I-ATO embalwa ethuthukile kufanele wazi ngakho
I-Arsenic trioxide-eyaziwa nangokuthi i-ATO, noma i-trisenox-iyindlela yokwelapha i-antiticancer ye-subtype ye-acute myeloid leukemia eyaziwa ngokuthi i-acute promyelocytic leukemia, noma i- APL . Le subtype ye- leukemia ibizwa nangokuthi "i-M3 subtype" ye- lemonemic acute myeloid .
Imiphumela esebenzayo i-ATO ekwelapheni iziguli ezitholakale zitholakale ezinezingozi eziphansi kuya eziphakathi i-APL ziye zazithanda kakhulu.
Lezi mpumelelo ziye zagqugquzela ucwaningo lwesayensi ukuhlola ukusetshenziswa okungenzeka kwe-ATO kuma-kansa amaningi ngaphandle kwe-APL, kufaka phakathi izinkinga ezingekho ze-leukemia ezifana nomdlavuza we- colon metastatic kanye ne- tumor yobuchopho , i-glioblastoma multiform.
I-ATO ivame ukuhlanganiswa nayo yonke i-trans retinoic acid (ATRA), i-agent e-retinoid esetshenziselwa ukwelashwa kwe-acute promyelocytic leukemia. Ama-retinoid compounds angakwazi ukubopha ama-receptors kumaseli ukuba abe nezinyathelo ezibalulekile emigqeni yokuphila kwamaselula. Inhlanganisela ye-ATRA kanye ne-ATO iboniswe ukuthi iphakeme kune-ATRA kanye ne-chemotherapy ekwelapheni iziguli ezinobungozi obujwayelekile ezinezifo eziphuthumayo ze-promyelocytic leukemia (APL).
I-ATO isebenza kanjani?
Indlela yokwenziwa kwe-ATO ayiqondakali ngokuphelele.
Ekuhloleni kwelabhuthrili amaseli e-human promyelocytic leukemia, i-ATO yenze ushintsho ekubukeni kwamaseli kanye nokuphuka ku-DNA-zombili zazo zibonisa inqubo eyaziwa ngokuthi i-apoptosis, noma ukufa kwe-cell program.
I-ATO nayo ibangela ukulimala kwiprotheni ye-fusion eyenziwa la maseli e-promyelocytic, okuthiwa i-Pro-Myelocytic Leukemia / Retinoic Acid Receptor-alpha (i-PML / RAR alpha). Amaprotheni ama-fusion amaprotheni adalwe ngokusebenzisa ukujoyina ama-gene amabili noma ngaphezulu okwakungowokuqala amakhomithini ahlukene.
I-ATO ye-APL
I-ATO ivunyelwe ukusetshenziswa ekwelapheni amacala athile we- acute promyelocytic leukemia , noma i-APL, kanje:
- I-APL engozini engaphansi kokuthola ingozi, lapho i-ATO isetshenziselwa ukuhlanganiswa nayo yonke i-trans-retinoic acid, noma i-ATRA.
- I-APL ephindaphindiwe / ekhonjisiwe, kubantu ababenesifo sangaphambilini esidinga imishanguzo ye-retinoid kanye ne-chemotherapy, lapho kunezinguquko ezithile zezakhi zofuzo emangqamuzaneni omdlavuza -thethe (15; 17) ukudluliselwa kanye / noma ukutholakala kwe-pro-myelocytic leukemia / retinoic-acid -receptor-alpha (i-PML / RAR-alpha) isakhi.
I-white blood cell (i-WBC) yomuntu ibalwa ngesethulo, noma ngesikhathi sokuhlolwa kokuqala nokuxilongwa kwe-APL, kuvame ukusetshenziswa ukudala la maqembu e-APL engozini, lapho izigaba ezilandelayo zisetshenziswa khona:
- I-APL = I-APL = Inani lokuqala le-WBC ≤ 10,000 / microL;
- I-APL eyingozi kakhulu = Ukubalwa kwe-WBC yokuqala> 10,000 / microL.
