HRP20020171A2 - Use of docetaxel for treating hepatocellular carcinoma - Google Patents
Use of docetaxel for treating hepatocellular carcinoma Download PDFInfo
- Publication number
- HRP20020171A2 HRP20020171A2 HR20020171A HRP20020171A HRP20020171A2 HR P20020171 A2 HRP20020171 A2 HR P20020171A2 HR 20020171 A HR20020171 A HR 20020171A HR P20020171 A HRP20020171 A HR P20020171A HR P20020171 A2 HRP20020171 A2 HR P20020171A2
- Authority
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- Croatia
- Prior art keywords
- docetaxel
- cells
- paclitaxel
- hours
- treatment
- Prior art date
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Gastroenterology & Hepatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Epoxy Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Medicinal Preparation (AREA)
- Steroid Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Izum se odnosi na liječenje hepatocelularnog karcinoma.
Hepatocelularni karcinom (HCC) je jedan od najčešćih karcinoma u zemljama jugoistočne Azije i Afrike. U Tajvanu je HCC vodeći uzrok smrti kod muških pacijenata oboljelih od raka. Postotak preživljavanja HCC pacijenata je vrlo nizak. Uzrok tome je uglavnom nedostatak efikasne terapije. Zračenje i kemoterapija se do sada nisu pokazali zadovoljavajućima; operacija je najefikasnija terapija za liječenje HCC. Međutim, operacija je prikladna jedino za pacijente s malim tumorima koji se mogu izrezati.
Nedavno su antimitotični lijekovi kao što je paklitaksel ("paclitaxel") zadobili obnovljeni interes. Paklitaksel je prvobitno izoliran iz kore drveta tise. Antitumorski efekt paklitaksela poznat je od 1971. Paklitaksel inhibira dijeljenje tumorskih stanica svojim djelovanjem na slaganje mikrotubula. In vitro analize korištenjem tumorskih stanica otkrile su da paklitaksel zaustavlja stanice uglavnom u G2/M fazi staničnog ciklusa (Schiff PB and Horwitz SB, Proc. Natl. Acad. Sci. 77,1561-1565,1980). Nedavna ispitivanja pokazala su da je paklitaksel efikasan protiv različitih malignih tumorskih stanica kao što je tumor mozga, rak želuca i prostate, rak dojke, melanom i rak jajnika.
Međutim, paklitaksel nije djelotvoran protiv hepatocelularnog karcinoma. Faza II kliničkih testova paklitaksela za pacijente s HCC objavljena je u British Journal of Cancer, 78 (1), 34-39,1998. Taj članak zaključuje da paklitaksel nije imao značajnog antikanceroznog djelovanja kod pacijenata s HCC.
Kao što je gore objašnjeno, ustanovljeno je da citotoksični efekt paklitaksela ovisi o staničnom ciklusu tako da se zastoj staničnog ciklusa uglavnom odvija u G2/M fazi. Međutim, sada je ustanovljeno da docetaksel ("docetaxel") može postići citotoksičnost neovisnu o staničnom ciklusu kod stanica HCC. Ovo ukazuje da se citotoksični efekt doceksatela na stanice HCC postiže mehanizmom različitim od mehanizma paklitaksela. Nadalje, in vitro aktivnost docetaksela protiv stanica HCC je značajno veća nego aktivnost paklitaksela pri koncentracijama do 1 μM. S obzirom na visoko citotoksičnu prirodu taksoida povećana aktivnost kod niskih koncentracija pokazuje da će docetaksel, za razliku od paklitaksela, imati praktičnu vrijednost za kliničko liječenje hepatocelularnog karcinoma.
U skladu s tim, predmetni izum omogućava upotrebu docetaksela ili njegovog hidrata u proizvodnji medikamenta za upotrebu u liječenju hepatocelularnog karcinoma.
Također je pružen postupak za liječenje pacijenta koji boluje od hepatocelularnog karcinoma koji obuhvaća davanje navedenom pacijentu efektivne količine docetaksela ili njegovog hidrata. Izum također pruža postupak za poboljšanje stanja pacijenta koji boluje od hepatocelularnog karcinoma koji obuhvaća davanje navedenom pacijentu efektivne količine docetaksela ili njegovog hidrata.
