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AASraw tsim NMN thiab NRC hmoov hauv qhov ntau!

Gefitinib

  1. Gefitinib Txheej txheem cej luam
  2. Gefitinib Mechanism ntawm kev ua
  3. Gefitinib Siv Hauv Ntiaj Teb
  4. Sab Sijhawm Los Ntawm Gefitinib
  5. Gefitinib Cia
  6. Tshawb ntxiv: "Lub Ntsws Killer Cancer" Gefitinib

 

Gefitinib Txheej txheem cej luam

Gefitinib yog kinase inhibitor.The lub npe tshuaj ntawm gefitinib yog 4-Quinazolinamine N- (3-chloro-4-fluorophenyl) -7-methoxy-6- [3- (4-morpholinyl) propoxy] .Gefitinib muaj cov qauv tshuaj molecular C22H24ClFN4O3 , ib tus txheeb ze molecular loj ntawm 446.9 daltons thiab yog hmoov dawb-xim. Gefitinib yog lub hauv paus dawb. Cov roj ntsha muaj pKas ntawm 5.4 thiab 7.2. Gefitinib tuaj yeem txhais tau tias yog sparingly soluble ntawm pH 1, tab sis yog xyaum insoluble saum pH 7, nrog solubility tsawg zuj zus ntawm pH 4 thiab pH 6. Hauv cov kuab tshuaj tsis-aqueous, gefitinib yog dawb soluble hauv glacial acetic acid thiab dimethyl sulfoxide, soluble hauv pyridine, sparingly soluble hauv tetrahydrofuran, thiab soluble me ntsis hauv methanol, ethanol (99.5%), ethyl acetate, propan-2-ol thiab acetonitrile.

Gefitinib ntsiav tshuaj muaj yog li xim av-txheej cov ntsiav tshuaj, muaj 250 mg ntawm gefitinib hmoov, rau cov thawj coj ntawm qhov ncauj. Cov khoom xyaw tsis haum ntawm cov ntsiav tshuaj tseem ceeb ntawm IRESSA ntsiav tshuaj yog lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, povidone, sodium lauryl sulfate thiab magnesium stearate. Cov ntsiav tshuaj txheej yog tsim ntawm hypromellose, polyethylene glycol 300, titanium dioxide, liab ferric oxide thiab daj ferric oxide.

 

Kev qhia:

lub npe Gefitinib
Lub Npe Ntawv N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholinyl)propoxy]-4-quinazolinamine
CAS Number 184475-35-2
Synonyms ZD 1839
molecular Formula C22H24ClFN4O3
Mis Lub Cev 446.9
purity ≥98%
Formulation Crystalline khoom
solubility DMF: 20 mg / ml
DMSO: 20 mg / ml
DMSO: PBS (pH7.2) (1: 1): 0.5 mg / ml
Ethanol: 0.3 mg / ml
SMILES COC1=CC2=C(C(NC3=CC=C(F)C(Cl)=C3)=NC=N2)C=C1OCCCN4CCOCC4
InChi Code InChI=1S/C22H24ClFN4O3/c1-29-20-13-19-16(12-21(20)31-8-2-5-28-6-9-30-10-7-28)22(26-14-25-19)27-15-3-4-18(24)17(23)11-15/h3-4,11-14H,2,5-10H2,1H3,(H,25,26,27)
InChi Key XGALLCVXEZPNRQ-UHFFFAOYSA-N
cia -20 ° C

 

Gefitinib yog siv los kho tsis mob qog nqaij hlav hauv hlwb tsawg uas tau kis mus rau lwm qhov ntawm lub cev hauv cov neeg muaj qee yam qog. Gefitinib yog nyob rau hauv chav kawm ntawm cov tshuaj hu ua kinase inhibitors. Nws ua haujlwm los ntawm thaiv qhov kev txiav txim ntawm qee yam ib txwm muaj tshwm sim uas yuav xav tau los pab cancer hlwb hlav ntau.