Ukuphepha nokusebenza kwe-ATO ezinganeni ezineminyaka engama-17 engakaze kusungulwe. Ayikho imininingwane etholakalayo ezinganeni ezineminyaka engaphansi kweminyaka emihlanu, kanti idatha ingalinganiselwe ezinganeni ezindala: ekuhlaziyweni okukodwa, iziguli eziyisikhombisa ezingaphansi kweminyaka eyi-18 ubudala (iminyaka emihlanu kuya kweyishumi nesithupha) ziphathwe nge-ATO kumthamo onconyiwe we-0.15 mg / kg / ngosuku, neziguli ezinhlanu zithole impendulo ephelele.
Izinga lokuphendula kwezinye i-AML subtypes kuya ku-ATO azikahlolwa. Ukuhlola nge-ATO kuqhubeka, futhi esikhathini esizayo, kungase kube nezinhlelo zokusebenza ezengeziwe ze-ejenti ekwelapheni umdlavuza.
I-ATO + ATRA njenge-Treatment Induction
Ukwelashwa kwe-APL kuhluke kokwezinye izinhlobo ze-AML. Isinyathelo sokuqala sokwelapha, esibizwa ngokuthi induction, sihlose ukuletha ukuxolelwa futhi kuhilela ukuphoqa amaseli angavamile we-APL, i-promyelocytes, ukuze akhule ibe ngamaseli avamile.
Wonke i-ac-retinoic acid, noma i-ATRA, imithi engeyona i-chemotherapy ejwayele ukusetshenziselwa ukufakelwa, njengoba iphoqa ama-promyelocyte amabi ukuze ahlume abe yi-neutrophils. Liyinkimbinkimbi ehlobene ne-vitamin A. ATRA, yedwa, kodwa-ke, akwanele ukwenza umsebenzi wokunciphisa ukuxolelwa-okuwukuthi, ukukhishwa kwe-ATRA, yedwa, okuhlala isikhathi esifushane, okuhlala isikhathi eside kuphela .
Ngakho-ke, i-ATRA ivame ukuhlanganiswa namanye ama-agent ukudala ukuxolelwa kubantu abane-APL. I-ATRA ehlanganiswe ne-anthracycline-based chemotherapy iyindlela yokwelashwa ejwayelekile lapho kukhona khona ulwazi olunzulu lomtholampilo kanye nenani elikhulu lemininingwane.
Kunesithakazelo esincane kakhulu, noma kunjalo, ekusetshenzisweni kwe-ATO (lapho kutholakala khona) nge-ATRA, endaweni ye-chemo ejwayelekile ye-anthracycline. Ekuqaleni, lokhu kubonakala njengendlela yokukhetha abantu abangakwazi ukubekezelela i-anthracycline-based chemotherapy. Idatha yesilingo yamanje emtholampilo, kodwa-ke, isikisela ukuthi inhlanganisela ye-ATRA + ATO ingaveza imiphumela enhle kakhulu, uma ingenasiphakamiso, imilayezo ejwayelekile ehlanganisa i-ATRA ne-chemotherapy-ezinhlotsheni zesiguli esifanele.
Iningi le-ATRA + ATO idatha livela kwizifundo lapho abantu babe ne-APL engozini encane kanye ne-APL engozini yomphakathi; kukhona ulwazi oluncane olutholakalayo mayelana nokuthi i-ATRA + ATO ingaqhathaniswa kanjani ne-ATRA + chemo kuziguli ezine-APL engozini enkulu.
Ukuhlanganiswa Kwezokwelapha
Njengezinye izinhlobo ze-AML, iziguli ezine-APL ziyaqhubeka zithola ukwelashwa okungeziwe, ngemuva kokuba umshini wabo wokuqala wokungeniswa usuqedile, futhi lokhu ukwelashwa kamuva kuyaziwa ngokuthi ukwelashwa kokuhlanganiswa.
Imithi ethile yezidakamizwa esetshenzisiwe ixhomeke ekuyingeni ukuthi yiziphi izindlela zokwelashwa ezinikezwa njenge-induction therapy. Izibonelo zokwelashwa kokuhlanganisa zilandela:
- I-Anthracycline + ATRA yemigqa embalwa (i-anthracycline ehlukile ingasetshenziswa kumjikelezo ohlukile)
- Anthracycline + cytarabine okungenani 2 imijikelezo
- ATO for 2 imijikelezo cishe izinsuku ezingaba ngu-75, ke i-ATRA + anthracycline emijikelezweni engu-2
- I-ATRA kanye ne-ATO yemijikelezo eminingana
Imithi yokondla
Kwezinye iziguli ezine-APL, ukuhlanganiswa kungalandelwa ukwelashwa kwesondlo nge-ATRA okungenani ngonyaka. Ngezinye izikhathi izilinganiso eziphansi zezidakamizwa ze-chemo 6-mercaptopurine (6-MP) kanye ne-methotrexate zinikezwa kanye.