Docetaksel je poznat spoj. Ima formulu
[image]
Postupci za preparaciju docetaksela su opisani u EP-A-253738 i EP-A336841.
Docetaksel se može koristiti, na primjer, u bezvodnom obliku ili kao hidrat. Kako je ovdje korišteno, reference za docetaksel uključuju reference za njegove hidrate.
Hidrati docetaksela mogu se prirediti otapanjem bezvodnog docetaksela u organskom otapalu kao što je aceton, etanol, acetonitril ili N, N-dimetilformamid i prekristalizacijom docetaksel hidrata dodavanjem tako dobivene otopine u vodu. Docetaksel hidrat je tipično dihidrat, trihidrat ili tetrahidrat. Određenije, za trihidrat je pronađeno da je naročito stabilan te je docetaksel trihidrat prema tome preferiran. Docetaksel trihidrat može se prirediti postupcima izloženim u EP-A-770070.
Docetaksel je neočekivano aktivan protiv hepatocelularnih karcinoma. Određenije, može se koristiti za liječenje raka stanica jetre, fibrolamelarnih varijanti i miješanih hepatocelularnih kolangiokarcinoma.
U predmetnom izumu docetaksel se može davati bilo kojim putem poznatim za davanje docetaksela. Tako se može, na primjer, davati parenteralno. Tipično se daje intravenozno, preferirano intravenoznom infuzijom.
U predmetnom izumu docetaksel se tipično formulira za davanje kao farmaceutski prihvatljiva kompozicija koja sadrži docetaksel i farmaceutski prihvatljiv nosač ili sredstvo za razrjeđivanje. Prikladni nosači i sredstva za razrjeđivanje uključuju netoksična otapala i medije za suspenziju, na primjer sterilni vodeni medij. Preferirano kompozicija ima oblik vodene otopine ili suspenzije, na primjer otopine pogodne za injekcije ili infuziju koje mogu sadržavati sredstva za emulgiranje, bojila, konzervanse ili stabilizatore.
Farmaceutske kompozicije prikladne za parenteralno davanje uključuju sterilne vodene ili nevodene otopine ili suspenzije. Prikladne sterilne nevodene otopine ili suspenzije uključuju otopine ili suspenzije u prirodnim biljnim uljima kao što je maslinovo ulje, sezamovo ulje ili tekućim ugljikovodicima ili u organskim esterima mogućim za injekcije kao što je etil oleat. Prikladne sterilne vodene otopine uključuju otopine docetaksela u vodi. Tipično pH sterilnih vodenih otopina prikladnih za parenteralno davanje je odgovarajuće prilagođen. Dalje, takve sterilne vodene otopine se općenito naprave da budu izotonične, na primjer dovoljnom količinom natrijevog klorida ili glukoze. Naročito je preferirano da otopine prikladne za davanje infuzijom imaju pH sličan pH krvi i da budu izotonične.
Sterilizacija se može provesti zagrijavanjem ili na neki drugi način koji ne djeluje nepovoljno na kompoziciju.
Farmaceutske kompozicije koje sadrže docetaksel prikladne za upotrebu u predmetnom izumu mogu dalje obuhvaćati površinski aktivne tvari.
Preferirane površinski aktivne tvari su polisorbati, polietilen glikol esteri i ester -eteri polietilen glikola te ricinusovo ulje. Primjeri prikladnih surfaktanata i farmaceutskih kompozicija koje ih sadrže mogu se naći u AU-A-666859.
Docetaksel se može također formulirati za upotrebu u predmetnom izumu kao liofolizirana kompozicija. Takve liofilizirane kompozicije imaju dobru fizikalnu i kemijsku stabilnost i mogu se, prema tome, skladištiti na dugo vrijeme. Liofilizirane kompozicije koje sadrže docetaksel mogu se prirediti lifoliziranjem vodene otopine docetaksela standardnim postupcima. Dalje mogu obuhvaćati punila kao što je laktoza. Mogu također obuhvaćati sredstva za podešavanje toničnosti kao što su šećeri i polimeri. Primjeri pogodnih sredstava za podešavanje toničnosti uključuju glukozu, dekstrozu i manitol te polimere, na primjer polivinilpirolidon.