 

Gefitinib Mechanism ntawm kev txiav txim

Gefitinib yog ib qho inhibitor ntawm qhov chaw loj hlob ntawm tus kabmob (EGFR) tyrosine kinase uas khi rau adenosine triphosphate (ATP) -binding qhov chaw ntawm enzyme. EGFR feem ntau pom tias muaj ntau dhau heev nyob rau qee cov kab mob ntawm cov neeg mob carcinoma, xws li mob ntsws thiab mis kabmob hlwbCov. Overexpression ua rau kev ua kom zoo dua ntawm cov anti-apoptotic Ras teeb liab transduction cascades, tom qab ntawd ua rau kom muaj sia nyob ntawm cov qog nqaij hlav cancer thiab tswj tsis tau ntawm tes. Gefitinib yog thawj qhov kev xaiv tshuaj loog ntawm EGFR tyrosine kinase uas tseem hu ua Her1 lossis ErbB-1. Los ntawm inhibiting EGFR tyrosine kinase, cov nqes dej uas tsis muaj kev cuam tshuam tseem ceeb raug cuam tshuam, uas ua rau muaj kev cuam tshuam tsis zoo rau cov kab mob ntawm tes.

 

Gefitinib Siv Hauv Ntiaj Teb

Gefitinib tam sim no muaj kev lag luam hauv ntau tshaj 64 lub teb chaws. Gefitinib tau txais kev pom zoo thiab ua lag luam txij thaum Lub Xya hli ntuj 2002 hauv Nyij Pooj, ua rau nws thawj lub teb chaws rau cov tshuaj yeeb tshuaj.

cov FDA pom zoo gefitinib thaum lub Tsib Hlis 2003 rau kev mob ntsws tsis yog mob cell me (NSCLC) .Nws tau pom zoo raws li monotherapy rau kev kho mob ntawm cov neeg mob hauv zos lossis qib siab NSCLC tom qab tsis ua haujlwm ntawm ob qho platinum-based thiab docetaxel chemotherapies, ua kev kho mob thib peb.

Nyob rau lub Rau Hli 2005 FDA tau thim kev pom zoo rau kev siv rau cov neeg mob tshiab vim tias tsis muaj pov thawj pom tau tias nws ncua lub neej.

Hauv Tebchaws Europe gefitinib yog qhia txij li xyoo 2009 hauv NSCLC siab heev hauv txhua kab ntawm kev kho mob rau cov neeg mob hem EGFR kev hloov pauv. Daim ntawv tso cai no tau tso cai tom qab gefitinib pom tias yog thawj txoj kab kev kho mob kom txhim kho kev vam meej-tsis muaj txoj sia nyob ntev thiab platinum doublet tsoomfwv hauv cov neeg mob harboring xws li kev hloov pauv. IPASS tau ua thawj ntawm plaub ntawm theem III kev sim kom tau paub tseeb gefitinib superiority hauv cov neeg mob no.

Hauv feem ntau ntawm lwm lub tebchaws uas gefitinib tab tom ua lag luam tam sim no nws tau pom zoo rau cov neeg mob uas muaj NSCLC qib siab uas tau txais tsawg kawg ib zaug dhau los txheej txheem tshuaj tua kab mob. Txawm li cas los xij, cov ntawv thov kom nthuav nws daim ntawv lo yog thawj kab kev kho mob hauv cov neeg mob kho cov neeg mob EGFR kev hloov pauv tam sim no nyob rau hauv cov txheej txheem raws li cov pov thawj tshawb fawb pom tseeb. EGFR kev hloov pauv rau naiveve hauv zos dhau los lossis metastatic, tsis muaj peev xwm tiv thaiv tau NSCLC. Qhov no yog tsoomfwv tau pab nyiaj rau thawj lub sijhawm 2012-lub hlis thiab rov ua dua tshiab yog tias tsis muaj kev mob siab ntxiv.Thaum Lub Xya Hli 4, 13, FDA tau pom zoo gefitinib yog thawj qhov kev kho mob rau NSCLC.

