎士比亚全集。 8.来自...的;出自 He was a graduate of the University of Hawaii. 他是夏威夷大学的毕业生。 9.因为 Her son died of hepatitis. 她儿子因患肝炎而死。 10.在...方面 My aunt is hard of hearing. 我姑妈耳朵有点聋。 11.【美】(时间)在...之前 12.(表示具有某种性质) It is a matter of importance. 这是一件重要的事。 For 1.为,为了 They fought for national independence. 他们为民族独立而战。 This letter is for you. 这是你的信。

双宾语 to for的用法

1.两者都可以引出间接宾语，但要根据不同的动词分别选用介词to 或for：(1) 在give, pass, hand, lend, send, tell, bring, show, pay, read, return, write, offer, teach, throw 等之后接介词to。 如： 请把那本字典递给我。 正：Please hand me that dictionary. 正：Please hand that dictionary to me. 她去年教我们的音乐。 正：She taught us music last year. 正：She taught music to us last year. (2) 在buy, make, get, order, cook, sing, fetch, play, find, paint, choose,prepare, spare 等之后用介词for 。如： 他为我们唱了首英语歌。 正：He sang us an English song. 正：He sang an English song for us. 请帮我把钥匙找到。 正：Please find me the keys. 正：Please find the keys for me. 能耽搁你几分钟吗(即你能为我抽出几分钟吗)? 正：Can you spare me a few minutes? 正：Can you spare a few minutes for me? 注：有的动词由于搭配和含义的不同，用介词to 或for 都是可能的。如：do sb a favour＝do a favour for sb 帮某人的忙 do sb harm＝do harm to sb 对某人有害

的地得的用法教案

“的、地、得”的用法教案 教学目标： 1.能通过看视频知道“的、地、得”的用法区别。 2.能在小组合作中正确掌握“的、地、得”的用法。 3.能正确熟练地运用“的、地、得”。 教学重点：通过看视频知道“的、地、得”的用法区别。 教学难点：正确熟练地运用“的、地、得”。 教学过程： 一、导入（板书课题：“的、地、得”的用法“的、地、得”） 这三个字认识吧！虽然它们都有一个相同的读音de，但用法却不一样，可不能把他们用错了。究竟他们的用法有什么不同，我们来听听他们的故事吧！ 二、看微视频，学习“的、地、得”的用法区别。 三、小结： 1.孩子们，刚才看了视频知道他们是谁吗？（白勺的，土也地，双人得。） （1）白勺的是个杂货铺老板，她的店里都有什么？（彩色的毛巾美味的汉堡结实的帐篷舒适的儿童车捕捉风的网会唱歌的小树开个没完的花朵优美动听的歌曲飘来飘去的云……）还可能有什么？ 你们一定会发现，白勺的的用法有什么特点？（后面是名词。）板书：名词 （2）土也地是个运动男孩，他喜欢？（悠闲地散步欢快地跳舞兴奋地跳跃开心地捕蝴蝶看图书踢球骑自行洗澡吃冰淇淋……）他还可能喜欢干什么呢？你发现了吗？土也地的用法特点？（后面是动词。）板书：动词 （3）双人得呢？她是个总喜欢评价别人的小妹妹。（球踢得真棒舞跳得精彩长得好高呀……） 她可能还怎么评价别人？（歌唱得动听饭吃得很饱人长得漂亮）你们会发现，双人得的前面通常都是——动词。板书：动词 2.小结：所以，他们的用法也很简单，区别就在这里。 （白勺的用在名词前面；土也地用在动词前面；双人得用在动词后面。）你明白了吗？ 四、我来考考你们，看哪一组完成得又对又快！ 1.菜鸟级练习 2.老鸟级练习 3.大虾级练习 五、总结

for和of的用法

for的用法： 1. 表示“当作、作为”。如: I like some bread and milk for breakfast. 我喜欢把面包和牛奶作为早餐。 What will we have for supper? 我们晚餐吃什么? 2. 表示理由或原因,意为“因为、由于”。如: Thank you for helping me with my English. 谢谢你帮我学习英语。 Thank you for your last letter. 谢谢你上次的来信。 Thank you for teaching us so well. 感谢你如此尽心地教我们。 3. 表示动作的对象或接受者,意为“给……”、“对…… (而言)”。如: Let me pick it up for you. 让我为你捡起来。 Watching TV too much is bad for your health. 看电视太多有害于你的健康。 4. 表示时间、距离,意为“计、达”。如:

I usually do the running for an hour in the morning. 我早晨通常跑步一小时。 We will stay there for two days. 我们将在那里逗留两天。 5. 表示去向、目的,意为“向、往、取、买”等。如: Let’s go for a walk. 我们出去散步吧。 I came here for my schoolbag.我来这儿取书包。 I paid twenty yuan for the dictionary. 我花了20元买这本词典。 6. 表示所属关系或用途,意为“为、适于……的”。如: It’s time for school. 到上学的时间了。 Here is a letter for you. 这儿有你的一封信。 7. 表示“支持、赞成”。如: Are you for this plan or against it? 你是支持还是反对这个计划? 8. 用于一些固定搭配中。如:

for和to区别

1.表示各种“目的”，用for （1）What do you study English for 你为什么要学英语？ （2）went to france for holiday. 她到法国度假去了。 （3）These books are written for pupils. 这些书是为学生些的。 （4）hope for the best, prepare for the worst. 作最好的打算，作最坏的准备。 2．“对于”用for （1）She has a liking for painting. 她爱好绘画。 （2）She had a natural gift for teaching. 她对教学有天赋/ 3．表示“赞成、同情”，用for （1）Are you for the idea or against it 你是支持还是反对这个想法？ （2）He expresses sympathy for the common people.. 他表现了对普通老百姓的同情。 （3）I felt deeply sorry for my friend who was very ill. 4. 表示“因为，由于”（常有较活译法），用for （1）Thank you for coming. 谢谢你来。

（2）France is famous for its wines. 法国因酒而出名。 5．当事人对某事的主观看法，“对于（某人），对…来说”，（多和形容词连用），用介词to，不用for. （1）He said that money was not important to him. 他说钱对他并不重要。 （2）To her it was rather unusual. 对她来说这是相当不寻常的。 （3）They are cruel to animals. 他们对动物很残忍。 6．和fit, good, bad, useful, suitable 等形容词连用，表示“适宜，适合”，用for。（1）Some training will make them fit for the job. 经过一段训练，他们会胜任这项工作的。 （2）Exercises are good for health. 锻炼有益于健康。 （3）Smoking and drinking are bad for health. 抽烟喝酒对健康有害。 （4）You are not suited for the kind of work you are doing. 7. 表示不定式逻辑上的主语，可以用在主语、表语、状语、定语中。 （1）It would be best for you to write to him. （2） The simple thing is for him to resign at once.

英语形容词和of for 的用法

加入收藏夹 主题： 介词试题It’s + 形容词 + of sb. to do sth.和It’s + 形容词 + for sb. to do sth.的用法区别。 内容： It's very nice___pictures for me. A.of you to draw B.for you to draw C.for you drawing C.of you drawing 提交人：杨天若时间：1/23/2008 20:5:54 主题：for 与of 的辨别 内容：It's very nice___pictures for me. A.of you to draw B.for you to draw C.for you drawing C.of you drawing 答：选A 解析：该题考查的句型It’s + 形容词+ of sb. to do sth.和It’s +形容词+ for sb. to do sth.的用法区别。 “It’s + 形容词+ to do sth.”中常用of或for引出不定式的行为者，究竟用of sb.还是用for sb.，取决于前面的形容词。 1) 若形容词是描述不定式行为者的性格、品质的，如kind，good，nice，right，wrong，clever，careless，polite，foolish等，用of sb. 例： It’s very kind of you to help me. 你能帮我，真好。 It’s clever of you to work out the maths problem. 你真聪明，解出了这道数学题。 2) 若形容词仅仅是描述事物，不是对不定式行为者的品格进行评价，用for sb.，这类形容词有difficult，easy，hard，important，dangerous，（im）possible等。例： It’s very dangerous for children to cross the busy street. 对孩子们来说，穿过繁忙的街道很危险。 It’s difficult for u s to finish the work. 对我们来说，完成这项工作很困难。 for 与of 的辨别方法： 用介词后面的代词作主语，用介词前边的形容词作表语，造个句子。如果道理上通顺用of，不通则用for. 如： You are nice.(通顺，所以应用of)。 He is hard.(人是困难的，不通，因此应用for.) 由此可知，该题的正确答案应该为A项。 提交人：f7_liyf 时间：1/24/2008 11:18:42

双宾语tofor的用法

1. 两者都可以引出间接宾语，但要根据不同的动词分别选用介词to 或for： (1) 在give, pass, hand, lend, send, tell, bring, show, pay, read, return, write, offer, teach, throw 等之后接介词to。 如： 请把那本字典递给我。 正：Please hand me that dictionary. 正：Please hand that dictionary to me. 她去年教我们的音乐。 正：She taught us music last year. 正：She taught music to us last year. (2) 在buy, make, get, order, cook, sing, fetch, play, find, paint, choose,prepare, spare 等之后用介词for 。如： 他为我们唱了首英语歌。 正：He sang us an English song. 正：He sang an English song for us. 请帮我把钥匙找到。 正：Please find me the keys. 正：Please find the keys for me. 能耽搁你几分钟吗(即你能为我抽出几分钟吗)? 正：Can you spare me a few minutes? 正：Can you spare a few minutes for me? 注：有的动词由于搭配和含义的不同，用介词to 或for 都是可能的。如： do sb a favou r do a favour for sb 帮某人的忙 do sb harnn= do harm to sb 对某人有害