Liofilizirana kompozicija može se ponovo otopiti u vrijeme upotrebe u bilo kojem kompatibilnom i farmaceutski prihvatljivom mediju za injekcije. Liofilizat može uz prednost biti preuzet dvostruko destiliranom vodom stupnja čistoće za injekcije u volumenu ekvivalentnom početnom volumenu otopine koju treba liofilizirati.
Farmaceutska kompozicija koja sadrži docetaksel pogodna za upotrebu u predmetnom izumu tipično sadrži najmanje 0.01 težinskih % terapeutski aktivnog spoja. Općenito farmaceutska kompozicija sadrži oko 0.01 do 1000 mg, preferirano od 0.1 do 500 mg, terapeutski aktivnog spoja.
Preferirano otopina pogodna za intravenozne injekcije sadrži od 38 do 42, više preferirano oko 40 mg/ml aktivnog spoja. Tipično takve otopine su na raspolaganju u ampulama koje sadrže 20 mg ili 80 mg aktivnog spoja.
Preferirano otopina pogodna za infuziju sadrži od 0.1 do 11, preferirano od 0.1 do 10, više preferirano od 0.3 do 0.9 mg/ml aktivnog spoja.
Terapeutska obrada docetakselom prema predmetnom izumu može se provoditi istovremeno s drugim terapijskim postupcima uključivši liječenje drugim antineoplastičnim lijekovima, monoklonalnim antitijelima, imunoterapiju ili radioterapiju ili modifikatorima biološkog odgovora. Pogodni modifikatori biološkog odgovora uključuju limfokine i citokine kao što su interleukini, interferoni (α, β ili δ) i TNF. Druga sredstva za kemoterapiju koja su korisna za liječenje poremećaja uzrokovanih nenormalnom diobom stanica uključuju sredstva za alkiliranje, na primjer dušikove spojeve tipa gorušice ("nitrogen mustard") kao što je mekloretamin, ciklofosfamid, melfalan i klorambucil, alkilne sulfonate kao busulfan, nitrozouree kao što je karmustin, lomustin, semustin i streptozocin, triazene kao što je dakarbazin, antimetabolite kao što su analozi folne kiseline, na primjer metotreksat, analoge pirimidina kao što je fluoruracil i citarabin, analoge purina kao što je merkaptopurin i tiogvanin, prirodne produkte, na primjer vinka alkaloide kao što je vinblastin, vinkristin i vindezin, epipodofilotoksine kao što je etopozid i tenipozid, antibiotike kao što je daktinomicin, daunorubicin, doksorubicin, bleomicin, plikamicin i mitomicin, enzime kao što je L-asparaginaza, različita sredstva kao što su koordinacijski kompleksi platine, na primjer cisplatin, supstituirane uree kao što je hidroksiurea, derivate metilhidrazina kao što je prokarbazin, adrenokortikalne supresante kao što je mitotan i aminoglutetimid, hormone i antagoniste kao što su adrenokortikosteroidi kao prednison, progestini kao hidroksiprogesteron kaproat, metoksiprogesteron acetat i megestrol acetat, estrogeni kao dietilstilbestrol i etinilestradiol, antiestrogeni kao tamoksifen, i androgeni kao testosteron propionat i fluoksimesteron.
Istovremena obrada ciklofosfamidom, 5-fluoruracilom, etopozidom, vinorelbinom ili metotreksatom je preferirana, jer se može postići sinegizam među ovim spojevima i docetakselom. Nadalje, 2-metoksiestradiol je aktivan protiv hepatocelularnih karcinoma i pronađeno je da se dobro tolerira nakon jednog mjeseca svakodnevnog davanja miševima (Klauber et al, Cancer Research, 57,81-86,1997). Istovremena obrada 2-metoksiestradiolom je, prema tome, također preferirana, naročito kada je potrebno kronično liječenje.
U predmetnom izumu docetaksel se daje u dozi koja omogućava liječenje hepatocelularnog karcinoma. Doza varira ovisno o načinu davanja i fizičkim karakteristikama pacijenta. Pogodne doze uključuju one koje su terapijski efikasne za liječenje poremećaja uzrokovanih nenormalnim dijeljenjem stanica. Docetaksel može se davati tako često kako je neophodno da se postigne željeni terapeutski efekt.