Gefitinib

Sab sij huam Gefitinib

Cov khoom tseem ceeb uas yuav tsum nco ntsoov txog cov kev mob tshwm sim ntawm gefitinib:

People Cov neeg feem coob tsis muaj kev mob tshwm sim txhua yam.

Effects Cov kev mob tshwm sim feem ntau kwv yees nyob rau ntawm lawv qhov pib thiab ntev.

Effects Cov kev mob tshwm sim yuav luag txhua qhov thim rov qab thiab yuav ploj mus tom qab kev kho tiav.

Muaj ntau txoj hauv kev los pab txo qis lossis tiv thaiv kev phiv.

Tsis muaj qhov sib thooj ntawm qhov muaj lossis qhov tshwm sim ntawm kev mob tshwm sim thiab qhov zoo ntawm kev noj tshuaj.

 

Cov kev mob tshwm sim hauv qab no yog tshwm sim (tshwm sim ntau dua 30%) rau cov neeg mob noj cov tshuaj gefitinib:

. Mob plab zawv

Reaction Daim tawv nqaij tawm pob (ua pob, pob khaus)

 

Cov kev mob tshwm sim no tsis tshua pom tshwm sim tshwm sim (kwv yees li ntawm 10-29%) ntawm cov neeg mob tau txais cov tshuaj gefitinib:

Ause xeev siab

Ntuav

Khaus

Appetite Tsis qab los noj mov

Ation Qhov muag khaus

 

Cov mob uas tsis tshua muaj mob (li 1%) ntawm kev cuam tshuam loj ntawm kev mob ntsws interstitial ntsws (mob ntsws, lossis mob rau lub ntsws tsis muaj kev kis kab mob). Thaum cov kev mob tshwm sim no, feem ntau ua rau ua pa nyuaj nrog hnoos lossis ua npaws kub qis uas yuav tsum tau mus pw hauv tsev kho mob. 1/3 ntawm cov kis tau ua kom tuag. Yog tias pib maj mam ua pa, hnoos thiab / lossis kub ib ce tshwm sim thaum noj cov tshuaj gefitinib, ceeb toom rau koj tus kws saib xyuas kev noj qab haus huv.

Qhov siab nyob rau hauv kev kuaj ntshav kuaj muaj nuj nqi (transaminase, bilirubin, thiab alkaline phosphatase) tau pom hauv cov neeg mob kho nrog gefitinib. Cov kev ntsuas siab no tsis nrog cov tsos mob ntawm daim siab toxicity. Txawm li cas los xij, koj tus kws saib xyuas kev noj qab haus huv tuaj yeem kuaj xyuas ntshav mus soj ntsuam koj lub siab ua haujlwm kom tsis tu ncua, thaum koj noj tshuaj gefitinib.

Tsis yog tag nrho cov kev mob tshwm sim muaj npe saum toj no. Qee qhov tsis tshua muaj tshwm sim (tshwm sim hauv tsawg dua 10% ntawm cov neeg mob) tsis muaj npe nyob ntawm no. Txawm li cas los xij, koj yuav tsum tau qhia koj tus kws saib xyuas kev noj qab haus huv yog tias koj muaj cov tsos mob txawv txawv.

 

Gefitinib cia

Khaws gefitinib rau hauv lub thawv nws nkag los, kaw kom nruj, thiab kom tsis txhob muaj menyuam yaus. Khaws nws hauv chav sov thiab deb ntawm qhov kub thiab noo noo (tsis nyob hauv chav dej).