I-ATO yezinye izindawo zokugula-Ucwaningo Lokuqala
Ukuphumelela nge-ATO ekwelapheni i-APL kuye kwakhuthaza isithakazelo sesayensi emisebenzini engaba khona ye-ATO ekwelapheni kwezinye izidakamizwa.
Ezimweni eziningi, ucwaningo luyisandulela kakhulu, ngezinye izikhathi lukhawulelwe "ukuhlola amashubhu nezifundo zezilwane," kodwa iqiniso lokuthi i-ATO ihlolwe ezinhlobonhlobo zezifo ezahlukene kanye nezilungiselelo, ngokwayo, iyamangalisa.
Isampula salezi zikhombisi-ndlela zocwaningo ezihlukile zilandela.
Ama-Metastases angamafutha avela kuCaron Cancer
Ukwelashwa kwe -T-cell etholakalayo kuyindlela yokwelashwa esetshenziselwa ukusiza amasosha omzimba ukulwa nomdlavuza nezinye izifo. Amaseli e-T aqoqiwe kusuka esigulini futhi agculwe ebhokisithri ukuze ukwandise izimpendulo zempendulo ye-immune system ephumelelayo, bese ubuyiselwa esigulini ukulwa nomdlavuza.
Esifundweni sezilwane esenziwa nguWang kanye nozakwethu eshicilelwe ku- Oncotarget , i-ATO ehlangene namaseli ase-cytotoxic T ayenomphumela wokuphila futhi isikhathi eside sesikhathi sokuphila emfanekisweni we-metastasis wamaphaphu wesifo somdlavuza. U-Wang nabacwaningi baphawula ukuthi impumelelo nge-T-cell therapy yokwamukela ivame ukubhekiswe ekunciphiseni kwamaseli e-T futhi ukuthi i-ATO ingaba nemiphumela emihle ngokususa lawa maseli.
Ama-Metastases e-Lung kusuka ku-Cancer Cancer
Njengoba kunikezwe impumelelo ye-ATO ku-APL, abacwaningi bazibuza ukuthi i-ATO ingase ibe nomthelela ofanayo kumdlavuza wesibindi. I-infusions ye-ATO iye yaboniswa ukuthi ivimbele ukukhula kwe-tumor emdlalweni wesifo somdlavuza wesibindi, ngokusho kombiko kaLu nozakwabo.
Ukwengeza, i-ATO ibikwa ngokuthi imithi ephumelelayo ekwelapheni amaphasethi emaphaphu kusukela emdlalweni wesifo somdlavuza onobuhlungu obuhlobene nomdlavuza. U-Lu kanye nozakwethu baqaphele ukuthi ucwaningo luye lwabonisa ukuthi i-ATO ingavimbela ukuhlasela kanye nemetastasis yamangqamuzana omdlavuza wesibindi ngokuvimbela iphrotheni ebizwa ngokuthi i-RhoC nokuthi i-RhoC kanye "nomswakama" wayo, i-ezrin, ingabandakanyeka emsebenzini wokulwa ne-ATO .
Ngakho-ke, babehlose ukutadisha indlela yokuvimbela amangqamuzana omdlavuza wesibindi se-metastatic by ATO. Basebenzisa amaphethini e-ezrin ngaphambi nangemva kwe-ATO ukwelashwa njengamawindi abo okubuka, futhi bathola ukuthi ukwelashwa kwe-ATO kunganciphisa ngokweqile inkulumo ye-ezrin emdlalweni wesibindi.
I-Glioblastoma multiforme
I-Glioblastoma multiforme, noma i-GBM, iyisisu esinomkhuhlane okhulayo okhulayo. Lona uhlobo lomdlavuza owawuthatha impilo kaTed Kennedy nalokho uSenator John McCain atholakala khona ngo-2017.