Tipična doza docetaksela za liječenje čovjeka je od 50 do 150, preferirano 60 do 100, više preferirano oko 100 mg docetaksela/m2 površine pacijentove kože. Kada se docetaksel daje infuzijom, brzina infuzije je tipično od 1 do 200, preferirano oko 100 mg/m2 doceksatela na sat.
Gornja doza može se ponavljati prema potrebi. Tipično se ponavlja dnevno ili tjedno. Preferirano se ponavlja svaka 3 tjedna. Na primjer, docetaksel se može davati u dozi od oko 100 mg/m2 kao intravenozna infuzija kroz l sat svaka 3 tjedna.
Sljedeći primjer ilustrira izum.
PRIMJER
Materijali i metode
Osim ako je drugačije naznačeno, primijenjeni postupci su standardne biokemijske metode. Upotrijebljene linije stanica su komercijalno raspoložive.
Stanična kultura
Eksperimenti opisani dolje uključuju linije humanih hepatoma stanica HepSB (ATCC oznaka HB 8064), HepG2 (ATCC oznaka HB 8065) i HA22T/VGH te linije hepatoma stanica murina Hepa 1-6. Ove stanice su uzgojene u DMEM (GIBCO, BRL) koji sadrži 10% fetalnog seruma goveda (Hyclone), 0.01 mg/ml gentamicina i 0.1 mM neesencijalne aminokiseline. Stanice su uzgajane u CO2 inkubatoru na 37°C s 5% CO2 i 95% filtriranog zraka.
Obrada lijekom
U dolje opisanim eksperimentima gornje hepatoma stanice su obrađivane različitim koncentracijama paklitaksela (0.001 - 10 μM) i docetaksela (0.001 - 10 μM) kroz 24 sata i 72 sata. Paklitaksel je otopljen u dimetilsulfoksidu (DMSO) a docetaksel je otopljen u etanolu, priređeni kao gotove otopine. Konačna komcentracija prenosnika bila je manje od 0.1%.
Proučavanje živosti stanica: MTT proba
Stanice su uzgojene u podlozi za kulture s 96 jažica (COSTAR) pri gustoći 4 x 104 stanica/ml. Nakon obrade lijekom kroz 24 sata ili 72 sata, medij je bačen i zamijenjen jednakim volumenom (100 μl) svježeg medija koji je sadržavao MTT (0.456 mg/ml; 3-[4,5-dimetiltiazol-2-il]-2,5-difenil-tetrazolium bromid) i inkubiran 1.5 sati na 37°C. Svježi medij je onda bačen i dodano je 100 μl DMSO. Živost stanica određivana je kolorimetrijskim uspoređivanjem putem očitavanja OD vrijednosti na čitaču s mikropločom (SPECTRA MAK 250) na valnoj duljini apsorpcije 570 nm.
Rezultati su prikazani na slici 1 u kojoj ispunjeni krugovi predstavljaju podatke nakon obrade kroz 24 sata a prazni krugovi predstavljaju podatke nakon obrade kroz 72 sata. Podaci su srednja vrijednost ± standardna pogreška srednje vrijednosti duplikata uzoraka iz tri neovisna eksperimenta.
Proba izlučivanja putem propidij jodida (PI)
Stanice su uzgojene u posudama od 5 cm2 (CORNING) i obrađivane paklitakselom i docetakselom kako je gore izloženo. Propidij jodid (10 μg/ml) je onda dodan za 15 minuta inkubacije na 37 °C. Onda je medij skupljen prije skupljanja stanica koje su se držale. I suspendirane i pridržane stanice su skupljene i ponovo suspendirane s 500 μl PBS za protočnu citometrijsku analizu kako je izneseno dolje. Otpadni signali uklonjeni su pomoću FSC-SSC obrade.