Cov roj ntshav uas tsis tau txais kev tso cai yuav tsum muab pov tseg rau hauv cov hauv kev tshwj xeeb kom ntseeg tau tias cov tsiaj, menyuam yaus, thiab lwm tus neeg tsis tuaj yeem haus lawv. Txawm li cas los xij, koj yuav tsum tsis txhob yaug qhov gefitinib hauv qab lub qhov viv. Hloov chaw, txoj kev zoo tshaj plaws rau pov tseg koj li ntawm gefitinib yog los ntawm kev muab tshuaj rov qab. Tham nrog koj tus kws muag tshuaj lossis tiv tauj koj lub chaw khaws khib nyiab / chaw khaws khoom ubno hauv ib cheeb tsam kom paub txog cov haujlwm thim rov qab hauv koj lub zej zog. Saib cov FDA Kev Nyab Xeeb Kev Nyab Xeeb Tshuaj ntawm lub vev xaib rau cov ntaub ntawv ntxiv yog tias koj tsis muaj txoj cai siv rov qab kev pab cuam.

Nws yog ib qho tseem ceeb rau kev noj txhua yam tshuaj kom tsis txhob pom thiab ncav cov menyuam yaus kom ntau lub thawv (xws li cov ntsiav tshuaj rau lub limtiam thiab cov neeg rau qhov muag tshuaj, cream, plhaw, thiab nqaum pa) tsis yog menyuam yaus thiab cov menyuam yaus tuaj yeem qhib tau yooj yim. Txhawm rau tiv thaiv cov me nyuam yaus kom txhob raug mob, nco ntsoov kaw lub hau kev ruaj ntseg thiab muab qhov chaw tso rau hauv qhov chaw nyab xeeb - ib qho uas tawm thiab deb thiab tawm ntawm lawv qhov muag thiab ncav cuag.

Gefitinib

Tshawb ntxiv: "Lub Ntsws Killer Cancer" Gefitinib

Gefitinib yog qhov kev hloov kho tshiab tsom qhov kev txwv tsis pub tyrosine kinase kev ua haujlwm ntawm cov kabmob epidermal loj hlob receptor los ntawm kev sib tw los tiv thaiv ATP kev khi. Hauv cov kev tshawb fawb preclinical gefitinib tau qhia tias muaj kev ua haujlwm muaj zog hauv ntau tus qauv qog, nrog rau ntau lub ntsws mob cancer ntawm tes thiab xenografts. Ob txoj kev tshawb fawb raws sij hawm loj (IDEAL 1 thiab IDEAL 2) hauv kev tsis ua mob qog nqaij hlav hauv lub ntsws tau tshaj tawm txog 20% ​​hauv cov neeg mob thib ob thiab ∼10% hauv cov tshuaj uas muaj ob los sis ntau cov tshuaj kho mob. Qhov nruab nrab muaj txoj sia nyob hauv ob txoj kev tshawb fawb no tau nce li 6-8 lub hlis. Raws li kev kho thawj zaug, gefitinib tau raug soj ntsuam ua ke nrog ob txoj kev kho tshuaj sib txawv hauv ob txoj kev tshawb nrhiav loj (INTACT 1 thiab INTACT 2). Ob txoj kev tshawb no ua tsis tiav los qhia txog kev txhim kho kom muaj txoj sia nyob ntawm tag nrho cov neeg mob ntawm> 1000 tus neeg mob hauv txhua qhov kev tshawb fawb. Lwm cov ntsiab lus xaus (piv txwv li, lub sij hawm hloov zuj zus thiab teb tus nqi) kuj tseem tsis tau txhim kho los ntawm kev ntxiv ntawm gefitinib. Cov kev tshawb fawb txuas ntxiv tau qhia txhawm rau txhawm rau lub luag haujlwm ntawm gefitinib hauv kev saib xyuas cov neeg mob uas tau txais kev kho mob lossis chemoradiotherapy. Kev tshawb nrhiav qhov tseeb ntawm gefitinib raws li thawj cov kab mob monotherapy tseem yuav tsum tau ua.