的 地 得 用法辨析

的、得、地的用法：动词前提土旁、动词后双人旁、一动不动白字旁 （一） 的地得，不一样，用法分别记心上， 左边白，右边勺，名词跟在后面跑。 美丽的花儿绽笑脸，青青的草儿弯下腰， 清清的河水向东流，蓝蓝的天上白云飘， 暖暖的风儿轻轻吹，绿绿的树叶把头摇， 小小的鱼儿水中游，红红的太阳当空照， 左边土，右边也，地字站在动词前， 认真地做操不马虎，专心地上课不大意， 大声地朗读不害羞，从容地走路不着急， 痛快地玩耍来放松，用心地思考解难题， 勤奋地学习要积极，辛勤地劳动花力气， 左边两人就使得，形容词前要用得， 兔子兔子跑得快，乌龟乌龟爬得慢， 青青竹子长得快，参天大树长得慢， 清晨锻炼起得早，加班加点睡得晚， 欢乐时光过得快，考试题目出得难。 （二）“的、地、得”快板 的地得、的地得，用作助词都读de. 作文写话用不准，朗读往往会念错。 有趣的活动、绿的树，活动是事，树是物。 事物前面用的字，小朋友们都记着。 认真地想、快快地跑，想跑看摸是动作。 动作前面用地字，位置千万不要挪。 看得清，记得准，唱得好，飞得高。 动作后面用得字，补充说明要记牢。 （三）“的、地、得”用法简要口诀 名词前面“白勺”“的”， 动词前面“土也”“地”， 形容动后“双人”“得”， 当作助词都读“de”。 二、“的、地、得”用法小析 “的”后面跟的都是表示事物名称的词或词语，如：敬爱的总理、慈祥的老人、戴帽子的男孩、珍贵的教科书、鸟的天堂、伟大的祖国、有趣的情节、优雅的环境、可疑的情况、团结友爱的集体、他的妈妈、可爱的花儿、谁的橡皮、清清的河水...... “地”后面跟的都是表示动作的词或词语，如：高声地喊、愉快地唱、拼命地逃、疯狂地咒骂、严密地注视、一次又一次地握手、迅速地包围、沙沙地直响、斩钉截铁地说、从容不迫地申述、用力地踢、仔细地看、开心地笑笑......” “得”前面跟的多数是表示动作的词或词语，后面跟的都是形容事物状态的词或词语，表示怎么怎么样的，如：走得很快、踩得稀烂、疼得直叫唤、瘦得皮包骨头、红得发紫、气得双脚直跳、理解得十分深刻、乐得合不拢嘴、惊讶得目瞪口呆、大得很、扫得真干净、笑得多甜啊...... 三、“的、地、得”的用法补充说明：

to和for的用法有什么不同(一)

to和for的用法有什么不同（一） 一、引出间接宾语时的区别 两者都可以引出间接宾语，但要根据不同的动词分别选用介词to 或for，具体应注意以下三种情况： 1. 在give, pass, hand, lend, send, tell, bring, show, pay, read, return, write, offer, teach, throw 等之后接介词to。如： 请把那本字典递给我。 正：Please hand me that dictionary. 正：Please hand that dictionary to me. 她去年教我们的音乐。 正：She taught us music last year. 正：She taught music to us last year. 2. 在buy, make, get, order, cook, sing, fetch, play, find, paint, choose, prepare, spare 等之后用介词for 。如： 他为我们唱了首英语歌。 正：He sang us an English song. 正：He sang an English song for us. 请帮我把钥匙找到。 正：Please find me the keys. 正：Please find the keys for me. 能耽搁你几分钟吗(即你能为我抽出几分钟吗)? 正：Can you spare me a few minutes?

正：Can you spare a few minutes for me? 3. 有的动词由于用法和含义不同，用介词to 或for 都是可能的。如： do sb a favor＝do a favor for sb 帮某人的忙 do sb harm＝do harm to sb 对某人有害 在有的情况下，可能既不用for 也不用to，而用其他的介词。如： play sb a trick＝play a trick on sb 作弄某人 请比较： play sb some folk songs＝play some folk songs for sb 给某人演奏民歌 有时同一个动词，由于用法不同，所搭配的介词也可能不同，如leave sbsth 这一结构，若表示一般意义的为某人留下某物，则用介词for 引出间接宾语，即说leave sth for sb；若表示某人死后遗留下某物，则用介词to 引出间接宾语，即说leave sth to sb。如： Would you like to leave him a message? / Would you like to leave a message for him? 你要不要给他留个话？ Her father left her a large fortune. / Her father left a large fortune to her. 她父亲死后给她留下了一大笔财产。 二、表示目标或方向的区别 两者均可表示目标、目的地、方向等，此时也要根据不同动词分别对待。如： 1. 在come, go, walk, move, fly, ride, drive, march, return 等动词之后通常用介词to 表示目标或目的地。如： He has gone to Shanghai. 他到上海去了。 They walked to a river. 他们走到一条河边。