Protočna citometrijska analiza sadržaja DNA
Pufer za razgradnju (0.5% Triton K-100, 0.2 μg/ml Na2 EDTA 2H20 i 1% albumin seruma goveda u PBS) dodan je u pločice stanica koje su onda ostavljene na ledu kroz 15 minuta. 100% metanol prethodno ohlađen na -20°C je onda dodan u smjesu koja je zatim centrifugirana na 300 x g 5 minuta. Matičnica je bačena i pločica stanica je oprana s PBS. Oprana pločica je zamrljana otopinom za bojane DNA (50 μg/ml propidij jodida i 5 kunitz/ml of RNaze A) kroz 30 minuta na 4°C u mraku. Sadržaj DNA svake stanice mjeren je pomoću Becton Dickinson FACSCalibur protočnog citometra kako je izneseno dolje.
Protočna citometrija
Stanice (10000) analizirane su na Becton Dickinson FACSCalibur protočnom citometru uz korištenje argon-ionskog lasera (15 mWatt) s upadnim snopom na 488 nm. Za PI probu isključivanja skupljana je crvena fluorescencija kroz 585 nm filter i otpadni stanični signali su uklonjeni pomoću FSC-SSC obrade. Podaci su dobiveni i analizirani korištenjem FACS/CELLQuest programa na Power Macintosh 7600/120 računalu. Apoptotične stanice i stanice u specifičnim fazama ciklusa određivane su programom ModFit LT.
Rezultati protočne citometrije prikazani su u tablicama 1 i 2 i na slici 2. Tablica l daje vrijednosti za permeabilnost stanične membrane hepatoma stanica nakon obrade paklitakselom i docetakselom. Tablica 2 daje postotak apoptotičnih (sub-GO/Gl) stanica nađen nakon obrade paklitakselom i docetakselom. Slika 2 prikazuje analizu DNA histograma koja pokazuje djelovanje paklitaksela i docetaksela na napredovanje staničnog ciklusa.
TABLICA 1
Permeabilnost stanične membrane hepatoma stanica nakon obrade paklitakselom i docetakselom.
[image]
Podaci su srednja vrijednost ± standardna pogreška srednje vrijednosti duplikata uzoraka iz najmanje tri neovisna eksperimenta. Stanice su obrađivane lijekovima 24-72 sata i permeabilnost membrane je mjerena protočnom citometrijskom analizom isključivanja propidijem u životnim hepatoma stanicama. Podaci su postotak stanica s nedirnutim staničnim membranama u usporedbi s kontrolnim.
TABLICA 2
Apoptoza inducirana paklitakselom i docetakselom
[image]
Vrijednosti su % apoptotičnih (sub-GO/GI) stanica kako je utvrđeno protočnom citometrijom.
Analiza elektroforezom fragmentacije DNA
Određivanje fragmentacije DNA bilo je prema postupku Herrmann et al, Nucleic Acids Res., 22,5506-5507,1994.
Ukratko, HEP G2 stanice (2 x 107) obrađivane su 72 sata paklitakselom i docetakselom kako je gore izloženo te centrifugirane. Tako dobivene pločice stanica resuspendirane su NP-40 puferom za razgradnju (1% NP-40 u 20 mM EDTA, 50 mM Tris-HC1, pH 7.5). Nakon razgrađivanja stanica nekoliko sekundi, skupljena je matičnica (5 minuta na 1600 x g). Ekstrakcija je ponovljena istim puferom za razgradnju. Dodan je SDS (konačna koncentracija 1%) i RNaza (konačna koncentracija 2.5 μg/μl)u matičnice i inkubirano je 2 sata na 56°C nakon čega je slijedilo rezanje proteinazom K (2.5 μg/μl) 2 sata na 37°C. Onda su smjese dodane u 10 M amonijev acetat prije taloženja 100% etanolom 30 minuta na -20°C. DNA je skupljena centrifugiranjem (10 min na 12000 x g) nakon čega je slijedila elektroforeza na 1.5% agaroznom gelu.
Rezultati su prikazani su na slici 3. Na slici 3, M je marker za 100 parova baza. Staza 1 prikazuje kontrolni medij. Staze 2 i 3 prikazuju srednje vrijednosti grupa obrađivanih paklitakselom (0.1 i 1 μM). Staze 4 i 5 prikazuju srednje vrijednosti grupa obrađivanih docetakselom (0.1 i 1 μM).