Feem ntau ntawm cov neeg mob uas tsis muaj cell mob ntsws cancer (NSCLC) nws thiaj li tsim cov kab mob ua mob lossis kab mob uas tsis zoo rau cov kev kho mob hauv zos xwb thiab yog cov muaj peev xwm xaiv tau cov kev kho mob raws chaw. Txawm hais tias kev siv tshuaj kho mob tuaj yeem txhim kho txoj kev ua neej nyob rau hauv cov neeg mob uas muaj cov kab mob siab dua, qhov kom zoo dua tsuas yog ∼2 lub hlis dhau ntawm kev txhawb nqa zoo tshaj plaws, thiab qhov no yog tus nqi ntawm kev cuam tshuam loj heev. Kev tshawb nrhiav rau cov neeg sawv cev tshiab uas tsawg kawg rau kev kho mob tab sis kev tiv thaiv zoo dua yog qhov tseem ceeb tshaj. Tus nab npawb ntawm cov neeg sawv cev tshiab tau ua tshwj xeeb tawm tsam xaiv cov hom phiaj tam sim no cancer cov hlwb, xws li cov kabmob loj hlob nthuav dav (EGFR), raug sim hauv NSCLC. Txog tam sim no, feem ntau cov neeg mob uas muaj NSCLC siab tau raug txheeb xyuas, tab sis nws muaj lub laj thawj zoo los tshawb xyuas ntau yam ntawm cov neeg sawv cev no hauv kev teeb tsa tus kab mob ua ntej, qhov twg qee yam ntawm cov caj ces neeg tsis txaus ntseeg tau tshwm sim.

EGFR yog qhia tau zoo nyob rau hauv ntau cov khoom hlav, suav nrog NSCLC. EGFR yog qhia tau hais qhia nyob rau hauv feem ntau (∼80%) lub siab ntsws txhaws taus cell, thiab kwv yees li ib nrab ntawm tag nrho cov ntsws adenocarcinomas thiab loj-cell carcinomas. Kev ua kom zoo ntawm EGFR hauv cov qog hlwb tau pom tias yuav txhawb cov txheej txheem koom nrog cov qog nqaij hlav loj, ua rau mob hlwb, ntxeem tau, thiab metastasis, thiab los tiv thaiv apoptosis. EGFR (erbB1 lossis HER1) yog tus tswv cuab ntawm tsev neeg tsis lees txais erbB, uas tseem suav nrog erbB2 (HER2), erbB3 (HER3), thiab erbB4 (HER4). Nws yog transmembrane glycoprotein muaj li ntawm cov ntawv txuas ligand-binding domain, transmembrane domain, thiab qhov ncauj lus dhau suab nrog lub lag luam nrog tyrosine kinase kev ua si. Tom qab khi ntawm lub cev ntawm lub cev ligand xws li qhov ua rau mob loj hlob tuaj, EGFR dimerizes nrog lwm EGFR monomer lossis lwm tus neeg ntawm tsev neeg erbB. Qhov no ua rau kev ua haujlwm ntawm tyrosine kinase, autophosphorylation ntawm tyrosine, thiab pib ntawm cov phiajcim uas thaum kawg ua rau ntau cov lus teb nqes hav zoov xws li kev nthuav tawm ntawm tes. Ntxiv mus, EGFR qhia nyob rau hauv cov qog tau cuam tshuam nrog cov lus teb tsis zoo rau kev kho, kev txhim kho cytotoxic tsis kam cov tshuaj, kev muaj mob, thiab kev muaj sia nyob tsis zoo. Lwm yam kev ua haujlwm ntawm kev nce qib ntawm EGFR uas yuav cuam tshuam nrog cov qog cell ntau ntxiv nrog rau cov qib ntxiv ntawm txoj hlab ntsws txuas, kev hloov kho ntawm EGFR, thiab kev hloov pauv ntawm EGFR. Feem ntau ntawm EGFR sib hloov hauv cov qog hlav yog EGFRvIII, uas pom muaj txog 39% ntawm NSCLC feem ntau. EGFRvIII nqa cov kev hloov pauv ntawm cov amino acids 6 txog 273 nyob rau hauv cov ntawv cog lus txuas ntxiv thiab nthuav tawm cov kev ua haujlwm tyrosine kinase kev ua haujlwm uas muaj kev ywj pheej ntawm cov ntxiv ntawm ligand khi