I-Arsenic trioxyde ibike ukuthi ingavimbela kodwa ingavuseleli ukukhula kwezidumbu ezinamandla ezibandakanya i-GBM emthamo ophephile emitholampilo (1-2 μM). U-Yoshimura kanye nosebenza nabo babike ukuthi ukuhlushwa okuphansi (2 μM) ye-arsenic trioxide kungaholela ekuhlukaniseni amakhemikhali e-GBM futhi kungathuthukisa umthelela wezinye izindlela zokwelapha ezenzakalelayo lapho zisetshenziselwa inhlanganisela esifundweni sabo segundane, futhi ithemba ukuthi lokhu kungabonisa amathuba amasha yezokwelapha ze-GBM esikhathini esizayo.
I-osteosarcoma
I-osteosarcoma iyisifo somdlavuza ovamile, futhi ukwelashwa kwamazinga akuzange kuhambisane neminyaka engama-25 kuya kwengu-30 edlule.
Inqubo ebizwa ngokuthi i-autophagy ibhekisela kuma-lysosomes amangqamuzana akho ahlambalaza futhi aqeda ama-protein amancane kanye ne-organelles eyonakele-ngokuyinhloko, ukukhipha udoti, ukugcina i-cytoplasm yeseli ihlanzekile.
Ukuguqulwa kwe-Autophagy kuye kwacatshangwa ukuthi kuyindlela yokwelashwa engase ibe yindlela yokwelashwa ye-osteosarcoma, kanti isifundo sangaphambilini sibonise ukuthi i-ATO ibonisa umsebenzi olwaphikisayo wokulwa ne-carcinogenic.
I-Wu kanye nozakwethu baveze ukuthi i-ATO yanda umsebenzi wokuzimela ngokuzenzakalelayo kumaseli e-osteosarcoma esilingo (isamba se-cell MG-63). Ngokuthakazelisayo, ukuvinjelwa kokuzenzekelayo (ukusebenzisa izidakamizwa noma ubuchwepheshe bezakhi zofuzo) kunciphise ukufa kwe-cell-AT, okuphakamisa ukuthi i-ATO ibangela ukufa kwe-cell cell ku-MG-63 amaseli.
UWu kanye nosebenza nabo baphetha ngokuthi, "Ukuhlanganiswa ndawonye, lemininingwane ibonisa ukuthi i-ATO inxusa ukufa kwe-cell osteosarcoma ngokunciphisa ukuzitholela ngokweqile, okukhulunywe ngayo nge-ROS-TFEB endleleni. Isifundo samanje sinikeza indlela entsha yokulwa ne-tumor yokwelashwa kwe-ATO ku-osteosarcoma. "
Izwi elivela
Kule minyaka engamashumi amathathu edlule, i-APL isuke isifo esibulalayo kakhulu kuya ephilisa kakhulu. Amasu wokwelapha nge-ATRA, chemotherapy, futhi, maduze nje, i-ATO, ibhekwe njengengxenye kulezi zintuthuko.
Ngale ntuthuko, kusekhona "indawo engaphazamiseki," kodwa. Ukuphepha okude isikhathi eside nokusebenza kwe-ATO kungacatshangelwa lapha, nakuba idatha yesikhathi eside ne-ATO + ATRA ebikwe kuze kube manje iye yathandwa. Enye indawo engaxhaswanga ingase ibe yiziphi izindlela zokwelapha ezithandwayo ngesikhathi se-ATRA / ATO.
> Imithombo:
> Abaza Y, Kantarjian H, Garcia-Manero G, et al. Umphumela wesikhathi eside we-acute promyelocytic leukemia ephathwe ngayo yonke i-trans-retinoic acid, i-arsenic trioxide, ne-gemtuzumab. Igazi . 2017; 129 (10): 1275-1283.
> Lu W, Yang C. Imiphumela ye-arsenic trioxide ekuboniseni i-ezrin e-hepatocellular carcinoma. Imithi (Baltimore). 2017 Sep; 96 (35): e7602.
> Wang H, Liu Y, Wang X, et al. Ukutadisha ukuhlolwa komtholampilo okungahleliwe kwe-locoregional therapy kuhlanganiswe ne-arsenic trioxide yokwelashwa kwe-hepatocellular carcinoma. I-Cancer . 2015; 121 (17): 2917-25.
> Wang L, Liang W, Peng N, et al. I-synergistic antitumor effect ye-arsenic trioxide ihlanganiswe namaseli e-cytotoxic T emzimbeni we-metastasis yamaphilisi yomdlavuza we-colon. I-Oncotarget . 2017; 8 (65): 109609-109618.