Rezultati
Proučavanje živosti stanica
Slika 1 pokazuje djelovanje paklitaksela i docetaksela ovisno o dozi na životnost stanica u linijama stanica hepatoma (Hep G2, Hep 3B, HA22T/VGH i Hepa 1-6). Kao što je vidljivo iz slike 1, docetaksel je postigao smanjenu životnost pri 0.01 i 0.1 u gotovo svakom slučaju.
U stanicama Hep G2 stanična živost pokazala je trend smanjivanja nakon obrade paklitakselom ili docetakselom. Živost Hep G2 stanica bila je 61.81% i 39.45% kontrolne za paklitaksel (10 M) grupe za 24 i 72 sata, istim redom. Za docetakselom obrađene Hep G2 stanice, maksimalno smanjenje životnosti opaženo je za 1 μM docetaksela, a nije opaženo daljnje maksimalno smanjenje životnosti za 10 μM docetaksela. Životnost je bila 65.03% i 48.99% za 1 μM docetakselom obrađene stanice pri 24 i 72 sata, istim redom.
Vrijedno je da se primijeti da je za Hep 3B stanice značajno smanjenje živosti (37.06%) opaženo nakon obrađivanja 0.01 μM docetakselom 72 sata .
U docetakselom obrađenim Hepa 1-6 stanicama, nađena je maksimalna citotoksičnost (65.34% i 30.71%) za grupe obrađeđne 1 μM docetakselom u 24 i 72 sata, istim redom.
Proba izlučivanja putem propidij jodida (PI)
Tablica 1 pokazuje da permeabilnost membrana Hep G2 stanica i Hep 3B stanica nakon obrade paklitakselom i docetakselom ovisi o dozi i vremenu.
Za HA22T/VGH stanice manji porast permeabilnosti membrane opažen je nakon obrade paklitakselom (0.01 - 1 μM) 72 sata u usporedbi s grupama obrađenim docetakselom. Vrijedno je da se primijeti da je samo 55.44% stanica imalo nedirnute membrane nakon obrađivanja 0.01 μM docetakselom 72 sata dok je nakon iste doze paklitaksela 92.58% obrađenih stanica imalo nedirnute membrane.
Analiza staničnog ciklusa
Slika 2 pokazuje da su Hep G2 stanice obrađivane 1. μM paklitakselom 24 sata dosegle očiti zastoj G2/M faze. Slični DNA histogrami opaženi su 72 sata nakon izlaganja.
Kako je prikazano u tablici 2, apoptotične stanice (sub-GO/Gl) nađene su nakon obrade 0.001 μM, 0.01 μM, 0.1 μM i 1 μM docetakselom 24 sata s apoptotičnim postotkom od 31.02%,. 45.24%, 38.77% i 28.33%, istim redom. 72 sata nakon obrade-docetakselom (0.001 - 1 μM) apoptotični postotak bio je 21.92%, 42.45%, 42.44% i 56.66%, istim redom.
U Hep 3B stanicama obrada 0.1 μM ili 1 μM paklitakselom 24 sata dovela je do G2/M zastoja te inkubacija s 0.1 μM ili 1 μM paklitakselom 72 sata dovela je do povećanog sub-GO/Gl postotka do 38.37% ili 47.01%, istim redom. Suprotno tome, 0.01 μM, 0.1 μM ili 1 μM docetakselom obrađivane Hep 3B stanice 24 sata ili 72 sata dovele su do visokih razina sub-GO/Gl populacija od 59.14%, 58.69% i 65.74% za 24 sata te 64.12%, 81.66% i 79.33% za 72 sata.
U HA22T/VGH stanicama povećanje koncentracije paklitaksela (0.001 μM do 1 μM) bilo je u skladu s povećanim postotkom G2/M stanica za 24 sata. Nije opažena nikakva značajna sub-GO/Gl populacija u grupama obrađenim 0.1 μM ili 1 μM paklitakselom za 72 sata. Suprotno tome, značajno je da su 0.01 μM docetakselom obrađene HA22T/VGH stanice za 24 sata imale viši sub GO/G1 postotak (41.75 %) nego grupe s 0.1 μM (18.61 %) ili 1 μM (22.94%) docetakselom. Kada su stanice obrađivane docetakselom 72 sata, nađen je značajan sub GO/Gl postotak u 0.01 μM (56.64 %), 0.1 μM (58.61 %) i 1 μM (60.98 %) docetakselom obrađenim HA22T/VGH stanicama.