 

reference

[1] Rukazenkov Y, Speake G, Marshall G, li al. Kev mob loj hlob cuam tshuam receptor tyrosine kinase inhibitors: zoo sib xws tab sis txawv? Anticancer Cov Tshuaj Phom 2009; 20: 856–866.

[2] Woodburn JRThe epidermal kev loj hlob tau receptor thiab nws cov inhibition hauv kev kho mob cancer. Pharmacol Ther Xyoo 1999; 82: 241–250.

[3] Tsis Yog-Lub Hlwb Hlwb Qiv Qiv Cancer Pawg. Kev siv tshuaj kho hauv cov mob ntsws tsis zoo ntawm tes mob ntsws: kev tshawb xyuas meta uas siv cov ntaub ntawv hloov kho tshiab ntawm ib tus neeg mob los ntawm 52 kev tshawb nrhiav. BMJ 1995; 311: 899–909.

[4] Douillard JY, Kim ES, Hirsh V, li al. Gefitinib (IRESSA) piv rau cov tshuaj docetaxel hauv cov neeg mob hauv cheeb tsam qib siab lossis cov mob ua kom tsis muaj mob me me ua rau mob ntsws ua ntej kho mob platinum-tshuaj khomob: kev sim, qhib-daim ntawv qhia theem III kawm (TXUJ CI). J Thoracic Oncol 2007; 2: PRS-02–

[5] Fukuoka M, Wu Y, Thongprasert S, li al. Biomarker txheeb xyuas los ntawm cov txheej txheem theem III, randomized, qhib-daim ntawv lo, thawj kab kev tshawb fawb ntawm gefitinib (G) tiv thaiv cov kab mob carboplatin / paclitaxel (C / P) hauv cov chaw kho mob tau xaiv cov neeg mob (pts) uas tsis yog-tus me me ntawm tes ntsws mob ntsws (NSCLC) Asia (IPASS). J Clin Oncol 2009; 27 Cov chaw muag khoom. 15: 8006–.

[6] Reck MA cov kauj ruam tseem ceeb ntawm kev kho mob rau tus kheej nrog mob qog nqaij hlav cancer nrog gefitinib: IPASS mus sib hais thiab dhau mus. Cov Kws Muaj Txuj Rev Anticancer Ther 2010; 10: 955–965.

[7] Barker, AJ Kev Tshawb Fawb uas ua rau muaj qhov cim ntawm ZD1839 (IRESSA): kev mob siab rau ntawm lub qhov ncauj, xaiv kev loj hlob nthuav tawm receptor tyrosine kinase inhibitor tsom mus rau kev kho mob cancer. Bioorg. Med. Chem. Ntawv tso. 11, 1911–1914 (2001).

[8] Wakeling, AE li al. ZD1839 (Iressa): lub qhov ncauj txwv tsis pub muaj kev cuam tshuam ntawm kev loj hlob ntawm daim tawv nqaij taw qhia tias muaj peev xwm siv tshuaj kho mob qog noj ntshav. Cancer Res. 62, 5749–5754 (2002).

[9] Yarden, Y. & Sliwkowski, MX Untangling ErbB teeb liab network. Xwm Rev Mol. Cell Biol. 2, 127–137 (2001).

[10] Cersosimo, RJ Mob ntsws cancer: xyuas. Am. J. Kev Noj Qab Haus Huv Syst. Cov Tshuaj. 59, 611–642 (2002).

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