Za Hepa 1-6 stanice obrada paklitakselom (0.01, 0.1 ili 1 μM) 24 sata dovelo je do povećanog nastajanja sub-GO/Gl populacija (24.02 %, 55.64 % ili 64.38 %, istim redom) i zastoj G2/M faze opažen je u grupama obrađenim 0.1 μM M i 1 μM paklitakselom. Kada su Hepa 1-6 stanice obrađivane 0.1 μM i 1 μM paklitakselom 72 sata većina stanica bila je mrtva ili nije bilo nikakvog vidljivog profila staničnog ciklusa. Obrada docetakselom (0.01 μM, 0.1 μM i 1 μM) Hepa 1-6 stanica dovela je do nastajanja sub-GO/Gl stanica (52.81 %, 50.76 % i 53.8 % za 24 sata i 31.25 %, 53.95 % i 62.49 % za 72 sata, istim redom).
Analiza DNA fragmentacije
Slika 3 pokazuje da obrađivanje paklitakselom (0.1 i 1 μM) i docetakselom (0.1 i 1 μM) inducira fragmentaciju DNA u Hep G2 stanicama.
Claims (5)
1. Kompozicija za liječenje hepatocelularnog karcinoma naznačena time da obuhvaća kao aktivni sastojak docetaksel ili njegov hidrat.
2. Kompozicija prema zahtjevu 1, naznačena time da hidrat je trihidrat.
3. Kompozicija prema zahtjevima 1 ili 2 naznačena time da je za parenteralno davanje.
4. Kompozicija prema zahtjevu 3 naznačena time da je pogodna za intraperitonealno, subkutano, intravenozno, intramuskularno ili intrasternalno davanje i sadrži od 38 do 42 mg/ml aktivnog spoja.
5. Kompozicija prema zahtjevu 3 naznačena time da je pogodna za davanje infuzijom i sadrži od 0.1 do 11 mg/ml aktivnog spoja.
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| CN1268619C (zh) * | 2003-05-08 | 2006-08-09 | 上海迪赛诺化学制药有限公司 | 多烯紫杉醇三水化合物的制备方法 |
| DE602004020506D1 (de) * | 2003-12-12 | 2009-05-20 | Quiral Quimica Do Brasil | Verfahren zur herstellung von wasserfreien und hydratisierten pharmazeutischen wirkstoffen (apis); aus diesen hergestellte stabile pharmazeutische zusammensetzungen und anwendungen für diese zusammensetzungen |
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| FR2601675B1 (fr) * | 1986-07-17 | 1988-09-23 | Rhone Poulenc Sante | Derives du taxol, leur preparation et les compositions pharmaceutiques qui les contiennent |
| FR2629819B1 (fr) * | 1988-04-06 | 1990-11-16 | Rhone Poulenc Sante | Procede de preparation de derives de la baccatine iii et de la desacetyl-10 baccatine iii |
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| FR2722191B1 (fr) * | 1994-07-08 | 1996-08-23 | Rhone Poulenc Rorer Sa | Procede de preparation du trihydrate du (2r,3s)-3-tertbutoxycarbonylamino-2-hydroxy-3-phenylpropionate de 4-acetoxy2alpha-benzoyloxy-5beta,20epoxy-1,7beta,10beta trihydroxy-9-oxo-tax-11-en-13alpha-yle |
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| FR2742751B1 (fr) * | 1995-12-22 | 1998-01-30 | Rhone Poulenc Rorer Sa | Nouveaux taxoides, leur preparation et les compositions pharmaceutiques qui les contiennent |
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| KR20080007561A (ko) * | 2005-12-13 | 2008-01-22 | 테바 파마슈티컬 인더스트리즈 리미티드 | 아토바스타틴 헤미칼슘의 결정형 및 이의 제조 방법 |
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